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The correlation between lactic acidosis and proportion of ΔmtDNA4977 in 104cells, ΔmtDNA4977 copy number/104 cells, and total mtDNA copy number/cell in younger mitochondrial disease patients.
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Large deletions in mitochondrial DNA (mtDNA) may be involved in the pathogenesis of mitochondrial disease. In this study, we investigated the relationship between a 4,977-bp deletion in the mitochondrial genome (ΔmtDNA4977) and the severity of clinical symptoms in patients with mitochondrial disease lacking known point mutations. A total of 160 pat...
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Damage to the mitochondrial genome (mtDNA) can lead to diseases for which there are no clearly effective treatments. Since mitochondrial function and biogenesis are controlled by the nutrient environment of the cell, it is possible that perturbation of conserved, nutrient-sensing pathways may successfully treat mitochondrial disease. We found that...
Mitochondria are double membrane-bound organelles that are present in all nucleated eukaryotic cells and responsible for the production of cellular energy in the form of ATP. Mitochondrial function is under dual genetic control - the 16.6?kb mitochondrial genome encoding just 37 genes with the remaining ~1300 proteins of the mitoproteome encoded by...
Citations
... 37,38 Most of these deletions occur in a specific part of the mitochondrial genome named "common deletion," or "mtDNA 4977 ," which eliminates nucleotides between 8470 and 13447 of the mitochondrial genome. 39,40 Consequently, the destruction of about one-third of the whole mtDNA might be affected by this mutation. This particular mtDNA deletion is not selective for, but highly enriched in, IBM patients, being also seen in other conditions, including Alzheimer's disease, malignancies, ultraviolet lightinjured skin, autosomal dominant progressive external ophthalmoplegia, as well as in normal aging. ...
Increasing evidence points towards mitochondria as crucial players in the initiation and progression of auto-immune and degenerative disorders, to which impaired cell metabolism is but a facet of the subjacent etiopathogenesis. This review aims to introduce the reader to essential concepts of mitochondrial abnormalities in idiopathic inflammatory myopathy (IIM), underscoring inclusion-body myositis and dermatomyositis. Far surpassing the initial simplistic view of being responsible for energy generation, mitochondria have gathered attention regarding their role in inflammatory processes, being able to fuel autoimmunity, as shown by the presence of anti-mitochondrial antibodies (AMAs) in up to 10% of IIM patients. As cellular respiration takes place, mitochondrial metabolites might help to shape the pro-inflammatory milieu in affected muscle, beyond generating reactive oxygen species, which are well-recognized inducers of damage-associated molecular patterns. A series of mitochondrial components might facilitate the sterile activation of pro-inflammatory cells and the production of several cytokines responsible for enhancing auto-immune responses. Marked variation in the mitochondrial genome has also been reported in IIM patients. As such, we summarize key historical and recent advances linking aberrations and instabilities of mitochondrial DNA to impaired muscle function. Besides discussing mitochondrial dysfunction as an essential part of IIM development, we also highlight possible associations between presence of AMAs and a particular phenotype of IIM, with its own characteristic clinical and radiological pattern. Finally, we present promising treatment approaches targeting mitochondria, while briefly discussing experimental models for gaining deeper insight into the disease process, and ultimately leading to novel drug development.
... The results obtained from associated studies showed that the glycolytic pathway might be much more important than the oxidative phosphorylation respiratory pathway in producing ATP in intestinal epithelial cells. However, accumulation of the deleted mtDNA in tissue with age may disturb metabolic homeostasis by mitochondrial dysfunction, since it has been proposed that this deletion has the potential to disrupting mitochondrial metabolism (22). Therefore, it can be expected that there may be a relationship between increased mitochondrial common deletion in intestinal tissue and intestinal permeability as a function of aging. ...
