Article

Mitochondrial DNA and survival after sepsis: A prospective study

January 2006
The Lancet 366(9503):2118-21

January 2006
366(9503):2118-21

DOI:10.1016/S0140-6736(05)67890-7

Source
PubMed

Authors:

Watcharee Tiangyou

Naresuan University

Joanna L Elson

Newcastle University

Show all 10 authorsHide

Human genome evolution has been shaped by infectious disease. Although most genetic studies have focused on the immune system, recovery after sepsis is directly related to physiological reserve that is critically dependent on mitochondrial function. We investigated whether haplogroup H, the most common type of mitochondrial DNA (mtDNA) in Europe, contributes to the subtle genetic variation in survival after sepsis. In a prospective study, we included 150 individuals who were sequentially admitted to the intensive care unit in a hospital in Newcastle upon Tyne, UK. After clinical data were obtained, patients underwent mtDNA haplotyping by analysis with PCR and restriction fragment length polymorphism. As endpoints, we used death during the 6-month period or survival at 6 months. Follow-up was complete for all study participants, although the haplotype of two patients could not be reliably determined. On admission to the intensive care unit, the frequency of mtDNA haplogroup H in study patients did not differ between study patients admitted with severe sepsis and 542 age-matched controls from the northeast of England. MtDNA haplogroup H was a strong independent predictor of outcome during severe sepsis, conferring a 2.12-fold (95% CI 1.02-4.43) increased chance of survival at 180 days compared with individuals without the haplogroup H. Although haplogroup H is the most recent addition to the group of European mtDNA, paradoxically it is also the most common. Increased survival after sepsis provides one explanation for this observation. MtDNA haplotyping offers a new means of risk stratification of patients with severe infections, which suggests new avenues for therapeutic intervention.

Mitochondrial DNA Haplogroups and Delirium During Sepsis

Article

May 2019
CRIT CARE MED

Objectives: Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis. Design: Retrospective cohort study. Setting: Medical and surgical ICUs at a large tertiary care center. Patients: Caucasian and African American adults with sepsis. Measurements and main results: We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03). Conclusions: Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.

Diagnostic and Prognostic Utility of Circulating Cytochrome c in Acute Myocardial Infarction

Article

Full-text available

Oct 2016

Rationale: In contrast to cardiomyocyte necrosis, which can be quantified by cardiac troponin (cTn), functional cardiomyocyte impairment, including mitochondrial dysfunction, has escaped clinical recognition in acute myocardial infarction (AMI) patients. Objective: To investigate the diagnostic accuracy for AMI and prognostic prediction of in-hospital mortality of cytochrome c Methods and Results: We prospectively assessed cytochrome c serum levels at hospital presentation in two cohorts: a diagnostic cohort of patients presenting with suspected AMI, and a prognostic cohort of definite AMI patients. Diagnostic accuracy for AMI was the primary diagnostic endpoint, and prognostic prediction of in-hospital mortality was the primary prognostic endpoint. Serum cytochrome c had no diagnostic utility for AMI (area under the receiver-operating characteristics curve 0.51; 95% confidence intervals [CI] 0.44-0.58; P=0.76). Among 753 AMI patients in the prognostic cohort, cytochrome c was detectable in 280 (37%) patients. These patients had higher in-hospital mortality than patients with non-detectable cytochrome c (6% vs. 1%; P<0.001). This result was mainly driven by the high mortality rate observed in ST-elevation AMI patients with detectable cytochrome c, as compared to those with non-detectable cytochrome c (11% vs. 1%; P<0.001). At multivariable analysis, cytochrome c remained a significant independent predictor of in-hospital mortality (odds ratio 3.0; 95% CI 1.9-5.7; P<0.001), even after adjustment for major clinical confounders (odds ratio 4.01; 95% CI 1.20-13.38; P=0.02). Conclusions: Cytochrome c serum concentrations do not have diagnostic, but substantial prognostic utility in AMI.

Not all mitochondrial DNAs are made equal and the nucleus knows it

Article

Full-text available

Dec 2020

The oxidative phosphorylation (OXPHOS) system is the only structure in animal cells with components encoded by two genomes, maternally transmitted mitochondrial DNA (mtDNA), and biparentally transmitted nuclear DNA (nDNA). MtDNA-encoded genes have to physically assemble with their counterparts encoded in the nucleus to build together the functional respiratory complexes. Therefore, structural and functional matching requirements between the protein subunits of these molecular complexes are rigorous. The crosstalk between nDNA and mtDNA needs to overcome some challenges, as the nuclear-encoded factors have to be imported into the mitochondria in a correct quantity and match the high number of organelles and genomes per mitochondria that encode and synthesize their own components locally. The cell is able to sense the mito-nuclear match through changes in the activity of the OXPHOS system, modulation of the mitochondrial biogenesis, or reactive oxygen species production. This implies that a complex signaling cascade should optimize OXPHOS performance to the cellular-specific requirements, which will depend on cell type, environmental conditions, and life stage. Therefore, the mitochondria would function as a cellular metabolic information hub integrating critical information that would feedback the nucleus for it to respond accordingly. Here, we review the current understanding of the complex interaction between mtDNA and nDNA.

Mitochondrial Haplogroup and the Risk of Acute Kidney Injury Following Cardiac Bypass Surgery

Article

Full-text available

Feb 2019

Although mitochondrial dysfunction plays a key role in the pathophysiology of acute kidney injury (AKI), the influence of mitochondrial genetic variability in this process remains unclear. We explored the association between the risk of post-cardiac bypass AKI and mitochondrial haplotype – inherited mitochondrial genomic variations of potentially functional significance. Our single-centre study recruited consecutive patients prior to surgery. Exclusions included stage 5 CKD, non-Caucasian race and subsequent off-pump surgery. Haplogroup analysis allowed characterisation of the study population using the common mutations and by phylogenetic supergroup (WXI and HV). Chi-square tests for association allowed the identification of potential predictors of AKI for use in logistic regression analysis. AKI occurred in 12.8% of the study population (n = 881; male 69.6%, non-diabetic 78.5%, median (interquartile range) age 68.0 (61.0–75.0) years). The haplogroup profile comprised H (42.7%), J (12.1%), T (10.9%), U (14.4%) and K (7.6%). Although the regression model was statistically significant (χ2 = 95.483, p < 0.0005), neither the phylogenetic supergroups nor any individual haplogroup was a significant contributor. We found no significant association between common European haplogroups and the risk of post-cardiac bypass AKI. However, given the major role of mitochondrial dysfunction in AKI, there is a need to replicate our findings in other cohorts and with other aetiologies of AKI.

Impacts of the Mitochondrial Genome on the Relationship of Long-Term Ambient Fine Particle Exposure with Blood DNA Methylation Age

Article

Jun 2017

The mitochondrial genome has long been implicated in age-related disease, but no studies have examined its role in the relationship of long-term fine particle (PM2.5) exposure and DNA methylation age (DNAm-age) – a novel measure of biological age. In this analysis based on 940 observations between 2000 and 2011 from 552 Normative Aging Study participants, we determined the roles of mitochondrial DNA haplogroup variation and mitochondrial genome abundance in the relationship of PM2.5 with DNAm-age. We used the GEOS-chem transport model to estimate address-specific, one-year PM2.5 levels for each participant. DNAm-age and mitochondrial DNA markers were measured from participant blood samples. Nine haplogroups (H, I, J, K, T, U, V, W, and X) were present in the population. In fully-adjusted linear mixed-effects models, the association of PM2.5 with DNAm-age (in years) was significantly diminished in carriers of haplogroup V (Pinteraction= 0.01; = 0.18, 95%CI: -0.41, 0.78) compared to non-carriers (= 1.25, 95%CI: 0.58, 1.93). Mediation analysis estimated that decreases in mitochondrial DNA copy number, a measure of mitochondrial genome abundance, mediated 12% of the association of PM2.5 with DNAm-age. Our data suggests that the mitochondrial genome plays a role in DNAm-age relationships particularly in the context of long-term PM2.5 exposure.

Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis

Article

Full-text available

May 2017
BMRI

Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called “cytopathic hypoxia,” perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system (“immunoparalysis”) translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.

Dysfonction énergétique au cours du sepsis

Article

Mar 2024

Le sepsis est caractérisé par une libération massive d’hormones de stress et de cytokines, qui modifient profondément le métabolisme de l’organisme induisant un déséquilibre énergétique. Une première phase d’atténuation du métabolisme permet à l’organisme de reprioriser les postes de dépense énergétique afin de lutter contre l’infection. Cet état est suivi par un hypermétabolisme chez les patients survivants accompagnant les processus de récupération cellulaire. Un catabolisme intense s’instaure rapidement afin de survivre, puisant dans les réserves énergétiques et altérant le métabolisme des glucides, des lipides et des protéines. La mitochondrie, véritable centrale énergétique de la grande majorité de nos cellules, est profondément endommagée et participe directement aux dysfonctions d’organes et au devenir des patients. La récupération mitochondriale dépend de ses voies de contrôle qualité, qui sont mises en défaut face à aux situations extrêmes observées chez les patients les plus graves. Cette revue abordera des éléments de physiologie du métabolisme puis détaillera les perturbations du métabolisme induites par le sepsis et enfin discutera de l’implication de la mitochondrie.

