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Background:
Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.
Methods:
We measured circulating MT-DNA levels in prospectively collected, cell-free plasma sampl...
Context in source publication
Context 1
... MT-CYTB, AUC for ICU admission was 0.75 (95%CI 0.65 -0.85, Figure 3B). On multivariable logistic regression, plasma MT-CYTB levels remained an independent risk factor for ICU admission after adjusting for age, sex and 2 or more comorbidities (ORadj , 3.97, 95% 1.83 -10.34, p = 0.002, Table 5). Notably, we also made similar findings for MT-COX3 [ Figure S1C, ORadj for age, sex and 2 or more comorbidities, 1.47, 95% CI 1.14 -1.95, p = 0.005), AUC of COX3 for ICU admission 0.69 (95% CI 0.58 -0.79)]. ...Similar publications
Introduction
The institutions (i.e., hubs) making up the National Institutes of Health (NIH)-funded network of Clinical and Translational Science Awards (CTSAs) share a mission to turn observations into interventions to improve public health. Recently, the focus of the CTSAs has turned increasingly from translational research (TR) to translational...
Citations
... There is a possibility that the process of autophagy is influenced by mtDNA, which can lead to the overproduction of inflammatory mediators and activation of apoptotic signal pathways, and the interaction between autophagy and apoptosis further supports this connection [90]. Defective autophagy (mitophagy) allows accumulation of damaged mitochondria and release of mtDNA, triggering inflammatory pathways like cGAS-STING and NLRP3 [91,92]. The cGAS-STING pathway activated by cytosolic mtDNA can induce apoptosis through various mechanisms including ER stress and NF-κB activation [93]. ...
... Quantitatively analysing systemic circulating mtDNA, Schneck et al. determined that patients suffering from septic shock showed consistently elevated levels when compared with patients suffering from post-operative inflammation [166]. Scozzi et al. demonstrated that high circulating levels of mtDNA were an early indicator of poor outcome in COVID-19 [91]. Edinger et al. conducted a study of 29 critically ill patients aged between 59 -80 and found that significantly increased levels of peak plasma mtDNA could be used as a predictive marker of mortality [167]. ...
This review investigates links between post-acute sequelae of SARS-CoV-2 infection (PASC), post-infection viral persistence, mitochondrial involvement and aberrant innate immune response and cellular metabolism during SARS-CoV-2 infection. Advancement of proteomic and metabolomic studies now allows deeper investigation of alterations to cellular metabolism, autophagic processes and mitochondrial dysfunction caused by SARS-CoV-2 infection while computational biology and machine learning have advanced methodologies of predicting virus-host gene and protein interactions. Particular focus is given to interaction between viral genes and proteins with mitochondrial function and that of the innate immune system. Finally, the authors hypothesise that viral persistence may be a function of mitochondrial involvement in sequestration of viral genetic material. While further work is necessary to understand the mechanisms definitively, a number of studies now point to resolution of questions regarding the pathogenesis of PASC.
... During the acute phase of COVID-19, SARS-CoV-2 can directly interact with mitochondria, exploiting mitochondrial dynamics for virus proliferation [81,82] and causing structural damage [32, [83][84][85][86]. This damage includes alterations in mitochondrial morphology, such as swelling and changes in size and number, driven by the effects of the virus on mitochondrial physiology. ...
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated. We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition.
... Studies have confirmed that both innate and adaptive immune pathways are involved in the pathogenesis of SARS-CoV-2 infection [15][16][17] . In severe COVID-19 patients, multiple DAMPs, including HMGB1 and S100 proteins, are significantly increased due to the massive release of inflammatory mediators and the occurrence of cell death [18][19][20] . DAMPs may contribute to the progression of severe COVID-19 by driving the uncontrolled immune response associated with COVID-19 21 . ...
