Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age

Miller, Francis; Rosenfeldt, Franklin; Zhang, Chunfang; Linnane, Anthony W.; Nagley, Phillip

doi:10.1093/nar/gng060

Cited by 301 publications

(228 citation statements)

References 26 publications

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“…[22][23][24][25] For a given chromosomal region, short reads mapped to the region were retrieved from the BAM file at the FTP site of the 1000 Genomes Project 26 using samtools. 27 This was done for the whole mtDNA region and the autosomal regions; the numbers of short reads in the two regions were used to compute mtDNA/nDNA.…”

Section: Estimation Of Mtdna Copy Numbermentioning

confidence: 99%

Population-level expression variability of mitochondrial DNA-encoded genes in humans

et al. 2014

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Human mitochondria contain multiple copies of a circular genome made up of double-stranded DNA (mtDNA) that encodes proteins involved in cellular respiration. Transcript abundance of mtDNA-encoded genes varies between human individuals, yet the level of variation in the general population has not been systematically assessed. In the present study, we revisited large-scale RNA sequencing data generated from lymphoblastoid cell lines of HapMap samples of European and African ancestry to estimate transcript abundance and quantify expression variation for mtDNA-encoded genes. In both populations, we detected up to over 100-fold difference in mtDNA gene expression between individuals. The marked variation was not due to differences in mtDNA copy number between individuals, but was shaped by the transcription of hundreds of nuclear genes. Many of these nuclear genes were co-expressed with one another, resulting in a module-enriched co-expression network. Significant correlations in expression between genes of the mtDNA and nuclear genomes were used to identify factors involved with the regulation of mitochondrial functions. In conclusion, we determined the baseline amount of variability in mtDNA gene expression in general human populations and cataloged a complete set of nuclear genes whose expression levels are correlated with those of mtDNA-encoded genes. Our findings will enable the integration of information from both mtDNA and nuclear genetic systems, and facilitate the discovery of novel regulatory pathways involving mitochondrial functions.

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Section: Estimation Of Mtdna Copy Numbermentioning

confidence: 99%

Population-level expression variability of mitochondrial DNA-encoded genes in humans

et al. 2014

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“…Although the literature is sparse and conflicting, animal studies have shown an increase in mtDNA copy number with age in several organs. [22][23][24] Regarding the mtDNA 4977 mutation, one might speculate that it may be a marker of either survival or aging. Although there is a large body of literature associating the mutation with aging and age-related pathology, there is little or no evidence to impute a causal role.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Injury and Mortality in Hemodialysis Patients

Madhumathi

Demello

et al. 2009

Journal of the American Society of Nephrology

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The role of mitochondrial injury in the pathogenesis of complications of uremia is incompletely defined, although diminished bioenergetic capacity and the accumulation of mitochondrial DNA (mtDNA) mutations have been reported. This study was undertaken to evaluate the prevalence of mtDNA injury in 180 patients who had ESRD and were enrolled into the baseline phase of the HEMO study and to relate these markers to all-cause mortality. The mitochondrial injury markers studied in peripheral blood mononuclear cells were the mtDNA copy number per cell, measured by quantitative PCR, and the presence of the mtDNA 4977 mutation. After frequency-matching healthy control subjects for age, mtDNA copy number was lower among older dialysis patients compared with older healthy subjects (P ϭ 0.01). A one-log increase in mtDNA copy number was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.64; 95% confidence interval 0.46 to 0.89). The mtDNA 4977 deletion was present in 48 (31%) patients and was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.33; 95% confidence interval 0.19 to 0.56). In summary, the mtDNA 4977 seems to predict survival in ESRD, but a reduced mitochondrial copy number seems to predict a poor outcome. Although further exploration of these associations is needed, evaluation of mitochondrial DNA copy number and somatic mtDNA mutations may provide simple genomic biomarkers to predict clinical outcomes among patients with ESRD. The uremic syndrome is characterized by abnormalities in energy metabolism, manifest as changes in basal metabolic rate, relative catabolism, negative nitrogen balance, protein energy malnutrition, insulin resistance, and dyslipidemia. 1 Mitochondria are integral to these metabolic processes, which they probably influence through cytokine-and adipokine-mediated mechanisms. 2 Early studies with 31-phosphorus nuclear magnetic resonance demonstrated that mitochondrial oxidative capacity was diminished in muscle of patients established on dialysis. 3 More recent studies showed a high prevalence of somatic mitochondrial DNA (mtDNA) mutations, specifically the "common deletion" (a 4977-bp deletion between nucleotide positions 8470 and 13,447 [mtDNA 4977 ]) in skeletal muscle of patients with ESRD. 4 Human mtDNA is particularly prone to oxidant injury because mitochondria generate reactive oxygen species during ATP production. 5 mtDNA injury may be qualitativedeletion or point mutations-or quantitative-abnormalities of mtDNA copy number per cell, mtDNA being polyploid. 6 mtDNA mutations are classically studied in skeletal muscle tissue, but recent observations suggested that the use of periph-

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“…Most somatic cells contain approximately 10 3 mitochondria (Giles et al, 1980;Barritt et al, 1999). The actual amount depends on such factors as their cell's metabolic activity and intracellular spatial organization (configuration) of cytoskeleton and membrane skeleton microfilament network; also their ultrastructuro-functional specialization within the framework of both cytodifferentiation and exactly defined tissue-and organ-related histological topography and tissue-specific nuclear DNA and mtDNA gene expression (transcriptional activity) patterns (Moyes et al, 1998;Garesse and Vallejo, 2001;Gahan et al, 2001;Smeitink et al, 2001;Miller et al, 2003;Takeda et al, 2003). In most types of somatic cells that are the source of nuclear donors in the cloning procedure, the number of mtDNA molecules ranges from about 2 × 10 3 to about 5 × 10 3 copies, i.e.…”

Section: The Causes Of Mtdna Heteroplasmy Induction In Somatic and Emmentioning

confidence: 99%

The role of mitochondrial genome (mtDNA) in somatic and embryo cloning of mammals. A review

Samiec¹

2005

J. Anim. Feed Sci.

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Mitochondria are semiautonomous organelles that contain double-stranded (α-helix) circular DNA molecules (mtDNAs) of about 16300 to 16500 base pairs (bp). The mtDNA encodes only 13 proteins, 22 tRNAs and 2 rRNAs. Up to 95% of proteins involved in biogenesis and functions of mitochondria are encoded by the cell nucleus. The copy number of mitochondrial genome in a typical mammalian somatic cell ranges from approximately 2 × 10 3 to about 5 × 10 3

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Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age

Cited by 301 publications

References 26 publications

Population-level expression variability of mitochondrial DNA-encoded genes in humans

Population-level expression variability of mitochondrial DNA-encoded genes in humans

Mitochondrial DNA Injury and Mortality in Hemodialysis Patients

The role of mitochondrial genome (mtDNA) in somatic and embryo cloning of mammals. A review

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