... An increased proportion of mitochondrial common DNA deletions is associated with mitochondria-related problems such as an overall decrease in energy supply and lactic acidosis. As such, it is an important factor correlated with the severity of mitochondrial disease symptoms (29,22). It has been suggested that among the deletions observed in humans, mtDNA 4977 may be involved in the age-dependent decline of cell or tissue function (19,18). ...
Some evidence points to a link between aging-related increased intestinal permeability and mitochondrial dysfunction in in-vivo models. Several studies have also demonstrated age-related accumulation of the of specific deletion 4834-bp of “common” mitochondrial DNA (mtDNA) in various rat tissues and suggest that this deletion may disrupt mitochondrial metabolism. The present study aimed to investigate possible associations among the mtDNA common deletion, mitochondrial function, intestinal permeability, and aging in rats. Our data showed were no significant differences in the abundance of mtDNA4834 deletions in intestinal tissue between young adult ((4-month-old) and aged (24-month-old) rats). In addition, Spearman's correlation coefficients of measured parameters in serum samples for intestinal permeability did not correlate with deletion frequency and measured levels of mitochondrial energy function parameters. However, the tissue lactate/pyruvate ratio (L/P) was three times lower in old rats than in young rats. Additionally, there were significant negative correlations between intestinal permeability parameters and L/P ratios. Considering our findings showing that the intestinal tissues of aged rats are not prone to accumulate mtDNA common deletion, we suggest that this mutation does not explain the age-related increase in intestinal permeability. Some data support the thought that altered glycolytic capacity could be a possible mechanism linked to increased intestinal permeability with age.
... Rights reserved III, and NADH dehydrogenase subunits 3, 4, 4 L and 5. This will in turn lead to dysfunction of the cellular energy metabolism 93 . Here, we ascertained the presence of mtDNA deletions in our samples by analysing the nanopore sequences, whose length allows the detection of structural DNA variants. ...
Cisplatin is the first-line chemotherapeutic agent for the treatment of oral squamous cell carcinoma (OSCC). However, the intrinsic or acquired resistance against cisplatin remains a major obstacle to treatment efficacy in OSCC. Recently, mitochondrial DNA (mtDNA) alterations have been reported in a variety of cancers. However, the role of mtDNA alterations in OSCC has not been comprehensively studied. In this study, we evaluated the correlation between mtDNA alterations (mtDNA content, point mutations, large-scale deletions, and methylation status) and cisplatin sensitivity using two OSCC cell lines, namely SAS and H103, and stem cell-like tumour spheres derived from SAS. By microarray analysis, we found that the tumour spheres profited from aberrant lipid and glucose metabolism and became resistant to cisplatin. By qPCR analysis, we found that the cells with less mtDNA were less responsive to cisplatin (H103 and the tumour spheres). Based on the findings, we theorised that the metabolic changes in the tumour spheres probably resulted in mtDNA depletion, as the cells suppressed mitochondrial respiration and switched to an alternative mode of energy production, i.e. glycolysis. Then, to ascertain the origin of the variation in mtDNA content, we used MinION, a nanopore sequencer, to sequence the mitochondrial genomes of H103, SAS, and the tumour spheres. We found that the lower cisplatin sensitivity of H103 could have been caused by a constellation of genetic and epigenetic changes in its mitochondrial genome. Future work may look into how changes in mtDNA translate into an impact on cell function and therefore cisplatin response.
... One of the best-described large-scale mtDNA deletions is the specific 4977 bp deletion (mtDNA 4977 ), which occurs between nucleotides 8470 and 13447 and eliminates seven genes encoding four subunits of Complex I (ND3, ND4, ND4L, partial ND5), one subunit of Complex IV (COIII) and two subunits of ATP-synthase (ATP6 and partial ATP8); all of which are crucial for OXPHOS (depicted in Figure 3). Accordingly, mtDNA 4977 has been linked to a spectrum of disorders, including heart disease, different forms of cancer and mitochondrial diseases [143][144][145][146]. Notably, this mutation has also been reported to accumulate in different human tissues as a consequence of natural aging [147]. ...