The death of coronavirus disease 2019 (COVID-19) is primarily due to from critically ill patients, especially from ARDS complications caused by SARS-CoV-2. Therefore, it is essential to contribute an in-depth understanding of the pathogenesis of the disease and to identify biomarkers for predicting critically ill patients at the molecular level. Immunogenic cell death (ICD), as a specific variant of regulatory cell death driven by stress, can induce adaptive immune responses against cell death antigens in the host. Studies have confirmed that both innate and adaptive immune pathways are involved in the pathogenesis of SARS-CoV-2 infection. However, the role of ICD in the pathogenesis of severe COVID-19 has rarely been explored. In this study, we systematically evaluated the role of ICD-related genes in COVID-19. We conducted consensus clustering, immune infiltration analysis, and functional enrichment analysis based on ICD differentially expressed genes. The results showed that immune infiltration characteristics were altered in severe and non-severe COVID-19. In addition, we used multiple machine learning methods to screen for five risk genes (KLF5, NSUN7, APH1B, GRB10 and CD4), which are used to predict COVID-19 severity. Finally, we constructed a nomogram to predict the risk of severe COVID-19 based on the classification and recognition model, and validated the model with external data sets. This study provides a valuable direction for the exploration of the pathogenesis and progress of COVID-19, and helps in the early identification of severe cases of COVID-19 to reduce mortality.
... Here, excessive myocardial inflammation increased ccf-mtDNA presence, namely, ccf-mtND1 and ccf-mtND4 in the heart-on-a-chip model, which was also observed in patients diagnosed with COVID-19 admitted to the intensity care unit (ICU) with low LVEF (<50%). Several clinical studies found that patients with higher ccf-mtDNA concentrations are more likely to require intensive care and higher mortality (36,37). Therefore, we suggest that ccf-mtDNA could be used as a biomarker to identify patients with COVID-19 + at risk of more serious LVEF dysfunction and predict clinical outcomes in ICU patients with COVID-19 + . ...
Despite tremendous progress in the development of mature heart-on-a-chip models, human cell–based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip with circulating immune cells to model severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced acute myocarditis. We observed hallmarks of coronavirus disease (COVID-19)–induced myocardial inflammation, as the presence of immune cells augmented the secretion of proinflammatory cytokines, triggered progressive impairment of contractile function, and altered intracellular calcium transients. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the heart-on-a-chip and then validated in COVID-19 patients with low left ventricular ejection fraction, demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation-induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2–induced myocardial inflammation, we established that administration of endothelial cell–derived exosomes effectively rescued the contractile deficit, normalized calcium handling, elevated the contraction force, and reduced the ccf-mtDNA and cytokine release via Toll-like receptor–nuclear factor κB signaling axis.
... Injured mitochondria produce less ATP, and mitochondrial membrane leakage causes proapoptotic molecules, such as ROS, mtDNA, and cytochrome C, to enter the cytoplasm [5,6]. Increased mtDNA in the peripheral blood circulation is associated with poor prognosis of sepsis and coronavirus disease 2019 [7,8]. Therefore, maintaining mitochondrial homeostasis is critical for preventing and treating severe infection [3]. ...
Mitochondria produce adenosine triphosphate and potentially contribute to proinflammatory responses and cell death. Mitophagy, as a conservative phenomenon, scavenges waste mitochondria and their components in the cell. Recent studies suggest that severe infections develop alongside mitochondrial dysfunction and mitophagy abnormalities. Restoring mitophagy protects against excessive inflammation and multiple organ failure in sepsis. Here, we review the normal mitophagy process, its interaction with invading microorganisms and the immune system, and summarize the mechanism of mitophagy dysfunction during severe infection. We highlight critical role of normal mitophagy in preventing severe infection.
... ; https://doi.org/10.1101/2024.01.05.574280 doi: bioRxiv preprint response and perturbation of mitochondrial energetics (22). Mitochondrial impairment and oxidative stress are recognized intermediaries of the inflammatory response to viral infections (95) and increased levels of circulating mtDNA are correlated with severity and mortality in COVID-19 (96). Mitochondrial dysfunction itself could alter the antiviral interferon response by modifying 2-5A levels (97) or by triggering the release of mitochondrial DNA into the cytoplasm to activate the cGAS-STING pathway (95,98), which was shown to contribute to endothelial cell damage during SARS-CoV-2 infection (99,100). ...
Background
Cardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome in humans, but the mechanisms behind COVID-19-linked arrhythmias are unknown. This study explores the acute and long term effects of SARS-CoV-2 on the cardiac conduction system (CCS) in a hamster model of COVID-19.