SIRT1-Rab7 axis attenuates NLRP3 and STING activation through late endosomal-dependent mitophagy during sepsis-induced acute lung injury

Article

Full-text available

Mar 2024
Int J Surg

Background Acute lung injury (ALI) is a leading cause of mortality in patients with sepsis due to proinflammatory endothelial changes and endothelial permeability defects. Mitochondrial dysfunction is recognized as a critical mediator in the pathogenesis of sepsis-induced ALI. Although mitophagy regulation of mitochondrial quality is well recognized, little is known about its role in lung ECs during sepsis-induced ALI. Sirtuin 1 (SIRT1) is a histone protein deacetylase involved in inflammation, mitophagy, and cellular senescence. Here, the authors show a type of late endosome-dependent mitophagy that inhibits NLRP3 and STING activation through SIRT1 signaling during sepsis-induced ALI. Methods C57BL/6J male mice with or without administration of the SIRT1 inhibitor EX527 in the CLP model and lung ECs in vitro were developed to identify mitophagy mechanisms that underlie the cross-talk between SIRT1 signaling and sepsis-induced ALI. Results SIRT1 deficient mice exhibited exacerbated sepsis-induced ALI. Knockdown of SIRT1 interfered with mitophagy through late endosome Rab7, leading to the accumulation of damaged mitochondria and inducing excessive mitochondrial reactive oxygen species (mtROS) generation and cytosolic release of mitochondrial DNA (mtDNA), which triggered NLRP3 inflammasome and the cytosolic nucleotide sensing pathways (STING) over-activation. Pharmacological inhibition of STING and NLRP3 i n vivo or genetic knockdown in vitro reversed SIRT1 deficiency mediated endothelial permeability defects and endothelial inflammation in sepsis-induced ALI. Moreover, activation of SIRT1 with SRT1720 in vivo or overexpression of SIRT1 in vitro protected against sepsis-induced ALI. Conclusion These findings suggest that SIRT1 signaling is essential for restricting STING and NLRP3 hyperactivation by promoting endosomal-mediated mitophagy in lung ECs, providing potential therapeutic targets for treating sepsis-induced ALI.

Mitochondrial haplogroups and cognitive progression in Parkinson's disease

Article

Mar 2023

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U # had a 41% lower risk of cog-nitive progression with P = 2.42 × 10 −6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10 −5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochon-drial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

How hot can mitochondria be? Incubation at temperatures above 43 °C induces the degradation of respiratory complexes and supercomplexes in intact cells and isolated mitochondria

Article

Full-text available

Feb 2023
MITOCHONDRION

Mitochondrial function generates an important fraction of the heat that contributes to cellular and organismal temperature maintenance, but the actual values of this parameter reached in the organelles is a matter of debate. The studies addressing this issue have reported divergent results: from detecting in the organelles the same temperature as the cell average or the incubation temperature, to increasing differences of up to 10 degrees above the incubation value. Theoretical calculations based on physical laws exclude the possibility of relevant temperature gradients between mitochondria and their surroundings. These facts have given rise to a conundrum or paradox about hot mitochondria. We have examined by Blue-Native electrophoresis, both in intact cells and in isolated organelles, the stability of respiratory complexes and supercomplexes at different temperatures to obtain information about their tolerance to heat stress. We observe that, upon incubation at values above 43 °C and after relatively short periods, respiratory complexes, and especially complex I and its supercomplexes, are unstable even when the respiratory activity is inhibited. These results support the conclusion that high temperatures (> 43 °C) cause damage to mitochondrial structure and function and question the proposal that these organelles can physiologically work at close to 50 °C.

Common mitochondrial haplogroups as modifiers of the onset-age for critical COVID-19

Article

Sep 2022
MITOCHONDRION

As a key regulator of innate immunity, mitochondrial function is essential to maintain antiviral activities. Common mitochondrial DNA variants (haplogroups) have been associated with different physiological capacities and the nrisk of developing several diseases. Haplogroup H was associated with increased survival among sepsis patients, and lower risk of progression toward AIDS in HIV infected and lower manifestation of severe manifestation of herpex virus disease. We studied 316 Spanish with critical COVID-19, and found that the 7028C (haplogroup H) was protective among patients with early-onset disease (≤65 vs >65 years, p=0.01), while the ancestral 16223T was a risk factor for early-onset critical COVID-19 (OR=3.36, 95%CI=1.49-7.54). Our work suggested that common mitochondrial variants may serve as predictors of COVID-19 severity. Additional studies to confirm this effect from other populations are of special interest.

The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression

Article

Full-text available

Dec 2021

Purpose A significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis. Patients and methods We studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA. Results Whole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3 ⁺ ) helper T-cell population, with the proportion of LAG-3 ⁺ cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation. Conclusion Numerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient’s constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility. Trial registration ClinicalTrials.gov NCT01816607; registration date: 22 March 2013.

Energetic dysfunction in sepsis: a narrative review

Article

Full-text available

Jul 2021

Background: Growing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role of substrate utilization and mitochondrial dysfunction in the pathophysiology of sepsis-related organ dysfunction. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions. Main text: Sepsis is characterized by systemic and organ-specific changes in metabolism. Alterations of oxygen consumption, increased levels of circulating substrates, impaired glucose and lipid oxidation, and mitochondrial dysfunction are all associated with organ dysfunction and poor outcomes in both animal models and patients. The pathophysiological relevance of bioenergetics and metabolism in the specific examples of sepsis-related immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury and diaphragmatic failure is also described. Conclusions: Recent understandings in substrate utilization and mitochondrial dysfunction may pave the way for new diagnostic and therapeutic approaches. These findings could help physicians to identify distinct subgroups of sepsis and to develop personalized treatment strategies. Implications for their use as bioenergetic targets to identify metabolism- and mitochondria-targeted treatments need to be evaluated in future studies.

Mitochondrial genetic variation in human bioenergetics, adaptation, and adult disease

Article

Jun 2021

Objectives Mitochondria are critical for the survival of eukaryotic organisms due to their ability to produce cellular energy, which drives virtually all aspects of host biology. However, the effects of mitochondrial DNA (mtDNA) variation in relation to disease etiology and adaptation within contemporary global human populations remains incompletely understood. Methods To develop a more holistic understanding of the role of mtDNA diversity in human adaptation, health, and disease, we investigated mitochondrial biology and bioenergetics. More specifically, we synthesized details from studies of mitochondrial function and variation in the context of haplogroup background, climatic adaptation, and oxidative disease. Results The majority of studies show that mtDNA variation arose during modern human dispersal around the world. Some of these variants appear to have been positively selected for their adaptiveness in colder climates, with these sequence changes having implications for tissue-specific function and thermogenic capacity. In addition, many variants modulating energy production are also associated with damaging metabolic byproducts and mitochondrial dysfunction, which, in turn, are implicated in the onset and severity of several different adult mitochondrial diseases. Thus, mtDNA variation that governs bioenergetics, metabolism, and thermoregulation may potentially have adverse consequences for human health, depending on the genetic background and context in which it occurs. Conclusions Our review suggests that the mitochondrial research field would benefit from independently replicating mtDNA haplogroup-phenotype associations across global populations, incorporating potentially confounding environmental, demographic, and disease covariates into studies of mtDNA variation, and extending association-based studies to include analyses of complete mitogenomes and assays of mitochondrial function.

Let fever do its job: The meaning of fever in the pandemic era

Article

Full-text available

Nov 2020

Although fever is one of the main presenting symptoms of COVID-19 infection, little public attention has been given to fever as an evolved defense. Fever, the regulated increase in the body temperature, is part of the evolved systemic reaction to infection known as the acute phase response. The heat of fever augments the performance of immune cells, induces stress on pathogens and infected cells directly, and combines with other stressors to provide a nonspecific immune defense. Observational trials in humans suggest a survival benefit from fever, and randomized trials published before COVID-19 do not support fever reduction in patients with infection. Like public health measures that seem burdensome and excessive, fevers involve costly trade-offs but they can prevent infection from getting out of control. For infections with novel SARS-CoV-2, the precautionary principle applies: unless evidence suggests otherwise, we advise that fever should be allowed to run its course. Lay summary: For COVID-19, many public health organizations have advised treating fever with medicines such as acetaminophen or ibuprofen. Even though this is a common practice, lowering body temperature has not improved survival in laboratory animals or in patients with infections. Blocking fever can be harmful because fever, along with other sickness symptoms, evolved as a defense against infection. Fever works by causing more damage to pathogens and infected cells than it does to healthy cells in the body. During pandemic COVID-19, the benefits of allowing fever to occur probably outweigh its harms, for individuals and for the public at large.

Extreme heterogeneity of human mitochondrial DNA from organelles to populations

Article

Sep 2020

Contrary to the long- held view that most humans harbour only identical mitochondrial genomes, deep resequencing has uncovered unanticipated extreme genetic variation within mitochondrial DNA (mtDNA). Most, if not all, humans contain multiple mtDNA genotypes (heteroplasmy); specific patterns of variants accumulate in different tissues, including cancers, over time; and some variants are preferentially passed down or suppressed in the maternal germ line. These findings cast light on the origin and spread of mtDNA mutations at multiple scales, from the organelle to the human population, and challenge the conventional view that high percentages of a mutation are required before a new variant has functional consequences.

An Activatable and Switchable Nanoaggregate Probe for Detecting H2S and Its Application in Mice Brains

Article

Full-text available

Oct 2020
CHEM-ASIAN J

Employing a sequentially activated probe design method, an activatable, switchable and dual‐mode probe was designed. This nanoprobe, HSDPP, could be effectively activated by H2S to form H‐type aggregates with green emission; subsequently, the aggregates could bind to mtDNA to form monomers and the emIssion color switched from green to deep‐red. We exploited HSDPP to image exogenous and endogenous H2S in living cells. Of note, for the first time, this novel nanoprobe with an optimal partition coefficient value (LogP=1.269) was successfully applied for tracking the endogenous H2S upregulation stimulated by cystathionase activator S‐adenosyl‐L‐methionine (SAM) in mice brains. Finally, our work provides an invaluable chemical tool for probing endogenous H2S upregulation in vitro/vivo and, importantly, affords a prospective design strategy for developing switchable chemosensors to unveil the relationship between biomolecules and DNA in mitochondria in many promising areas.

The Critical Roles and Mechanisms of Immune Cell Death in Sepsis

Article

Full-text available

Aug 2020

Sepsis was first described by the ancient Greek physicians over 2000 years ago. The pathophysiology of the disease, however, is still not fully understood and hence the mortality rate is still unacceptably high due to lack of specific therapies. In the last decade, great progress has been made by shifting the focus of research from systemic inflammatory response syndrome (SIRS) to multiple organ dysfunction syndrome (MODS). Sepsis has been re-defined as infection-induced MODS in 2016. How infection leads to MODS is not clear, but what mediates MODS becomes the major topic in understanding the molecular mechanisms and developing specific therapies. Recently, the mechanism of infection-induced extensive immune cell death which releases a large quantity of damage-associated molecular patterns (DAMPs) and their roles in the development of MODS as well as immunosuppression during sepsis have attracted much attention. Growing evidence supports the hypothesis that DAMPs, including high-mobility group box 1 protein (HMGB1), cell-free DNA (cfDNA) and histones as well as neutrophil extracellular traps (NETs), may directly or indirectly contribute significantly to the development of MODS. Here, we provide an overview of the mechanisms and consequences of infection-induced extensive immune cell death during the development of sepsis. We also propose a pivotal pathway from a local infection to eventual sepsis and a potential combined therapeutic strategy for targeting sepsis.

