Evidence for frequent and tissue-specific sequence heteroplasmy in human mitochondrial DNA

Naue, Jana; Hörer, Steffen; Sänger, Timo; Strobl, Christina; Hatzer-Grubwieser, Petra; Parson, Walther; Lutz-Bonengel, Sabine

doi:10.1016/j.mito.2014.12.002

Cited by 90 publications

(77 citation statements)

References 69 publications

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“…Three samples (EST-33, EST-81, and EST-106) exhibited two point heteroplasmy positions each. A similar extent of heteroplasmy (16.2 %), along with heteroplasmy at multiple positions per sample, has been observed previously in buccal cell mtDNA [31].…”

Section: Resultssupporting

confidence: 86%

Whole mitochondrial genome genetic diversity in an Estonian population sample

et al. 2015

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Mitochondrial DNA is a useful marker for population studies, human identification, and forensic analysis. Commonly used hypervariable regions I and II (HVI/HVII) were reported to contain as little as 25% of mitochondrial DNA variants and therefore the majority of power of discrimination of mitochondrial DNA resides in the coding region. Massively parallel sequencing technology enables entire mitochondrial genome sequencing. In this study, buccal swabs were collected from 114 unrelated Estonians and whole mitochondrial genome sequences were generated using the Illumina MiSeq system. The results are concordant with previous mtDNA control region reports of high haplogroup HV and U frequencies (47.4 and 23.7% in this study, respectively) in the Estonian population. One sample with the Northern Asian haplogroup D was detected. The genetic diversity of the Estonian population sample was estimated to be 99.67 and 95.85%, for mtGenome and HVI/HVII data, respectively. The random match probability for mtGenome data was 1.20 versus 4.99% for HVI/HVII. The nucleotide mean pairwise difference was 27 ± 11 for mtGenome and 7 ± 3 for HVI/HVII data. These data describe the genetic diversity of the Estonian population sample and emphasize the power of discrimination of the entire mitochondrial genome over the hypervariable regions.

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Section: Resultssupporting

confidence: 86%

Whole mitochondrial genome genetic diversity in an Estonian population sample

et al. 2015

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“…[17][18][19][20][21][22][23][24] Generally, in the same individual mutant mtDNA molecules accumulate in tissues, such as muscle, brain, heart; the opposite of what occurs in blood and lung where mutant load is lower. [17][18][19][20] In line with in vivo results, we found that mutated mtDNA was accumulated in RD.Myo cybrids, 21,22 while WT mtDNA was selected in A549.B2 cybrids. 23,24 A better understanding of the molecular mechanisms underpinning the selection of mutant or wild-type mtDNA would provide new therapeutic approaches for mitochondrial diseases that are currently largely incurable.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

et al. 2016

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Pathological mutations in the mitochondrial DNA (mtDNA) produce a diverse range of tissue-specific diseases and the proportion of mutant mitochondrial DNA can increase or decrease with time via segregation, dependent on the cell or tissue type. Previously we found that adenocarcinoma (A549.B2) cells favored wild-type (WT) mtDNA, whereas rhabdomyosarcoma (RD.Myo) cells favored mutant (m3243G) mtDNA. Mitochondrial quality control (mtQC) can purge the cells of dysfunctional mitochondria via mitochondrial dynamics and mitophagy and appears to offer the perfect solution to the human diseases caused by mutant mtDNA. In A549.B2 and RD.Myo cybrids, with various mutant mtDNA levels, mtQC was explored together with macroautophagy/autophagy and bioenergetic profile. The 2 types of tumor-derived cell lines differed in bioenergetic profile and mitophagy, but not in autophagy. A549.B2 cybrids displayed upregulation of mitophagy, increased mtDNA removal, mitochondrial fragmentation and mitochondrial depolarization on incubation with oligomycin, parameters that correlated with mutant load. Conversely, heteroplasmic RD.Myo lines had lower mitophagic markers that negatively correlated with mutant load, combined with a fully polarized and highly fused mitochondrial network. These findings indicate that pathological mutant mitochondrial DNA can modulate mitochondrial dynamics and mitophagy in a cell-type dependent manner and thereby offer an explanation for the persistence and accumulation of deleterious variants.

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“…It is also apparent that regulated normative expression of high levels of heteroplasmic mtDNA genomes within the intra-mitochondrial compartment in individual human cell types is required for normative mitochondrial bioenergetics that is markedly compromised in human disease states [2,5,9–11]. Additionally, the critical regulatory roles of cell-specific patterns of mtDNA heteroplasmy are fundamental to the maintenance of requisite metabolic capacity during normal aging processes and limited lifespan [12–14]. …”

Section: Discussionmentioning

confidence: 99%

Aging Reversal and Healthy Longevity is in Reach: Dependence on Mitochondrial DNA Heteroplasmy as a Key Molecular Target

Stefano¹,

Kream²

2017

Med Sci Monit

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Recent trends in biomedical research have highlighted the potential for effecting significant extensions in longevity with enhanced quality of life in aging human populations. Within this context, any proposed method to achieve enhanced life extension must include therapeutic approaches that draw upon essential biochemical and molecular regulatory processes found in relatively simple single cell organisms that are evolutionarily conserved within complex organ systems of higher animals. Current critical thinking has established the primacy of mitochondrial function in maintaining good health throughout plant and animal phyla. The mitochondrion represents an existentially defined endosymbiotic model of complex organelle development driven by evolutionary modification of a permanently enslaved primordial bacterium. Cellular mitochondria are biochemically and morphologically tailored to provide exponentially enhanced ATP-dependent energy production accordingly to tissue- and organ-specific physiological demands. Thus, individual variations in longevity may then be effectively sorted according to age-dependent losses of single-cell metabolic integrity functionally linked to impaired mitochondrial bioenergetics within an aggregate presentation of compromised complex organ systems. Recent empirical studies have focused on the functional role of mitochondrial heteroplasmy in the regulation of normative cellular processes and the initiation and persistence of pathophysiological states. Accordingly, elucidation of the multifaceted functional roles of mitochondrial heteroplasmy in normal aging and enhanced longevity will provide both a compelling genetic basis and potential targets for therapeutic intervention to effect meaningful life extension in human populations.

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Evidence for frequent and tissue-specific sequence heteroplasmy in human mitochondrial DNA

Cited by 90 publications

References 69 publications

Whole mitochondrial genome genetic diversity in an Estonian population sample

Whole mitochondrial genome genetic diversity in an Estonian population sample

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

Aging Reversal and Healthy Longevity is in Reach: Dependence on Mitochondrial DNA Heteroplasmy as a Key Molecular Target

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