A state of oxidative stress (OS) and the presence of reactive oxygen species (ROS) in the male reproductive tract are strongly correlated with infertility. While physiological levels of ROS are necessary for normal sperm functioning, elevated ROS production can overwhelm the cell’s limited antioxidant defenses leading to dysfunction and loss of fertilizing potential. Among the deleterious pleiotropic impacts arising from OS, sperm motility appears to be particularly vulnerable. Here, we present a mechanistic account for how OS contributes to altered sperm motility profiles. In our model, it is suggested that the abundant polyunsaturated fatty acids (PUFAs) residing in the sperm membrane serve to sensitize the male germ cell to ROS attack by virtue of their ability to act as substrates for lipid peroxidation (LPO) cascades. Upon initiation, LPO leads to dramatic remodeling of the composition and biophysical properties of sperm membranes and, in the case of the mitochondria, this manifests in a dissipation of membrane potential, electron leakage, increased ROS production and reduced capacity for energy production. This situation is exacerbated by the production of cytotoxic LPO byproducts such as 4-hydroxynonenal, which dysregulate molecules associated with sperm bioenergetic pathways as well as the structural and signaling components of the motility apparatus. The impact of ROS also extends to lesions in the paternal genome, as is commonly seen in the defective spermatozoa of asthenozoospermic males. Concluding, the presence of OS in the male reproductive tract is strongly and positively correlated with reduced sperm motility and fertilizing potential, thus providing a rational target for the development of new therapeutic interventions.
... 28 One of the best-described large scale mtDNA deletion is the specific 4977-bp deletion in mitochondrial genome, which has been accumulated in various disorders, including mitochondrial diseases and many different types of cancer. 29 The mDNA 4977 has been broadly studied and has been observed to exist with increasing age in normal human brain, heart and skeletal muscle. 20 In addition, the mDNA 4977 has also been exhibited to occur more frequently with increasing sun exposure in human skin, as compared with sun-protected skin. ...
Mitochondria are cellular machines essential for energy production. The biogenesis of mitochondria is a highly complex and it depends on the coordination of the nuclear and mitochondrial genome. Mitochondrial DNA (mtDNA) mutations and deletions are suspected to be associated with carcinogenesis. The most described mtDNA deletion in various human cancers is called the 4977-bp common deletion (mDNA4977) and it has been explored since two decades. In spite of that, its implication in carcinogenesis still unknown and its predictive and prognostic impact remains controversial. This review article provides an overview of some of the cellular and molecular mechanisms underlying mDNA4977 formation and a detailed summary about mDNA4977 reported in various types of cancers. The current knowledges of mDNA4977 as a prognostic and predictive marker are also discussed.
... The findings with respect to blood as fast replicating tissue are controversial. Several studies have reported that ΔmtDNA 4977 increases with age [27][28][29] whereas other studies have found that this deletion is not age-dependent [30][31][32][33][34]. The discrepancy might be due to experimental differences related to the other lifestyle and environmental parameters. ...
Background:
Age-related decrease in the mitochondrial activity has been reported in several tissues. Reactive Oxygen Species (ROS) produced from defected mitochondria leads to aging and accumulate through time. However, studies about the mitochondrial DNA mutation level in blood is contradictory. Other lifestyle factors may modify the effects of age in post-mitotic tissues such as blood. The BMI represents the sum of the various lifestyle factors.
Objective:
We proposed that age, obesity and mtDNA deletion are three ROS producing factors, which may interact with each other and induce senescence.
Method:
In a cross-sectional study 172 male and female volunteers without known mitochondrial diseases selected and presence of common mitochondrial 4977bp deletion (ΔmtDNA4977) evaluated using Nested-PCR.
Results:
Our results showed that a high percentage of samples (54.06%) harbor common deletion in blood. Furthermore, both BMI and the ΔmtDNA4977 level significantly decreases with age. The chronological age, BMI and ΔmtDNA4977 are reciprocally affecting each other.