Methods
Radiotelemetry in conscious animals was used to non-invasively record electrocardiograms and subpleural pressures after intranasal SARS-CoV-2 infection. Cardiac cytokines, interferon-stimulated gene expression, and macrophage infiltration of the CCS, were assessed at 4 days and 4 weeks post-infection. A double-stranded RNA mimetic, polyinosinic:polycytidylic acid (PIC), was used in vivo and in vitro to activate viral pattern recognition receptors in the absence of SARS-CoV-2 infection.
Results
COVID-19 induced pronounced tachypnea and severe cardiac conduction system (CCS) dysfunction, spanning from bradycardia to persistent atrioventricular block, although no viral protein expression was detected in the heart. Arrhythmias developed rapidly, partially reversed, and then redeveloped after the pulmonary infection was resolved, indicating persistent CCS injury. Increased cardiac cytokines, interferon-stimulated gene expression, and macrophage remodeling in the CCS accompanied the electrophysiological abnormalities. Interestingly, the arrhythmia phenotype was reproduced by cardiac injection of PIC in the absence of virus, indicating that innate immune activation was sufficient to drive the response. PIC also strongly induced cytokine secretion and robust interferon signaling in hearts, human iPSC-derived cardiomyocytes (hiPSC-CMs), and engineered heart tissues, accompanied by alterations in electrical and Ca ²⁺ handling properties. Importantly, the pulmonary and cardiac effects of COVID-19 were blunted by in vivo inhibition of JAK/STAT signaling or by a mitochondrially-targeted antioxidant.
Conclusions
The findings indicate that long term dysfunction and immune cell remodeling of the CCS is induced by COVID-19, arising indirectly from oxidative stress and excessive activation of cardiac innate immune responses during infection, with implications for long COVID Syndrome.
... Our study revealed that most of the authors, including ourselves, who previously studied this novel type of circulating biomarker had improperly assumed that they studied circulating fragmented mtDNA or mtDNA-associated EVs [8,17,23,51,52,[53][54][55][56][57][58][59]. We continue to believe, however, that highly fragmented cir-mtDNA degradation products as well as mtDNA containing EVs may have particular diagnostic relevance, despite their small proportions compared to that of cir-mtDNA deriving from exMT. ...
... Despite the uncertainty about the true mtDNA level introduced by the confounding factors as revealed here, we remain extremely enthusiastic about cir-mtDNA's potential diagnostic capacity for such conditions as inflammation diseases [65], neurological disorder [51,66], trauma [52], cardiovascular diseases [67], various cancers [2,[53][54][55][56]68] and, as it was seen recently, SARS-CoV2 infection [57,58]. The origins of cir-exMT, exMT in EVs, and vesicles encapsulating mtDNA still need to be distinguished, as the cir-mtDNA sources may depend on the biological observation, especially with respect to the nature of the plasma preparation protocols. ...
... CfDNA in the form of nucleosomes is the product of chromatin degradation by endonucleases and consists of an octamer of two copies of each of the four core histones (H2A, H2B, H3, and H4) wrapped by 145-147 base pairs of helical DNA. Our findings are in line with other studies demonstrating that cfDNA is a potentially useful marker to monitor COVID-19 progression and severity [35][36][37][38]. ...
... Nucleosomes are the product of chromatin degradation by endonucleases and consists of an octamer of two copies of each of the four core histones (H2A, H2B, H3, and H4) wrapped by 145-147 base pairs of helical DNA. Our findings are in line with other studies demonstrating that cfDNA is a potentially useful marker to monitor COVID-19 progression and severity [35][36][37][38]. ...
