Deletion of a 4977-bp Fragment in the Mitochondrial Genome Is Associated with Mitochondrial Disease Severity

Zhang, Yanchun; Ma, Yue; Bu, Dingfang; Liu, Hui; Xia, Chang-Yu; Zhang, Ying; Zhu, Sai-Nan; Pan, Hong; Pei, Pei; Xing, Zheng; Wang, Songtao; Xu, Yufeng; Qi, Yu

doi:10.1371/journal.pone.0128624

Cited by 25 publications

(30 citation statements)

References 37 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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Liver Mitochondrial DNA Copy Number and Deletion Levels May Contribute to Nonalcoholic Fatty Liver Disease Susceptibility

et al. 2016

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BackgroundThere 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.ObjectivesIn 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.MethodsThis 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.ResultsThe 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).ConclusionsThis 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Liver Mitochondrial DNA Copy Number and Deletion Levels May Contribute to Nonalcoholic Fatty Liver Disease Susceptibility

et al. 2016

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“…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].…”

Section: Sperm Dna Modificationsmentioning

confidence: 99%

Molecular Changes Induced by Oxidative Stress that Impair Human Sperm Motility

2020

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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.

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“…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 .…”

Section: Ethodsmentioning

confidence: 99%

Reference Intervals of Mitochondrial DNA Copy Number in Peripheral Blood for Chinese Minors and Adults

Xia

Liu

Yang

et al. 2017

Chinese Medical Journal

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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.

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Deletion of a 4977-bp Fragment in the Mitochondrial Genome Is Associated with Mitochondrial Disease Severity

Cited by 25 publications

References 37 publications

Liver Mitochondrial DNA Copy Number and Deletion Levels May Contribute to Nonalcoholic Fatty Liver Disease Susceptibility

Liver Mitochondrial DNA Copy Number and Deletion Levels May Contribute to Nonalcoholic Fatty Liver Disease Susceptibility

Molecular Changes Induced by Oxidative Stress that Impair Human Sperm Motility

Reference Intervals of Mitochondrial DNA Copy Number in Peripheral Blood for Chinese Minors and Adults

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