Conclusion:
Our data suggest that the age affects purifying selection and BMI, which may influence the relative level of the mtDNA common deletion in blood.
... The absolute mtDNA copy number was measured by a quantitative real-time polymerase chain reaction (PCR)-based method as previously described. [12,17] mtDNA was quantified as the ratio of a mitochondrial gene copy number (ND1) to a single-copy nuclear gene (human β-globin gene, HBB). mtDNA copy number per cell was calculated by the formula 2×ND1/HBB. ...
Background
Mitochondrial DNA (mtDNA) content measured by different techniques cannot be compared between studies, and age- and tissue-related control values are hardly available. In the present study, we aimed to establish the normal reference range of mtDNA copy number in the Chinese population.
Methods
Two healthy cohorts of 200 Chinese minors (0.1–18.0 years) and 200 adults (18.0–88.0 years) were recruited. Then, they were further categorized into eight age groups. The absolute mtDNA copy number per cell was measured by a quantitative real-time polymerase chain reaction. We subsequently used this range to evaluate mtDNA content in four patients (0.5–4.0 years) with molecularly proven mitochondrial depletion syndromes (MDSs) and 83 cases of mitochondrial disease patients harboring the m.3243A>G mutation.
Results
The reference range of mtDNA copy number in peripheral blood was 175–602 copies/cell (mean: 325 copies/cell) in minors and 164–500 copies/cell (mean: 287 copies/cell) in adults. There was a decreasing trend in mtDNA copy number in blood with increasing age, especially in 0–2-year-old and >50-year-old donors. The mean mtDNA copy number level among the mitochondrial disease patients with m.3243A>G mutation was significantly higher than that of healthy controls. The mtDNA content of POLG, DGUOK, TK2, and SUCLA2 genes in blood samples from MDS patients was reduced to 25%, 38%, 32%, and 24%, respectively.
Conclusions
We primarily establish the reference intervals of mtDNA copy number, which might contribute to the clinical diagnosis and monitoring of mitochondrial disease.
... The 4,977 bp deletion is located between nucleotides 8,469 and 13,447 and includes several essential oxidative phosphorylation genes encoding ATPase6/8, cytochrome oxidase III, NADH dehydrogenase subunit 3 (ND3), ND4, and ND5. This large deletion is the most common deletion in the mitochondrial genome that has been detected in several types of human diseases (16,17). Moreover, it has been suggested that variations in mtDNA copy numbers may also be associated with some disorders. ...
... Our results showed that the 4977bp deletion was observed in 18.6% (8/43) of NAFLD patients, whereas this deletion was not detected in any of liver tissue samples obtained from the 20 control subjects. Several studies have found the mtDNA 4,977-bp deletion in various types of diseases (16,17). The exact cause of the increased mtDNA deletion levels in different tissues remains unknown. ...
Background:
There is growing evidence that deficiencies observed in the mitochondrial DNA (mtDNA) functions could play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We hypothesized that genetic variations in mtDNA could affect the mitochondrial function and contribute to the NAFLD susceptibility.
Objectives:
In this study, the possible association of the mtDNA copy number and 4,977-bp deletion levels with NAFLD susceptibility in a sample of Iranian population was evaluated.
Methods:
This case-control study included 43 NAFLD patients and 20 control subjects. Genomic DNA was extracted from fresh liver tissue samples by using a DNA isolation kit. The mtDNA copy number and mtDNA deletion levels were measured by quantitative real-time PCR and multiplex PCR.
Results:
The relative expression of mtDNA copy number was 3.7 fold higher in NAFLD patients than healthy controls (P < 0.0001). The results remained significant after adjustment for age, BMI, and gender (P = 0.02). In addition, the mtDNA copy number was 4.3 (P < 0.0001) and 3.2-fold (P < 0.0001) higher in nonalcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) patients than healthy controls, respectively. Finally, the results showed that the 4,977-bp deletion is not detected in any of liver tissue samples obtained from the 20 control subjects whereas 8 out of 43 NAFLD patients (18.6%) showed the 4,977 -bp deletion in their liver tissues (P = 0.039).