Severe COVID-19 is characterized by systemic inflammation and multiple organ dysfunction syndrome (MODS). Arterial and venous thrombosis are involved in the pathogenesis of MODS and fatality in COVID-19. There is evidence that complement - and neutrophil activation in the form of neutrophil extracellular traps are main drivers for development of microvascular complications in COVID-19. Plasma and serum samples were collected from 83 patients infected by SARS-CoV-2 during the two first waves of COVID-19, before the availability of SARS-CoV-2 vaccination. Samples were collected at enrollment, day 11, and day 28; and patients had differing severity of disease. In this comprehensive study, we measured cell-free DNA, neutrophil activation, deoxyribonuclease 1 activity, complement activation, and D-dimers in longitudinal samples of COVID-19 patients. We show that all the above markers, except deoxyribonuclease 1 activity, increased with disease severity. Moreover, we provide evidence that in severe disease there is continued neutrophil and complement activation, as well as D-dimer formation and nucleosome release, whereas in mild and moderate disease all these markers decrease over time. These findings suggest that neutrophil and complement activation are important drivers of microvascular complications and that they reflect immunothrombosis in these patients. Neutrophil activation, complement activation, cell-free DNA and D-dimer levels have the potential to serve as reliable biomarkers for disease severity and fatality in COVID-19. They might also serve as suitable markers with which to monitor the efficacy of therapeutic interventions in COVID-19.
... All plasma samples were pipetted into aliquots and stored at − 80 °C. In the following, ccf-mtDNA levels were determined by the qPCR -based assay according to a the method described by Scozzi [8]. Primers for human cytochrome b (CYB; forward 5′-ATGACCCCAATACGCAAAAT-3′ and reverse 5′-CGAAGTTTCATCATGCGGAG-3′) and human cytochrome c oxidase subunit III (COX3: forward 5′-ATGACCCACCAATCACATGC-3′ and reverse 5′-ATCACATGGCTAGGCCGGAG-3′) were used. ...
... Several studies identified higher age and preexisting comorbid conditions as the key risk factors for COVID-19 severity and mortality [17][18][19]. Moreover, several studies have demonstrated that high levels of ccf-mtDNA elevated the probability of ICU admission and heightened the risk of death in patients with COVID-19 [8,20,21] . ...
Background
In viral infections, mitochondria act as one of the main hubs of the pathogenesis. Recent findings present new insights into the potential role of circulating cell-free mitochondrial DNA (ccf-mtDNA) in COVID-19 pathogenesis by the induction of immune response and aggressive cytokine storm in SARS-CoV-2 infection.
Methods and results
The levels of ccf-mtDNA were investigated in 102 hospitalized patients with COVID-19 using the quantitative PCR (q-PCR) method. Statistical analysis confirmed a strong association between the levels of ccf-mtDNA and and mortality, ICU admission, and intubation. Also, our findings highlighted the pivotal role of comorbidities as a risk factor for COVID-19 mortality and severity.
Conclusion
Higher levels of ccf-mtDNA can serve as a potential early indicator for progress and poor prognosis of COVID-19.
... Perhaps the mechanisms for clearance from the circulation will also be distinct. Increased levels of mtDNA in the plasma have been associated with the prediction of mortality in COVID-19 patients [35] and contributes to the pathogenesis in patients infected with Dengue virus [36]. Previous studies [37] have shown that the mean size of mtDNA fragments in the plasma is less than 100 bp; this may be because mtDNA, in contrast to gDNA, is not protected by histones, and hence does not exist within nucleosomes. ...
African swine fever virus (ASFV) causes severe hemorrhagic disease in domestic pigs and wild boar, often with high case fatality rates. The virus replicates in the circulating cells of the monocyte–macrophage lineage and within lymphoid tissues. The infection leads to high fever and a variety of clinical signs. In this study, it was observed that ASFV infection in pigs resulted in a >1000-fold increase in the level of circulating cell-free DNA (cfDNA), derived from the nuclei of host cells in the serum. This change occurred in parallel with the increase in circulating ASFV DNA. In addition, elevated levels (about 30-fold higher) of host mitochondrial DNA (mtDNA) were detected in the serum from ASFV-infected pigs. For comparison, the release of the cellular enzyme, lactate dehydrogenase (LDH), a commonly used marker of cellular damage, was also found to be elevated during ASFV infection, but later and less consistently. The sera from pigs infected with classical swine fever virus (CSFV), which causes a clinically similar disease to ASFV, were also tested but, surprisingly, this infection did not result in the release of cfDNA, mtDNA, or LDH. It was concluded that the level of cfDNA in the serum is a sensitive host marker of virulent ASFV infection.