Inheritance of mitochondrial DNA in humans: implications for rare and common diseases: Implication of mtDNA inheritance for human diseases

Article

Full-text available

Mar 2020

The first draft human mitochondrial DNA (mtDNA) sequence was published in 1981, paving the way for two decades of discovery linking mtDNA variation with human disease. Severe pathogenic mutations cause sporadic and inherited rare disorders that often involve the nervous system. However, some mutations cause mild organ-specific phenotypes that have a reduced clinical penetrance, and polymorphic variation of mtDNA is associated with an altered risk of developing several late-onset common human diseases including Parkinson's disease. mtDNA mutations also accumulate during human life and are enriched in affected organs in a number of age-related diseases. Thus, mtDNA contributes to a wide range of human pathologies. For many decades, it has generally been accepted that mtDNA is inherited exclusively down the maternal line in humans. Although recent evidence has challenged this dogma, whole-genome sequencing has identified nuclear-encoded mitochondrial sequences (NUMTs) that can give the false impression of paternally inherited mtDNA. This provides a more likely explanation for recent reports of 'bi-parental inheritance', where the paternal alleles are actually transmitted through the nuclear genome. The presence of both mutated and wild-type variant alleles within the same individual (heteroplasmy) and rapid shifts in allele frequency can lead to offspring with variable severity of disease. In addition, there is emerging evidence that selection can act for and against specific mtDNA variants within the developing germ line, and possibly within developing tissues. Thus, understanding how mtDNA is inherited has far-reaching implications across medicine. There is emerging evidence that this highly dynamic system is amenable to therapeutic manipulation, raising the possibility that we can harness new understanding to prevent and treat rare and common human diseases where mtDNA mutations play a key role.

Mitochondrial DNA Haplogroups and Frailty in Adults Living with HIV

Article

Full-text available

Dec 2019

Objective: Mitochondrial DNA (mtDNA) haplogroup has been associated with disease risk and longevity. Among persons with HIV (PWH), mtDNA haplogroup has been associated with AIDS progression, neuropathy, cognitive impairment, and gait speed decline. We sought to determine if haplogroup is associated with frailty and its components among older PWH. Methods: A cross-sectional analysis was performed of AIDS Clinical Trials Group A5322 (HAILO) participants with available genome-wide genotype and frailty assessments. Multivariable logistic regression models adjusted for age, sex, education, smoking, hepatitis C, and prior use of didanosine/stavudine. Results: Among 634 participants, 81% were male, 49% non-Hispanic white, 31% non-Hispanic black, and 20% Hispanic. Mean age was 51.0 (SD 7.5) years and median nadir CD4 count 212 (IQR 72, 324) cells/L; 6% were frail, 7% had slow gait and 21% weak grip. H haplogroup participants were more likely to be frail/pre-frail (p=0.064), have slow gait (p=0.09), or weak grip (p=0.017) compared to non-H haplogroup participants (not all comparisons reached statistical significance). In adjusted analyses, PWH with haplogroup H had a greater odds of being frail vs non-frail (OR 4.0 [95% CI 1.0, 15.4]) and having weak grip (OR 2.1 [1.1, 4.1]), but not slow gait (OR 1.6 [0.5, 5.0]) compared to non-H. Among black and Hispanic participants, haplogroup was not significantly associated with frailty, grip, or gait. Conclusions: Among ART-treated PWH, mtDNA haplogroup H was independently associated with weak grip and frailty. This association could represent a mechanism of weakness and frailty in the setting of HIV and ART.

Mitochondrial Biology and Medicine

Chapter

Jan 2019

Since their discovery 30 years ago, mutations in mitochondrial genes causing defects in oxidative phosphorylation (OXPHOS) have emerged as among the most common inherited metabolic disorders. Mitochondrial dysfunction can result from mutations in the multicopy mitochondrial DNA (mtDNA) or in any of the approximately 1500 nuclear DNA (nDNA) encoded mitochondrial genes. Clinically relevant mtDNA variants include pathogenic mutations causing maternally inherited diseases, ancient functional polymorphisms, and developmental and somatic tissue mutations. Clinically relevant nDNA mutations can affect structural, assembly, metabolic, and biogenesis genes. Mitochondrial OXPHOS is also acutely sensitive to environmental factors such as temperature, altitude, calorie availability and demands, infections, and toxins. Bioenergetic adaptation to genetic and environmental variations can also occur through the epigenome and signal transduction pathways. Perturbations in this bioenergetics system biology are being implicated in a broad range of common diseases such as diabetes and metabolic syndrome, inflammatory problems, deafness and blindness, cardiac and muscle diseases, Leigh syndrome, autism, and Alzheimer and Parkinson diseases. The discovery of the mitochondrial etiology of both rare and common diseases has revealed new therapeutic targets. These include mitochondrial biogenesis, antioxidant and antiapoptotic drugs, various somatic mitochondrial gene therapy approaches, and the demonstration that nuclear transplantation can purge deleterious mtDNAs from the female germline.

Impaired cognition in geriatric patients with relation to earlier life mood disorder and traumatic brain injury: a hypothesis

Article

Full-text available

Jul 2019

Edward H Tobe

The challenges of the geriatric years require cognitive integrity through organic resilience of the brain. Impaired cognition in geriatric patients (age >65 years) is commonly ascribed to age but is multifactorial. Among those multiple factors this author hypothesizes that mood disorders, with major depressive disorder (MDD) as one focus of this paper and traumatic brain injury (TBI) are part of a common spectrum of pathology that, when undiagnosed and untreated at age <65 years, reduces the resilience of the brain to negotiate common challenges during geriatric years. Mood disorders and TBI may be acute, transient, and benign; however, chronic mood disorders may be an organic brain disease, as shown by objective studies. The consequence of the ineffective treatment of MDD and TBI at an earlier age may cause geriatric patients to have impaired capacity to manage stressors. The solution may include more astute observation of the presentation to enable earlier diagnosis and treatment. Mitigating the consequences of mood disorders and TBI may enable greater resilience to face the challenges of aging.

Correlations between mitochondrial DNA haplogroup D5 and chronic hepatitis B virus infection in Yunnan, China

Article

Full-text available

Jan 2018

Mitochondrial abnormality is frequently reported in individuals with hepatitis B virus (HBV) infection, but the associated hosts' mitochondrial genetic factors remain obscure. We hypothesized that mitochondria may affect host susceptibility to HBV infection. In this study, we aimed to detect the association between chronic HBV infection and mitochondrial DNA in Chinese from Yunnan, Southwest China. A total of 272 individuals with chronic HBV infection (CHB), 310 who had never been infected by HBV (healthy controls, HC) and 278 with a trace of HBV infection (spontaneously recovered, SR) were analysed for mtDNA sequence variations and classified into respective haplogroups. Haplogroup frequencies were compared between HBV infected patients, HCs and SRs. Haplogroup D5 presented a higher frequency in CHBs than in HCs (P = 0.017, OR = 2.87, 95% confidence interval [CI] = (1.21-6.81)) and SRs (P = 0.049, OR = 2.90, 95% CI = 1.01-8.35). The network of haplogroup D5 revealed a distinct distribution pattern between CHBs and non-CHBs. A trend of higher viral load among CHBs with haplogroup D5 was observed. Our results indicate the risk potential of mtDNA haplogroup D5 in chronic HBV infection in Yunnan, China.

Involvement of Mitochondrial Disorders in Septic Cardiomyopathy

Article

Full-text available

Oct 2017
OXID MED CELL LONGEV

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It remains a leading cause of death worldwide, despite the development of various therapeutic strategies. Cardiac dysfunction, also referred to as septic cardiomyopathy, is a frequent and well-described complication of sepsis and associated with worse clinical outcomes. Recent research has increased our understanding of the role of mitochondrial dysfunction in the pathophysiology of septic cardiomyopathy. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions.

The Crosstalk between the Gut Microbiota and Mitochondria during Exercise

Article

Full-text available

May 2017

Many physiological changes occur in response to endurance exercise in order to adapt to the increasing energy needs, mitochondria biogenesis, increased reactive oxygen species (ROS) production and acute inflammatory responses. Mitochondria are organelles within each cell that are crucial for ATP production and are also a major producer of ROS and reactive nitrogen species during intense exercise. Recent evidence shows there is a bidirectional interaction between mitochondria and microbiota. The gut microbiota have been shown to regulate key transcriptional co-activators, transcription factors and enzymes involved in mitochondrial biogenesis such as PGC-1α, SIRT1, and AMPK genes. Furthermore, the gut microbiota and its metabolites, such as short chain fatty acids and secondary bile acids, also contribute to host energy production, ROS modulation and inflammation in the gut by attenuating TNFα- mediated immune responses and inflammasomes such as NLRP3. On the other hand, mitochondria, particularly mitochondrial ROS production, have a crucial role in regulating the gut microbiota via modulating intestinal barrier function and mucosal immune responses. Recently, it has also been shown that genetic variants within the mitochondrial genome, could affect mitochondrial function and therefore the intestinal microbiota composition and activity. Diet is also known to dramatically modulate the composition of the gut microbiota. Therefore, studies targeting the gut microbiota can be useful for managing mitochondrial related ROS production, pro-inflammatory signals and metabolic limits in endurance athletes.