Conclusions:
This study indicated an association between mtDNA content in the liver tissue and NAFLD susceptibility that may be a consequence of compensatory response to the cumulative exposures to oxidative damage.
... The mitochondrial DNA common deletion is one of the first described and most-studied mtDNA mutations, and it has been implicated in many human diseases (Dimberg et al., 2015;Li et al., 2015;Zhang et al., 2015). Multiple reports have ...
The 4977bp common deletion is one of the most frequently observed mitochondrial DNA (mtDNA) mutations in human tissues and has been implicated in various human cancer types. It is generally believed that continuous generation of intracellular reactive oxygen species (ROS) during oxidative phosphorylation (OXPHOS) is a major underlying mechanism for generation of such mtDNA deletions while antioxidant systems, including Manganese superoxide dismutase (MnSOD), mitigating the deleterious effects of ROS. However, the clinical significance of this common deletion remains to be explored. A comprehensive investigation on occurrence and accumulation of the common deletion and mtDNA copy number was carried out in breast carcinoma (BC) patients, benign breast disease (BBD) patients and age-matched healthy donors in our study. Meanwhile, the representative oxidative (ROS production, mtDNA and lipid oxidative damage) and anti-oxidative features (MnSOD expression level and variation) in blood samples from these groups were also analyzed. We found that the mtDNA common deletion is much more likely to be detected in BC patients at relatively high levels while the mtDNA content is lower. This alteration has been associated with a higher MnSOD level and higher oxidative damages in both BC and BBD patients. Our results indicate that the mtDNA common deletion in blood may serve a biomarker for the breast cancer.
Some evidence points to a link between aging-related increased intestinal permeability and mitochondrial dysfunction in in-vivo models. Several studies have also demonstrated age-related accumulation of the of specific deletion 4834-bp of “common” mitochondrial DNA (mtDNA) in various rat tissues and suggest that this deletion may disrupt mitochondrial metabolism. The present study aimed to investigate possible associations among the mitochondrial DNA (mtDNA) common deletion, mitochondrial function, intestinal permeability, and aging in rats. The study was performed on the intestinal tissue from (24 months) and young (4 months) rats. mtDNA4834 deletion, mtDNA copy number, mitochondrial membrane potential, and ATP, lactate and pyruvate levels were analyzed in tissue samples. Zonulin and intestinal fatty acid-binding protein (I-FABP) levels were also evaluated in serum. Serum zonulin and I-FABP levels were significantly higher in 24-month-old rats than 4-month-old rats (p = 0.04, p = 0.026, respectively). There is not significant difference in mtDNA4834 copy levels was observed between the old and young intestinal tissues (p > 0.05). The intestinal mitochondrial DNA copy number was similar between the two age groups (p > 0.05). No significant difference was observed in ATP levels in the intestinal tissue lysates between old and young rats (p > 0.05). ATP levels in isolated mitochondria from both groups were also similar. Analysis of MMP using JC-10 in intestinal tissue mitochondria showed that mitochondrial membrane potentials (red/green ratios) were similar between the two age groups (p > 0.05). Pyruvate tended to be higher in the 24-month-old rat group and the L/P ratio was found to be approximately threefold lower in the intestinal tissue of the older rats compared to the younger rats (p < 0.002). The tissue lactate/pyruvate ratio (L/P) was three times lower in old rats than in young rats. Additionally, there were significant negative correlations between intestinal permeability parameters and L/P ratios. The intestinal tissues of aged rats are not prone to accumulate mtDNA common deletion, we suggest that this mutation does not explain the age-related increase in intestinal permeability. It seems to be more likely that altered glycolytic capacity could be a link to increased intestinal permeability with age. This observation strengthens assertions that the balance between glycolysis and mitochondrial metabolism may play a critical role in intestinal barrier functions.
