The Pleiotropic Effect of Physical Exercise on Mitochondrial Dynamics in Aging Skeletal Muscle
Chad Cox in Clinical Nutrition and Aging, 2017
Wilkinson et al. [130] showed that, in young adults, a single bout of RT causes both myofibrillar and mitochondrial protein synthesis before training, while, after training, it causes only myofibrillar synthesis. Tang et al. [131] also reported an increase in mitochondrial enzyme activity following RT in young adults. In older adults, Parise et al. [114, 132] showed that RT results in high levels of antioxidant enzymes and lower oxidative stress, while Tarnopolsky [129] investigating the effects of 14 weeks of RT on oxidant status and ETC did not observe changes in the activity of complexes I+III and II+III, but they observed an upregulation of complex IV. Complex IV is the terminal electron acceptor in the ETC, and an increase in its enzymatic capacity may reduce electron leakage, leading to lower ROS production [133]. It should also be noted that complex IV possesses more proteins encoded by mtDNA than other complexes and thus is more affected by mtDNA mutations. In the skeletal muscle of older adults, as well as of some patients with mitochondrial diseases, there is heteroplasmy, which means the presence of mtDNA copies belonging to wild-type or mutant mtDNA populations. The degree of mutant mtDNA heteroplasmy found in mature skeletal muscle fibers is higher than that which is found in peripheral blood mononuclear cells, fibroblasts, and satellite cells.
Genomic Instability During Aging of Postmitotic Mammalian Cells
Alvaro Macieira-Coelho in Molecular Basis of Aging, 2017
Mitochondrial genomic instability. The data supporting the view that mitochondrial genomic instability is the primary reason postmitotic cells age seems to be strong,301 and future experiments should be promising. Base damages, point mutations, and various deletions of mtDNA increased in senescent tissues.311–321 The aging changes in mtDNA appear to be more conspicuous in fixed postmitotic cells, such as cardiac and neural tissues. The levels of measured single lesions might appear to be insufficient to account for major functional decrements, given the genomic and cellular redundancies of mammalian cells, but the totality of all lesions combined may be more than sufficient to cause cellular senescence. Thus, there needs to be an adding up of all the damages and mutations. Concerning informational gaps, we clearly need to know more about mtDNA repair enzymes and systems. The distribution of mtDNA deletions, etc., among different cell types in aging tissues is of importance. Clearer correlation between mitochondrial function and mitochondrial genomic instability are of more importance, but experimentally may be difficult to show due to heteroplasmy. Although not yet attempted, creation of recombinant mtDNA genomes, and mitochondrial genome replacement experiments seem to be exciting future possibilities.
Instability of Human Mitochondrial DNA, Nuclear Genes and Diseases
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Mitochondrial DNA is a multicopy molecule within the cell (hundreds to thousands copies in somatic cells). This means that in the case of mtDNA terms homozygous or heterozygous cannot be used. Homoplasmy is when all the molecules have the same sequence and heteroplasmy are when at least two types of mtDNA molecules are present. For years it was believed that homoplasmy is the natural state in healthy cell. Now in the era of next generation sequencing it turned out that low level heteroplasmy is common, but not visible using routine laboratory techniques. In case of large-scale mtDNA deletions (as well as in case of the most of the pathogenic point mutations) heteroplasmy is clearly visible. This type of mtDNA lesion is never even close to homoplasmy. All mitochondrial encoded genes are essential and a large-scale deletion cuts out at least a few genes, so only an adequate proportion of wild type molecules provides all necessary mtDNA products. In the case of various mtDNA mutations including large-scale deletions the threshold effect can be observed; the respiratory chain defect appears when the percentage of mutated molecules exceeds a certain value. It is considered that for large-scale mtDNA deletions it is around 60% at the cellular level.
Forensic evaluation of mitochondrial DNA heteroplasmy in Gujarat population, India
Published in Annals of Human Biology, 2022
Mohammed H. M. Alqaisi, Molina Madhulika Ekka, Bhargav C. Patel
The mitochondrial DNA is homoplasmic when all mitochondrial DNA molecules are identical. On the other hand, if mutant mtDNA coexists alongside wild-type mtDNA and has two distinct populations of mtDNA, it is called heteroplasmy (Melton 2004; Wallace and Chalkia 2013; Li et al. 2016). Heteroplasmy is primarily caused by the higher mutation rates observed in mitochondrial genomes compared to nuclear genomes (Brown et al. 1982; Wallace et al. 1987; Wallace and Chalkia 2013). Moreover, hypervariable regions are more susceptible to having heteroplasmies than other mitochondrial genome regions (Greenberg et al. 1983; Li et al. 2015). In mtDNA sequences, two forms of heteroplasmy may be found: point heteroplasmy (PH) and length/C-stretch heteroplasmy (LH). PH is the most common type of heteroplasmy used in forensic analysis. It is possible to detect two nucleotides as two peaks at a single position in an electropherogram, indicating the presence of PH (Figure 1). However, LH (Figure 2) is generally triggered when C residues are inserted or when thymine is substituted for cytosine (Bendall and Sykes 1995; Bendall et al. 1997; Lutz-Bonengel et al. 2008; Parson et al. 2014).
The Natural History of Leber’s Hereditary Optic Neuropathy in an Irish Population and Assessment for Prognostic Biomarkers
Published in Neuro-Ophthalmology, 2022
Kirk A. J. Stephenson, Joseph McAndrew, Paul F. Kenna, Lorraine Cassidy
Heteroplasmy in LHON families (i.e., a subset of genetically normal mitochondria) may decrease penetrance and infer a better prognosis and treatment response.1,38 Heteroplasmy is more common in de novo (37.5–80%) versus inherited (5%) mtDNA mutations, suggesting a trend towards homoplasmy in subsequent generations.1,7,59 Blood leukocytes, hair cells, retina and optic nerve may each have different percentages of mutant mtDNA thus blood testing may not accurately represent the degree of mitochondrial dysfunction in RGCs.60,61 LHON-affected people usually have > 95% mutant mtDNA.7 Disease may still manifest in heteroplasmy due to unfavourable mitochondrial haplotype or nuclear modifiers; however, 13.6–19% of unaffected maternal relatives show mtDNA heteroplasmy and 1:300 UK citizens harbour an LHON mutation (1:1000 homoplasmic) without necessarily manifesting disease, thus other modifiers are likely.7,59,62,63 In our cohort, heteroplasmic patients had less severe visual loss over the study period. Kim et al. reported patients with the m.14459 G >A mutation manifesting LHON in heteroplasmy and neurological manifestations in homoplasmy thus degree of heteroplasmy may determine disease phenotype.14
Recent advances in delivering RNA-based therapeutics to mitochondria
Published in Expert Opinion on Biological Therapy, 2022
Yuma Yamada, Sen Ishizuka, Manae Arai, Minako Maruyama, Hideyoshi Harashima
Human mtDNA is approximately 16.6 kb in size and encodes 13 proteins that are involved in oxidative phosphorylation, 22 transfer RNA (tRNA) and two ribosomal RNA (rRNA) [23,24]. It is known that mitochondrial dysfunctions are caused by mutations in mtDNA or nuclear DNA that encode mitochondrial proteins [25]. The status of mtDNA is debated as to whether it is heteroplasmy or homoplasmy. Heteroplasmy means that mitochondria contains both mutated and wild-type mtDNA. On the other hand, homoplasmy means that there is a pure genome (100% wild-type or 100% mutated mtDNA) in mitochondria. Mitochondrial diseases develop, when the percentage of mutated mtDNA exceeds a certain threshold [26,27].
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