Mitochondrial DNA and primary mitochondrial dysfunction in Parkinson's disease: mt DNA AND PD

Article

Mar 2017

In 1979, it was observed that parkinsonism could be induced by a toxin inhibiting mitochondrial respiratory complex I. This initiated the long-standing hypothesis that mitochondrial dysfunction may play a key role in the pathogenesis of Parkinson's disease (PD). This hypothesis evolved, with accumulating evidence pointing to complex I dysfunction, which could be caused by environmental or genetic factors. Attention was focused on the mitochondrial DNA, considering the occurrence of mutations, polymorphic haplogroup-specific variants, and defective mitochondrial DNA maintenance with the accumulation of multiple deletions and a reduction of copy number. Genetically determined diseases of mitochondrial DNA maintenance frequently manifest with parkinsonism, but the age-related accumulation of somatic mitochondrial DNA errors also represents a major driving mechanism for PD. Recently, the discovery of the genetic cause of rare inherited forms of PD highlighted an extremely complex homeostatic control over mitochondria, involving their dynamic fission/fusion cycle, the balancing of mitobiogenesis and mitophagy, and consequently the quality control surveillance that corrects faulty mitochondrial DNA maintenance. Many genes came into play, including the PINK1/parkin axis, but also OPA1, as pieces of the same puzzle, together with mitochondrial DNA damage, complex I deficiency and increased oxidative stress. The search for answers will drive future research to reach the understanding necessary to provide therapeutic options directed not only at limiting the clinical evolution of symptoms but also finally addressing the pathogenic mechanisms of neurodegeneration in PD. © 2017 International Parkinson and Movement Disorder Society.

Fever: Views in Anthroposophic Medicine and Their Scientific Validity

Article

Full-text available

Nov 2016
EVID-BASED COMPL ALT

David D Martin

Objective . To conduct a scoping review to characterize how fever is viewed in anthroposophic medicine (AM) and discuss the scientific validity of these views. Methods . Systematic searches were run in Medline, Embase, CAMbase, and Google Scholar. Material from anthroposophic medical textbooks and articles was also used. Data was extracted and interpreted. Results . Most of the anthroposophic literature on this subject is in the German language. Anthroposophic physicians hold a beneficial view on fever, rarely suppress fever with antipyretics, and often use complementary means of alleviating discomfort. In AM, fever is considered to have the following potential benefits: promoting more complete recovery; preventing infection recurrences and atopic diseases; providing a unique opportunity for caregivers to provide loving care; facilitating individual development and resilience; protecting against cancer and boosting the anticancer effects of mistletoe products. These views are discussed with regard to the available scientific data. Conclusion . AM postulates that fever can be of short-term and long-term benefit in several ways; many of these opinions have become evidence-based (though still often not practiced) while others still need empirical studies to be validated, refuted, or modified.

Mitochondrial Haplogroups as a Risk Factor for Herpes Zoster

Article

Full-text available

Oct 2016

Background Herpes zoster, or shingles, is a common, painful reactivation of latent varicella zoster virus infection. Understanding host factors that predispose to herpes zoster may permit development of more effective prevention strategies. Our objective was to examine mitochondrial haplogroups as a potential host factor related to herpes zoster incidence. Methods Study participants were drawn from BioVU, a deoxyribonucleic acid (DNA) biobank connected to deidentified electronic medical records (EMRs) from Vanderbilt University Medical Center. Our study used 9691 Caucasian individuals with herpes zoster status determined by International Classification of Diseases, Ninth Revision codes 053–053.9. Cases and controls were matched on sex and date of birth within 5 years. Mitochondrial haplogroups were defined from mitochondrial DNA variants genotyped on the Illumina 660W or Illumina Infinium Human-Exome Beadchip. Sex and date of birth were extracted from the EMR. Results European mitochondrial haplogroup H had a protective association with herpes zoster status (odds ratio [OR] = .82; 95% confidence interval [CI], .71–.94; P = .005), whereas haplogroup clade IWX was a risk factor for herpes zoster status (OR = 1.38; 95% CI, 1.07–1.77; P = .01). Conclusions Mitochondrial haplogroup influences herpes zoster risk. Knowledge of a patient's mitochondrial haplogroup could allow for a precision approach to the management of herpes zoster risk through vaccination strategies and management of other modifiable risk factors.

Ovarian ageing: The role of mitochondria in oocytes and follicles

Article

Aug 2016

BACKGROUND There is a great inter-individual variability of ovarian ageing, and almost 20% of patients consulting for infertility show signs of premature ovarian ageing. This feature, taken together with delayed childbearing in modern society, leads to the emergence of age-related ovarian dysfunction concomitantly with the desire for pregnancy. Assisted reproductive technology is frequently inefficacious in cases of ovarian ageing, thus raising the economic, medical and societal costs of the procedures. OBJECTIVE AND RATIONAL Ovarian ageing is characterized by quantitative and qualitative alteration of the ovarian oocyte reserve. Mitochondria play a central role in follicular atresia and could be the main target of the ooplasmic factors determining oocyte quality adversely affected by ageing. Indeed, the oocyte is the richest cell of the body in mitochondria and depends largely on these organelles to acquire competence for fertilization and early embryonic development. Moreover, the oocyte ensures the uniparental transmission and stability of the mitochondrial genome across the generations. This review focuses on the role played by mitochondria in ovarian ageing and on the possible consequences over the generations. SEARCH METHODS PubMed was used to search the MEDLINE database for peer-reviewed original articles and reviews concerning mitochondria and ovarian ageing, in animal and human species. Searches were performed using keywords belonging to three groups: ‘mitochondria’ or ‘mitochondrial DNA’; ‘ovarian reserve’, ‘oocyte’, ‘ovary’ or ‘cumulus cells‘; and ‘ageing’ or ‘ovarian ageing’. These keywords were combined with other search phrases relevant to the topic. References from these articles were used to obtain additional articles. OUTCOMES There is a close relationship, in mammalian models and humans, between mitochondria and the decline of oocyte quality with ageing. Qualitatively, ageing-related mitochondrial (mt) DNA instability, which leads to the accumulation of mtDNA mutations in the oocyte, plays a key role in the deterioration of oocyte quality in terms of competence and of the risk of transmitting mitochondrial abnormalities to the offspring. In contrast, some mtDNA haplogroups are protective against the decline of ovarian reserve. Quantitatively, mitochondrial biogenesis is crucial during oogenesis for constituting a mitochondrial pool sufficiently large to allow normal early embryonic development and to avoid the untimely activation of mitochondrial biogenesis. Ovarian ageing also seriously affects the dynamic nature of mitochondrial biogenesis in the surrounding granulosa cells that may provide interesting alternative biomarkers of oocyte quality. WIDER IMPLICATIONS A fuller understanding of the involvement of mitochondria in cases of infertility linked to ovarian ageing would contribute to a better management of the disorder in the future.

‘Infertile’ studies on mitochondrial DNA variation in asthenozoospermic Tunisian men

Article

Full-text available

Aug 2016

We reviewed five studies undertaken by the same research group on the possible links between mitochondrial DNA (mtDNA) variation and asthenozoospermia, all carried out on Tunisian men. A thorough assessment of these articles reveals that all five studies were carried out on virtually the same cohort of patients, although this information was concealed by the authors. Thus, the results were ‘sliced’ in order to unjustifiably maximize the number of publications. In addition, a phylogenetic analysis of their data indicates that the reported results are notably incomplete and deficient. Overall, contrary to the original claims, the association of mtDNA variants with asthenozoospermia finds no support on this saga on Tunisian infertile men.

The rise of mitochondria in medicine

Article

Full-text available

Jul 2016
MITOCHONDRION

Once considered exclusively the cell's powerhouse, mitochondria are now recognized to perform multiple essential cellular functions beyond energy production, impacting most areas of cell biology and medicine. Since the emergence of molecular biology and the discovery of pathogenic mitochondrial DNA defects in the 1980's, research advances have revealed a number of common human diseases which share an underlying pathogenesis involving mitochondrial dysfunction. Mitochondria undergo function-defining dynamic shape changes, communicate with each other, regulate gene expression within the nucleus, modulate synaptic transmission within the brain, release molecules that contribute to oncogenic transformation and trigger inflammatory responses systemically, and influence the regulation of complex physiological systems. Novel “mitopathogenic” mechanisms are thus being uncovered across a number of medical disciplines including genetics, oncology, neurology, immunology, and critical care medicine. Increasing knowledge of the bioenergetic aspects of human disease has provided new opportunities for diagnosis, therapy, prevention, and in connecting various domains of medicine. In this article, we overview specific aspects of mitochondrial biology that have contributed to – and likely will continue to enhance the progress of modern medicine.

Mitochondrial Haplogroups and Risk of Pulmonary Arterial Hypertension

Article

Full-text available

May 2016
PLOS ONE

Pulmonary arterial hypertension (PAH) is a serious and often fatal disease. It is a panvasculopathy of the pulmonary microcirculation characterized by vasoconstriction and arterial obstruction due to vascular proliferation and remodeling and ultimately right ventricular failure. Mitochondrial dysfunction is a universal finding in pulmonary vascular cells of patients with PAH, and is mechanistically linked to disease origins in animal models of pulmonary hypertension. Mitochondria have their own circular DNA (mtDNA), which can be subgrouped into polymorphic haplogroup variants, some of which have been identified as at-risk or protective from cardiovascular and/or neurodegenerative diseases. Here, we hypothesized that mitochondrial haplogroups may be associated with PAH. To test this, mitochondrial haplogroups were determined in a cohort of PAH patients and controls [N = 204 Caucasians (125 PAH and 79 controls) and N = 46 African Americans (13 PAH and 33 controls)]. Haplogroup L was associated with a lower rate of PAH as compared to macrohaplogroups N and M. When haplogroups were nested based on ancestral inheritance and controlled for age, gender and race, haplogroups M and HV, JT and UK of the N macro-haplogroup had significantly higher rates of PAH compared to the ancestral L (L0/1/2 and L3) (all p ≤ 0.05). Overall, the findings suggest that mitochondrial haplogroups influence risk of PAH and that a vulnerability to PAH may have emerged under the selective enrichment of specific haplogroups that occurred with the migration of populations out of Africa.

Common European Mitochondrial Haplogroups in the Risk for Radiation-induced Subcutaneous Fibrosis in Breast Cancer Patients

Article

Mar 2016

Aims: The contribution of mitochondrial DNA (mtDNA) variations to clinical radiosensitivity is largely unknown. In the present study, we evaluated the association between mtDNA haplogroups and the risk of radiation-induced subcutaneous fibrosis after postoperative radiotherapy in breast cancer patients. Materials and methods: Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale in 286 Italian breast cancer patients who received radiotherapy after breast-conserving surgery. Eight mtDNA single nucleotide polymorphisms that define the nine major haplogroups in the European population were determined by polymerase chain reaction restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood. Results: In a Kaplan-Meier analysis evaluated by the Log-rank test, carriers of haplogroup H were found to be at lower risk of grade ≥2 subcutaneous fibrosis (P = 0.018) compared with all other haplotypes combined. In the multivariate Cox regression analysis adjusted for clinical factors (body mass index, breast diameter, adjuvant treatment, dose per fraction, radiation type and acute skin toxicity), haplogroup H emerged as a protective factor for moderate to severe radiation-induced fibrosis at a nominal significance level (hazard ratio: 0.50, 95% confidence interval 0.27-0.92, P = 0.027), which did not survive correction for multiple testing. Conclusions: Our results suggest a protective effect of the mitochondrial haplogroup H in the development of radiation-induced fibrosis in breast cancer patients. However, the loss of statistical significance after correction for multiple comparisons and the lack of an independent validation cohort make our findings preliminary, requiring further confirmation in large-scale prospective studies.

Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study

Article

Full-text available

Apr 2024

One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear. Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of the impact of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

Recovery of Neurophysiological Measures in Post-COVID Fatigue - a 12-month Longitudinal Follow-up Study

Preprint

Full-text available

Nov 2023

One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear. Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

The significance of mitochondrial haplogroups in preeclampsia risk

Article

Nov 2023

The pyruvate dehydrogenase complex: Life’s essential, vulnerable and druggable energy homeostat

Article

Mar 2023
MITOCHONDRION

Found in all organisms, pyruvate dehydrogenase complexes (PDC) are the keystones of prokaryotic and eukaryotic energy metabolism. In eukaryotic organisms these multi-component megacomplexes provide a crucial mechanistic link between cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. As a consequence, PDCs also influence the metabolism of branched chain amino acids, lipids and, ultimately, oxidative phosphorylation (OXPHOS). PDC activity is an essential determinant of the metabolic and bioenergetic flexibility of metazoan organisms in adapting to changes in development, nutrient availability and various stresses that challenge maintenance of homeostasis. This canonical role of the PDC has been extensively probed over the past decades by multidisciplinary investigations into its causal association with diverse physiological and pathological conditions, the latter making the PDC an increasingly viable therapeutic target. Here we review the biology of the remarkable PDC and its emerging importance in the pathobiology and treatment of diverse congenital and acquired disorders of metabolic integration.

Mitochondrial haplogroups and cognitive progression in Parkinson's disease

Article

Nov 2022
BRAIN

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

Modulating Mitochondrial DNA Mutations: Factors Shaping Heteroplasmy in the Germ Line and Somatic Cells

Article

Sep 2022
PHARMACOL RES

Until recently it was thought that most humans only harbor one type of mitochondrial DNA (mtDNA), however, deep sequencing and single-cell analysis has shown the converse – that mixed populations of mtDNA (heteroplasmy) are the norm. This is important because heteroplasmy levels can change dramatically during transmission in the female germ line, leading to high levels causing severe mitochondrial diseases. There is also emerging evidence that low level mtDNA mutations contribute to common late onset diseases such as neurodegenerative disorders and cardiometabolic diseases because the inherited mutation levels can change within developing organs and non-dividing cells over time. Initial predictions suggested that the segregation of mtDNA heteroplasmy was largely stochastic, with an equal tendency for levels to increase or decrease. However, transgenic animal work and single-cell analysis have shown this not to be the case during germ-line transmission and in somatic tissues during life. Mutation levels in specific mtDNA regions can increase or decrease in different contexts and the underlying molecular mechanisms are starting to be unraveled. In this review we provide a synthesis of recent literature on the mechanisms of selection for and against mtDNA variants. We identify the most pertinent gaps in our understanding and suggest ways these could be addressed using state of the art techniques.

Síndrome de disfunción de órganos y adaptación mitocondrial en el paciente séptico

Article

Full-text available

Nov 2021

The ability to maintain an adequate energy balance and to respond and adapt to environmental stress at the cellular level are cornerstones for the survival and evolution of organisms. Therefore, in the presence of various factors, a cellular protection response is triggered by activation of mitochondrial function-dependent signaling. However, this essential reaction for individual cell survival can be detrimental to organ function (maladaptation), transforming the close balance between the two into the pathogenetic axis of organ dysfunction and eventual recovery in septic patients. Macrocirculatory and microcirculatory disruption undoubtedly contributes to organ dysfunction in the early stage of septic shock, while intrinsic metabolic-bioener-getic failure (cytopathic hypoxia) perpetuates inadequate cellular function. Therefore, mitochondrial dysfunction is a key process in the induction of multiple organ dysfunction syndrome in the septic patient. This syndrome can be considered as a complex hypometabolic adaptive phenomenon in the face of an excessive and / or prolonged inflammatory stimulus in order to achieve the regulation of energy homeostasis and preservation of organ function. In the future, there should be a transition between the current consensual therapeutic options, which are limited to the control of the infectious focus, hemodynamic and vital support, towards a metabolic resuscitation based on the molecular and genetic alterations triggered by the infection.

An Organelle-redirected Chameleon Sensor Enabled Live Cell Imaging of Mitochondrial DNA

Article

Nov 2019

Mitochondrial DNA (mtDNA) plays important roles in diverse physiological processes and myriad diseases. We herein report mtDNA imaging with a chameleon sensor containing a cationic rhodamine B (RB) entity for mitochondria targeting and a fluorogenic SYBR Green-I (SG) entity for DNA sensing. SG-RB selectively binds to mtDNA and gives green SG fluorescence in mitochondria of living cells but gives red RB fluorescence upon delivery of mitochondria into lysosomes in mitophagy. With the dual color imaging, mtDNA aggregation and elevated mitophagy were identified in HeLa cells stressed with anticancer doxorubicin. These results suggest the utility of organelle-redirected DNA sensors for live cell imaging of mtDNA involved in myriad pathological disorders.

Mitochondrial genetic medicine

Article

Oct 2018

Douglas C. Wallace

Inherited mitochondrial DNA (mtDNA) diseases were discovered 30 years ago, and their characterization has provided a new perspective on the etiology of the common metabolic and degenerative diseases, cancer, and aging. The maternally inherited mtDNA contains 37 critical bioenergetic genes that are present in hundreds of copies per cell, but the ‘mitochondrial genome’ encompasses an additional 1,000–2,000 nuclear DNA (nDNA) mitochondrial genes. The interaction between these two mitochondrial genetic systems provides explanations for phenomena such as the non-Mendelian transmission of the common ‘complex’ diseases, age-related disease risk and progression, variable penetrance and expressivity, and gene–environment interactions. Thus, mtDNA genetics contributes to the quantitative and environmental components of human genetics that cannot be explained by Mendelian genetics. Because mtDNA is maternally inherited and cytoplasmic, it has fostered the first germline gene therapy, nuclear transplantation. However, effective interventions are still lacking for existing patients with mitochondrial dysfunction.

Mitochondria, its DNA and telomeres in ageing and human population

Article

Full-text available

Jul 2018
BIOGERONTOLOGY

In the last decades, studies about ageing have become more essential as our population grows older. The incidence of age-related diseases increases, which pose challenges both for societies and individuals in terms of life quality and economic impact. Understanding ageing and ageing-related processes will help us to slow down or even prevent these diseases and provide opportunities for healthy ageing; additionally, we all want to live longer. Ageing is a consequence of the interaction between processes that occur over time and genetics interacting with various disease states and an individual’s lifestyle. There are several hallmarks of ageing that are generally accepted, but neither of the theories appears to be fully satisfactory. The focus of this article is on two theories of ageing: telomere shortening and mitochondrial DNA (mtDNA) alterations and dysfunction. We discuss characteristic molecular features such as mitochondrial haplogroups, telomere length, mtDNA copy number and heteroplasmy, and how all these traits come together in the ageing population. The recent evidence shows the existence of a strong linkage between these two theories suggesting common molecular mechanisms and a complicated telomere-mitochondria interplay during the humans’ ageing. However, this relationship is still not completely understood, which is why it needs more attention.

A common haplotype of the LBP gene predisposes to severe sepsis *

Article

Oct 2009
CRIT CARE MED

Subcellular Energetics and Metabolism: A Cross-Species Framework

Article

Oct 2017
ANESTH ANALG

Fieber: Thesen innerhalb der Anthroposophischen Medizin und ihre wissenschaftliche Validität

Article

Full-text available

Oct 2017

David D Martin

Mechanisms of Organ Dysfunction and Altered Metabolism in Sepsis

Chapter

May 2017

The term “sepsis” was first described by Hippocrates (c.a. 460–370 BC) in reference to blood putrefaction (septicemia) and fever, and the connection between sepsis and bacteria was made by French chemist Louis Pasteur (1822–1895). No treatment has been shown to prevent the onset or hasten recovery of failed organ systems during sepsis, which often persists long after the infection has been eliminated and ultimately leads to the death of the patient. Mechanisms linking host-pathogen interactions to organ dysfunction remain poorly understood and related insights may provide the key to more effectively treating sepsis-induced organ failures. This chapter will discuss the current theories of sepsis-induced organ failure and potential future therapies that might be derived from new understanding of the pathophysiology of sepsis.

Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing

Article

Full-text available

Jul 2016

Human mitochondrial DNA (mtDNA) shows extensive within-population sequence variability. Many studies suggest that mtDNA variants may be associated with ageing or diseases, although mechanistic evidence at the molecular level is lacking. Mitochondrial replacement has the potential to prevent transmission of disease-causing oocyte mtDNA. However, extension of this technology requires a comprehensive understanding of the physiological relevance of mtDNA sequence variability and its match with the nuclear-encoded mitochondrial genes. Studies in conplastic animals allow comparison of individuals with the same nuclear genome but different mtDNA variants, and have provided both supporting and refuting evidence that mtDNA variation influences organismal physiology. However, most of these studies did not confirm the conplastic status, focused on younger animals, and did not investigate the full range of physiological and phenotypic variability likely to be influenced by mitochondria. Here we systematically characterized conplastic mice throughout their lifespan using transcriptomic, proteomic, metabolomic, biochemical, physiological and phenotyping studies. We show that mtDNA haplotype profoundly influences mitochondrial proteostasis and reactive oxygen species generation, insulin signalling, obesity, and ageing parameters including telomere shortening and mitochondrial dysfunction, resulting in profound differences in health longevity between conplastic strains.

Langzeitmorbidität, -letalität und Lebensqualität

Chapter

Nov 2016

U. Janssens

Sepsis, schwere Sepsis und der septische Schock sind mit einer zunehmenden Intensiv- und Krankenhaussterblichkeit assoziiert. Auch in den kommenden Monaten und Jahren besteht noch eine Übersterblichkeit der Betroffenen, welche eine Folge der komplexen Störungen in der Akutphase mit z. T. erheblichen Organfunktionsstörungen ist. Auch lange nach der akuten Erkrankung finden sich schwere Beeinträchtigungen der körperlichen und psychischen Gesundheit. Dabei stehen v. a. neuromuskuläre Defizite, kognitive und funktionelle Einschränkungen im Vordergrund, etwa Störungen der Lungen- und Nierenfunktion. Lang anhaltende psychische Störungen wie Depressionen, Angst und die posttraumatische Belastungsstörung können nicht nur den Patienten, sondern auch deren Angehörige betreffen. Studien zur intensivierten Rehabilitation nach schwerer Sepsis und septischem Schock sollen die Bedeutung multidisziplinärer Interventionen zur Verbesserung der körperlichen und psychischen Rollenfunktion untersuchen.

Septic patients with mitochondrial DNA haplogroup JT have higher respiratory complex IV activity and survival rate

Article

Feb 2016

Objective: The influence of mitochondrial deoxyribonucleic acid (mtDNA) haplogroup or oxidative phosphorylation system (OXPHOS) function on survival of septic patients has been scarcely studied. However, the association between mtDNA haplogroup, OXPHOS capacity at diagnosis of severe sepsis, and survival has been not previously reported, and that was the objective of the present study. Methods: This was a prospective, multicenter, observational study. Blood samples from 198 patients at diagnosis of severe sepsis were analyzed to determine mtDNA haplogroup and platelet respiratory complex IV (CIV) specific activity. The end point of the study was 30-day survival. Results: Septic patients with mtDNA haplogroup JT showed higher 30-day survival than those with mtDNA haplogroup non-JT (31/38 [81.6%] vs 99/160 [61.9%]; P= .02). Septic patients with mtDNA haplogroup JT showed higher platelet CIV specific activity than those with mtDNA haplogroup non-JT (P= .002). Conclusions: The main novel finding of our study, including the largest series providing data on platelet CIV specific activity according to mtDNA haplogroup in severe septic patients, was that those with mtDNA haplogroup JT showed higher survival and higher platelet CIV specific activity at diagnosis of severe sepsis than patients with mtDNA haplogroup non-JT.

APACHE II

Article

Full-text available

Oct 1985
CRIT CARE MED

This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases.When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.

APACHE II: a severity of disease classification system

Article

Full-text available

Nov 1985
CRIT CARE MED

This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases. When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.

The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine

Article

Full-text available

Aug 1996

R EPORTS Effects of Purifying and Adaptive Selection on Regional Variation

Article

Full-text available

Feb 2004
SCIENCE

A phylogenetic analysis of 1125 global human mitochondrial DNA (mtDNA) sequences permitted positioning of all nucleotide substitutions according to their order of occurrence. The relative frequency and amino acid conservation of internal branch replacement mutations was found to increase from tropical Africa to temperate Europe and arctic northeastern Siberia. Particularly highly conserved amino acid substitutions were found at the roots of multiple mtDNA lineages from higher latitudes. These same lineages correlate with increased propensity for energy deficiency diseases as well as longevity. Thus, specific mtDNA replacement mutations permitted our ancestors to adapt to more northern climates, and these same variants are influencing our health today.

Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians

Article

Full-text available

Jun 2005

It has been proposed that European mitochondrial DNA (mtDNA) haplogroups J and K, and their shared 10398G single-nucleotide polymorphism (SNP) in the ND3 gene, are protective from Parkinson's disease (PD). We evaluated the distribution of the different mtDNA haplogroups in a large cohort of 620 Italian patients with adult-onset (>50, <65 years of age) idiopathic PD vs two groups of ethnic-matched controls. Neither the frequencies of haplogroup J nor that of 10398G were significantly different. However, the frequency of haplogroup K was significantly lower in PD. Stratification by sex and age indicated that the difference in the distribution of haplogroup K was more prominent in >50 year old males. In spite of the common 10398G SNP, haplogroups J and K belong to widely diverging mitochondrial clades, a consideration that may explain the different results obtained for the two haplogroups in our cohorts. Our study suggests that haplogroup K might confer a lower risk for PD in Italians, corroborating the idea that the mitochondrial oxidative phosphorylation pathway is involved in the susceptibility to idiopathic PD.

Mitochondrial respiratory chain disorders

Chapter

Jan 2010

Fever and survival

Article

May 1975

The significance of fever in response to a bacterial infection has been investigated using the lizard Dipsosaurus dorsalis as an animal model. These lizards develop a fever of about 2 degrees C after injection with the bacterium Aeromonas hydrophila. To determine whether this elevation in body temperature increases the resistance of the host to this infection, as measured by survival, lizards were infected with the live bacteria and placed in a neutral (38 degrees C), low (34 degrees or 36 degrees C), or high (40 degrees or 42 degrees C) ambient temperature. An elevation in temperature following experimental bacterial infection results in a significant increase in host survival.

Genetic and Environmental Influences on Premature Death in Adult Adoptees

Article

Apr 1988

To assess genetic and environmental influences on adult mortality, we followed 960 families that included children born during the period 1924 through 1926 who were placed early in life with adoptive parents unrelated to them. We evaluated the risks of dying from all causes or from specific groups of causes between the ages of 16 and 58 years for adoptees with a biologic or adoptive parent who died of the same cause before the age of either 50 or 70. We compared these risks with the adoptees' risk of dying from the same causes between the ages of 16 and 58 when either the biologic or adoptive parents were still alive at the ages of 50 and 70. The death of a biologic parent before the age of 50 resulted in relative risks of death in the adoptees of 1.71 (95 percent confidence interval, 1.14 to 2.57) for all causes, 1.98 (1.25 to 3.12) for natural causes, 5.81 (2.47 to 13.7) for infections, 4.52 (1.32 to 15.4) for cardiovascular and cerebrovascular causes, and 1.19 (0.16 to 8.99) for cancers. The death of an adoptive parent resulted in relative risks of death in the adoptees that were close to unity for all causes, natural causes, and infections, 3.02 (0.72 to 12.8) for vascular causes, and 5.16 (1.20 to 22.2) for cancers. A similar but weaker pattern was observed when either a biologic or adoptive parent died before the age of 70. We conclude that premature death in adults has a strong genetic background--especially death due to infections and vascular causes.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketogenesis during sepsis in relation to hepatic energy metabolism

Article

Feb 1984

The concentrations of acetoacetate, beta-hydroxybutyrate, and adenine nucleotides, and the mitochondrial phosphorylative activities, induced by cecal ligation and punctured in the liver of septic rats, were determined. The concentrations of glucose, free fatty acids (FFA), and free amino acids in arterial blood were also studied along with ketone body concentrations. Hepatic energy charge levels decreased from 0.84 to 0.77 at 12h after the induction of sepsis (P less than 0.01) and to 0.60 at 18h (P less than 0.001). Mitochondrial phosphorylative activity was enhanced at 6h (P less than 0.001) and decreased at 18h later. Ketone body concentrations in the liver and the arterial blood decreased concomitant with the decrease in hepatic energy charge. The mitochondrial redox state increased significantly at 12 and 18h after the induction of sepsis (P less than 0.01) concomitant with a marked decrease in the concentrations of ketone bodies (P less than 0.01). Blood glucose levels remained within normal limits except for a transient increase at 6h, but plasma FFA levels decreased (P less than 0.01). The plasma concentrations of aromatic amino acids (P less than 0.001), proline, and alanine (P less than 0.05) increased slightly at 18h. It is suggested that the ketogenic capacity of the liver is inhibited during sepsis, but that the liver maintains gluconeogenesis at relatively normal levels until a more advanced stage of sepsis.

Significance of Mitochondrial Enhancement in Hepatic Energy Metabolism in Relation to Alterations in Hemodynamics in Septic Pigs with Severe Peritonitis

Article

Feb 1984

Liver mitochondrial phosphorylative activity, hepatic adenine nucleotides, and hemodynamic parameters were studied in 23 pigs with peritonitis induced by cecal ligation and perforation. Between 2 and 7 days after treatment, the onset of an apparent hyperdynamic state, characterized by an increased cardiac index and decreased total peripheral resistance index, occurred. In this period, the energy charge level was barely maintained and the occurrence of liver mitochondrial enhancement was observed. However, 10-14 days after treatment, the onset of a hypodynamic state with its inverse patterns in hemodynamics took place. In this period, the energy charge level fell to 0.68, concomitant with a marked decrease in mitochondrial function. Further, a high positive correlation between the cardiac index and liver mitochondrial phosphorylative activity was noted (r = 0.85, p less than 0.01). These results suggest that liver mitochondria play a major role in the metabolic and hemodynamic adaptations occurring during sepsis.

Genetic Regulation of Fever in Plasmodium falciparum Malaria in Gambian Twin Children

Article

Aug 1995

The role of genetic factors in determining the clinical response of children to Plasmodium falciparum infection is not fully understood. A longitudinal survey of malaria morbidity in a cohort of 258 pairs of twin children was conducted in a rural area of Gambia to assess the extent to which genetic factors determine the host's susceptibility and clinical response to infection. The marginal correlation (which measures the excess probability of both twins being affected above that expected assuming independence) for malaria was higher in dizygous (DZ) than in monozygous (MZ) twin pairs, indicating that infection per se is largely determined by environmental factors. Once infected however, both members of an MZ pair were more likely to develop fever than were twins of a DZ pair, suggesting that genetic factors influence the presentation of clinical disease.

Altered mitochondrial redox responses in Gram negative septic shock in primates

Article

Jun 1994
Circ Shock

Gram negative sepsis causes changes in oxygen supply-demand relationships. We have used a primate model of hyperdynamic gram negative sepsis produced by intravenous infusion of Escherichia coli (E. coli) to evaluate sepsis-induced alterations in mitochondrial oxidation-reduction (redox) state in muscle in vivo. The redox state of cytochrome a,a3, the terminal member of the intramitochondrial respiratory chain, was assessed in the intact forearm by near-infrared (NIR) spectroscopy. The muscle NIR data were compared to routine measures of oxygen delivery (DO2) and oxygen consumption (VO2). After E. coli infusion and fluid resuscitation, DO2 and VO2 showed minimal changes through 24 hr of sepsis. In contrast, changes in cytochrome a,a3 redox state evaluated by NIR occurred within a few hours and were progressive. Mitochondrial functional responses were correlated with structural changes observed on serial muscle biopsies. Gross morphological changes in muscle mitochondria were present in some animals as early as 12 hr, and, in most animals, by 24 hr. The morphologic changes were consistent with decreases in oxidative capacity as suggested by NIR spectroscopy. The NIR data also suggest that two mechanisms are operating to explain abnormalities in oxygen metabolism and mitochondrial function in lethal sepsis. These mechanisms include an early defect in oxygen provision to mitochondria that is followed by a progressive loss in functional cytochrome a,a3 in the muscle.

Mitochondrial DNA haplogroups and susceptibility to AD and Dementia with Lewy bodies

Article

Aug 2000

The authors analyzed the relationship between nuclear genetic risk factors (apolipoprotein E genotype) and mitochondrial DNA (mtDNA) sequence variants in pathologically proved cases of AD (n = 185), dementia with Lewy bodies (DLB; n = 84), and control subjects (n = 179). Specific European mtDNA haplogroups and the A4336G mutation were not associated with an increased risk of AD. mtDNA haplogroup H was overrepresented in the DLB patients when compared with control subjects. Additional studies are needed to clarify the significance of the association.

Human mtDNA Haplogroups Associated with High or Reduced Spermatozoa Motility

Article

Oct 2000

A variety of mtDNA mutations responsible for human diseases have been associated with molecular defects in the OXPHOS system. It has been proposed that mtDNA genetic alterations can also be responsible for sperm dysfunction. In addition, it was suggested that if sperm dysfunction is the main phenotypic consequence, these mutations could be fixed as stable mtDNA variants, because mtDNA is maternally inherited. To test this possibility, we have performed an extensive analysis of the distribution of mtDNA haplogroups in white men having fertility problems. We have found that asthenozoospermia, but not oligozoospermia, is associated with mtDNA haplogroups in whites. Thus, haplogroups H and T are significantly more abundant in nonasthenozoospermic and asthenozoospermic populations, respectively, and show significant differences in their OXPHOS performance.

Mitochondrial dysfunction in sepsis

Article

Feb 1999

The current mainstream view of organ failure induced by sepsis revolves around inflammation and loss of vascular control. However, there has been a resurgence in interest in bioenergetic failure due to mitochondrial dysfunction. This concept is not new--studies date back 30 years; however, the data have been highly conflicting with findings of either decreased, increased or unchanged mitochondrial activity and/or nucleotide levels. These studies are virtually all based on non-human cells, isolated perfused organs or in vivo animal models that have received a variety of insults ranging from mild to severe, and monitored for different durations ranging from minutes to weeks. As a generalization, there does appear to be depression of mitochondrial function with longer-duration models of greater severity. This is confirmed by the scanty human data currently available. This chapter provides an overview, and attempts to relate the biochemical changes to the clinical condition. The potential roles of nitric oxide, intracellular calcium and reactive oxygen species are highlighted.

Cytopathic Hypoxia:: Mitochondrial Dysfunction as Mechanism Contributing to Organ Dysfunction in Sepsis

Article

Feb 2001
CRIT CARE CLIN

Mitchell P Fink

Several lines of evidence support the notion that cellular energetics are deranged in sepsis, not on the basis of inadequate tissue perfusion, but rather on the basis of impaired mitochondrial respiration and/or coupling; that is, organ dysfunction in sepsis may occur on the basis of cytopathic hypoxia. If this concept is correct, then the therapeutic implications are enormous. Efforts to improve outcome in patients with sepsis by monitoring and manipulating cardiac output, systemic Do2, and regional blood flow are doomed to failure. Instead, the focus should be on developing pharmacologic strategies to restore normal mitochondrial function and cellular energetics.

Epidemiology of sepsis: An update

Article

Aug 2001
CRIT CARE MED

We review the case definition, occurrence, and outcome of sepsis. We discuss whether the epidemiology of sepsis has changed over time and discuss issues important to our understanding of sepsis. Literature review. Our understanding of the epidemiology of sepsis is hampered by the lack of a reliable case definition. Inconsistent application of sepsis definition criteria contributes to confusion and variability in the literature. Variability in the time course of sepsis also introduces difficulty. The Centers for Disease Control estimated an incidence of 73.6 per 100,000 population in 1979, rising to 175.9 per 100,000 in 1989. However, this study was of septicemia, not severe sepsis. There are several hospital-based studies of the occurrence of severe sepsis, defined using the American College of Chest Physicians/Society of Critical Care Medicine consensus criteria. These studies reported variable hospital and intensive care unit (ICU) occurrence rates, ranging from 2% to 11% of all hospital or ICU admissions. Most of these data are from academic, tertiary care centers, which limits generalizability. More population-based studies are required to better delineate the incidence and risk factors of sepsis in the general population. Hospital mortality from sepsis has ranged from 25% to 80% over the last few decades. Although mortality may be lower in recent years, sepsis is clearly still a very serious condition. Achieving a better understanding of whether the mortality rate for sepsis is falling, however, is confounded by the lack of a uniform definition. Risk factors for adverse outcome include the degree of physiologic derangement, organ dysfunction, underlying illness, site of infection, and microbiological etiology. We do not know, however, the factors that predict response to new therapies. This dilemma has led researchers to explore whether markers of the inflammatory cascade might be more specific for sepsis, more accurate for risk prediction, or more useful for predicting response to therapy. However, there as yet is no equivalent of the CPK-MB for acute myocardial infarction. Whether we will find such a marker as we develop a greater understanding of the genetic control of the inflammatory cascade is uncertain but promising. One might assume intuitively that the epidemiology of sepsis is changing. For example, the number of patients being treated in ICUs has increased over time, the technologies used in the ICU have changed, and the choice and the use of antibiotics have changed. Predisposing factors, such as chemotherapeutic regimens, have also changed, and there have been marked changes in antibiotic resistance. Furthermore, there have been wide changes in the microbiological etiologies of diseases such as pneumonia and acute exacerbations of chronic bronchitis. However, lacking good case definitions and true incidence studies, we can only make inferences about whether the epidemiology of sepsis is truly changing. Many studies have documented many aspects of the epidemiology of sepsis. However, the composite picture they provide, although rich in many aspects, remains incomplete and emphasizes the heterogeneity of the condition. Unfortunately, few population-based prospective cohort studies exist that allow us to accurately delineate the risk factors for sepsis, its course, and its outcome. To place new information, such as the role of genetic predisposition, in the correct context, it is essential that such studies be conducted.

Association between mitochondrial dysfunction and severity and outcome of septic shock

Article

Aug 2002

Sepsis-induced multiple organ failure is the major cause of mortality and morbidity in critically ill patients. However, the precise mechanisms by which this dysfunction is caused remain to be elucidated. We and others have shown raised tissue oxygen tensions in septic animals and human beings, suggesting reduced ability of the organs to use oxygen. Because ATP production by mitochondrial oxidative phosphorylation accounts for more than 90% of total oxygen consumption, we postulated that mitochondrial dysfunction results in organ failure, possibly due to nitric oxide, which is known to inhibit mitochondrial respiration in vitro and is produced in excess in sepsis. We did skeletal muscle biopsies on 28 critically ill septic patients within 24 h of admission to intensive care, and on nine control patients undergoing elective hip surgery. The biopsy samples were analysed for respiratory-chain activity (complexes I-IV), ATP concentration, reduced glutathione (an intracellular antioxidant) concentration, and nitrite/nitrate concentrations (a marker of nitric oxide production). Skeletal muscle ATP concentrations were significantly lower in the 12 patients with sepsis who subsequently died than in the 16 septic patients who survived (p=0.0003) and in controls (p=0.05). Complex I activity had a significant inverse correlation with norepinephrine requirements (a proxy for shock severity, p=0.0003) and nitrite/nitrate concentrations (p=0.0004), and a significant positive correlation with concentrations of reduced glutathione (p=0.006) and ATP (p=0.03). In septic patients, we found an association between nitric oxide overproduction, antioxidant depletion, mitochondrial dysfunction, and decreased ATP concentrations that relate to organ failure and eventual outcome. These data implicate bioenergetic failure as an important pathophysiological mechanism underlying multiorgan dysfunction.

Hotchkiss RS, Karl IEThe pathophysiology and treatment of sepsis. N Engl J Med 348:138-150

Article

Feb 2003
NEW ENGL J MED

R. J., LangleyE. L., TsalikJ. C. v., VelkinburghS. W., GlickmanB. J., RiceC., WangB., ChenL., CarinA., SuarezR. P., MohneyD. H., FreemanM., WangJ., YouJ., WulffJ. W., ThompsonM. A., MoseleyS., ReisingerB. T., EdmondsB., GrinnellD. R., NelsonD. L., DinwiddieN. A., MillerC. J., SaundersS. S., SodenA. J., RogersL., GazourianL. E., FredenburghA. F., MassaroR. M., BaronA. M. K., ChoiG. R., CoreyG. S., GinsburgC. B., CairnsR. M., OteroV. G., FowlerE. P., RiversC. W., WoodsS. F., Kingsmore. (2013) An Integrated Clinico-Metabolomic Model Improves Prediction of Death in Sepsis. Science Translational Medicine 5, 195ra95-195ra95 CrossRef

DiMauro, S. & Schon, E.A. Mitochondrial respiratory-chain diseases. N. Engl. J. Med. 348, 2656-2668

Article

Jul 2003
NEW ENGL J MED

The mitochondrial respiratory chain has the crucial function of supplying the cell with energy in the form of ATP. Mutations affecting this chain can arise in mitochondrial or nuclear DNA and cause diseases known as mitochondrial encephalomyopathies. Because the rules of inheritance of mitochondrial and nuclear DNA differ considerably, these brain–muscle syndromes often have unpredictable clinical and genetic features.

Genetic Polymorphisms in Sepsis and Septic Shock _ Role in Prognosis and Potential for Therapy

Article

Oct 2003

Genetic epidemiologic studies suggest a strong genetic influence on the outcome from sepsis, and genetics may explain the wide variation in the individual response to infection that has long puzzled clinicians. Several candidate genes have been identified as important in the inflammatory response and investigated in case-controlled studies, including the tumor necrosis factor (TNF)-alpha and TNF-beta genes, positioned next to each other within the cluster of human leukocyte antigen class III genes on chromosome 6. Other candidate genes for sepsis and septic shock include the interleukin (IL)-1 receptor antagonist gene, the heat shock protein gene, the IL-6 gene, the IL-10 gene, the CD-14 gene, the Toll-like receptor (TLR)-4 gene, and the TLR-2 gene, to name a few. In this review, we summarize the evidence for a genetic susceptibility to development of sepsis and death from sepsis, discuss design of clinical genetics studies relevant to the study of complex disorders, consider the candidate genes likely to be involved in the pathogenesis of sepsis, and discuss the potential for targeted therapy of sepsis and septic shock based on genetic variability.

Mitochondrial Dysfunction in Sepsis

Article

Nov 2003
Curr Infect Dis Rep

Sepsis is an increasingly common problem, particularly among critically ill patients. Mechanisms by which sepsis induces organ dysfunction have not been elucidated. The coexisting findings (unique to sepsis) of metabolic acidosis yet increased tissue oxygen tensions suggest cellular availability but decreased use of oxygen (tissue dysoxia). Because mitochondria use more than 90% of total body oxygen consumption for adenosine triphosphate (ATP) generation, a bioenergetic abnormality is implied. Cell and animal data have shown that nitric oxide (and its metabolites), produced in considerable excess in patients with sepsis, can affect oxidative phosphorylation by inhibiting several of its component respiratory enzymes. Human data are scarce. However, in skeletal muscle biopsies taken from patients with sepsis, we have recently demonstrated a relationship between increased nitric oxide production, antioxidant depletion, reduced respiratory chain complex I activity, and low ATP levels. These findings correlated with severity of disease and outcome and support the notion that mitochondrial dysfunction resulting in bioenergetic failure may be an important factor in the pathophysiology of sepsis-associated multiorgan failure. However, a reasonable argument can be made that the reduction in energy supply could represent a last-ditch adaptive response to ongoing inflammation, resulting in a cellular shutdown analogous to hibernation that allows eventual restoration of organ function and long-term survival in patients fit enough to survive the acute phase.

Epidemiology of severe sepsis occurring in the first 24 h in intensive care units in England, Wales, and Northern Ireland

Article

Sep 2003
CRIT CARE MED

To investigate the numbers, clinical characteristics, resource use, and outcomes of admissions who met precise clinical and physiologic criteria for severe sepsis (as defined in the PROWESS trial) in the first 24 hrs in the intensive care unit. Observational cohort study, with retrospective analysis of prospectively collected data. Ninety-one adult general intensive care units in England, Wales, and Northern Ireland between 1995 and 2000. Patients were 56,673 adult admissions. None. We found that 27.1% of adult intensive care unit admissions met severe sepsis criteria in the first 24 hrs in the intensive care unit. Most were nonsurgical (67%), and the most common organ system dysfunctions were seen in the cardiovascular (88%) and respiratory (81%) systems. Modeling the data for England and Wales for 1997 suggested that 51 (95% confidence interval, 46-58) per 100,000 population per year were admitted to intensive care units and met severe sepsis criteria in the first 24 hrs.Of the intensive care unit admissions who met severe sepsis criteria in the first 24 hrs, 35% died before intensive care unit discharge and 47% died during their hospital stay. Hospital mortality rate ranged from 17% in the 16-19 age group to 64% in those >85 yrs. In England and Wales in 1997, an estimated 24 (95% confidence interval, 21-28) per 100,000 population per year died after intensive care unit admissions with severe sepsis in the first 24 hrs. For intensive care unit admissions who met severe sepsis criteria in the first 24 hrs, median intensive care unit length of stay was 3.56 days (interquartile range, 1.50-9.32) and median hospital length of stay was 18 days (interquartile range, 8-36 days). These admissions used 45% of the intensive care unit and 33% of the hospital bed days used by all intensive care unit admissions. Severe sepsis is common and presents a major challenge for clinicians, managers, and healthcare policymakers. Intensive care unit admissions meeting severe sepsis criteria have a high mortality rate and high resource use.

Genomic polymorphisms in sepsis

Article

Mar 2004
CRIT CARE MED

This article aims to review all relevant genetic polymorphism studies that may contribute to the pathogenesis of sepsis with emphasis on polymorphisms of the innate immunity, pro- and anti-inflammatory cytokines, and coagulation mediators. Published articles reporting on studies of associations between genetic polymorphisms, sepsis, septic shock, and other relevant infectious disease models. Research into the pathogenesis of sepsis has led to the development of many potential therapeutic strategies. Several therapeutic agents and treatment modalities have been shown to decrease mortality rates in large, prospective, and randomized clinical trials. However, although these advances have resulted in improved survival for certain patient populations, the overall mortality rate for septic patients remains high. With the rapid development of molecular and genetic techniques, substantial interests have developed in using genomic information to define disease-mediating genetic variants in sepsis. Combined with microarray technology, it is anticipated in the near future that one will be able to tailor drug selection and dosage and predict outcome by correlating genetic profile with disease presentation. Numerous genetic association studies in sepsis have already been reported and more are likely to be published. Although studies examined in this review are of small heterogeneous populations, the identification of strong associations between certain genetic polymorphisms and increased mortality rate or susceptibility to severe sepsis is intriguing and supports further research using this approach. The establishment of these associations does not equal causation, and further research is required in both genetic and molecular aspect of sepsis.

Analysis of European mitochondrial haplogroups with Alzheimer disease risk

Article

Aug 2004
NEUROSCI LETT

We examined the association of mtDNA variation with Alzheimer disease (AD) risk in Caucasians (989 cases and 328 controls) testing the effect of individual haplogroups and single nucleotide polymorphisms (SNPs). Logistic regression analyses were used to assess risk of haplogroups and SNPs with AD in both main effects and interaction models. Males classified as haplogroup U showed an increase in risk (OR = 2.30; 95% CI, 1.03-5.11; P = 0.04) of AD relative to the most common haplogroup H, while females demonstrated a significant decrease in risk with haplogroup U (OR = 0.44 ; 95% CI, 0.24-0.80; P = 0.007). Our results were independent of APOE genotype, demonstrating that the effect of mt variation is not confounded by APOE4 carrier status. We suggest that variations within haplogroup U may be involved in AD expression in combination with environmental exposures or nuclear proteins other than APOE.

The Molecular Dissection of mtDNA Haplogroup H Confirms That the Franco-Cantabrian Glacial Refuge Was a Major Source for the European Gene Pool

Article

Dec 2004

Complete sequencing of 62 mitochondrial DNAs (mtDNAs) belonging (or very closely related) to haplogroup H revealed that this mtDNA haplogroup--by far the most common in Europe--is subdivided into numerous subhaplogroups, with at least 15 of them (H1-H15) identifiable by characteristic mutations. All the haplogroup H mtDNAs found in 5,743 subjects from 43 populations were then screened for diagnostic markers of subhaplogroups H1 and H3. This survey showed that both subhaplogroups display frequency peaks, centered in Iberia and surrounding areas, with distributions declining toward the northeast and southeast--a pattern extremely similar to that previously reported for mtDNA haplogroup V. Furthermore, the coalescence ages of H1 and H3 (~11,000 years) are close to that previously reported for V. These findings have major implications for the origin of Europeans, since they attest that the Franco-Cantabrian refuge area was indeed the source of late-glacial expansions of hunter-gatherers that repopulated much of Central and Northern Europe from ~15,000 years ago. This has also some implications for disease studies. For instance, the high occurrence of H1 and H3 in Iberia led us to re-evaluate the haplogroup distribution in 50 Spanish families affected by nonsyndromic sensorineural deafness due to the A1555G mutation. The survey revealed that the previously reported excess of H among these families is caused entirely by H3 and is due to a major, probably nonrecent, founder event.

Mitochondrial DNA haplogroup cluster UKJT reduces the risk of PD

Article

Apr 2005

There is increasing evidence that genetic variants of mitochondrial DNA have an important role in the cause of idiopathic Parkinson's disease. We determined the mitochondrial DNA haplogroup of 455 Parkinson's disease cases, 185 Alzheimer's disease cases, and 447 healthy English control subjects. The UKJT haplogroup cluster was associated with a 22% reduction in population-attributable risk for Parkinson's disease. There was no association between individual haplogroups or the UKJT cluster and Alzheimer's disease, confirming that the association with Parkinson's disease was disease specific and not a general effect seen in all neurodegenerative diseases.

International sepsis definitions conference. 2001SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference

Article

May 2003
CRIT CARE MED

In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes. Several North American and European intensive care societies agreed to revisit the definitions for sepsis and related conditions. This conference was sponsored by the SCCM, The European Society of Intensive Care Medicine (ESICM), The American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS). The conference was attended by 29 participants from Europe and North America. In advance of the conference, five subgroups were formed to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiologic data, and coagulation parameters. The subgroups corresponded electronically before the conference and met in person during the conference. A spokesperson for each group presented the deliberation of each group to all conference participants during a plenary session. A writing committee was formed at the conference and developed the current article based on executive summary documents generated by each group and the plenary group presentations. The present article serves as the final report of the 2001 International Sepsis Definitions Conference. This document reflects a process whereby a group of experts and opinion leaders revisited the 1992 sepsis guidelines and found that apart from expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience, no evidence exists to support a change to the definitions. This lack of evidence serves to underscore the challenge still present in diagnosing sepsis in 2003 for clinicians and researchers and also provides the basis for introducing PIRO as a hypothesis-generating model for future research.

The pathophysiology and treatment of sepsis

Jan 2003
138

Hotchkiss

APACHE II: a severity of disease classification system

Jan 1985
818

Knaus

Mitochondrial DNA and survival after sepsis: A prospective study

Abstract

No full-text available

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