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The Complicated Nature of Somatic mtDNA Mutations in Aging

Sanchez-Contreras, Monica, Kennedy, Scott R.·2022·Frontiers in Aging
DOI 10.3389/fragi.2021.805126PMC PMC8896747
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Abstract

Mitochondria are the main source of energy used to maintain cellular homeostasis. This aspect of mitochondrial biology underlies their putative role in age-associated tissue dysfunction. Proper functioning of the electron transport chain (ETC), which is partially encoded by the extra-nuclear mitochondrial genome (mtDNA), is key to maintaining this energy production. The acquisition of de novo somatic mutations that interrupt the function of the ETC have long been associated with aging and common diseases of the elderly. Yet, despite over 30 years of study, the exact role(s) mtDNA mutations play in driving aging and its associated pathologies remains under considerable debate. Furthermore, even fundamental aspects of age-related mtDNA mutagenesis, such as when mutations arise during aging, where and how often they occur across tissues, and the specific mechanisms that give rise to them, remain poorly understood. In this review, we address the current understanding of the somatic mtDNA mutations, with an emphasis of when, where, and how these mutations arise during aging. Additionally, we highlight current limitations in our knowledge and critically evaluate the controversies stemming from these limitations. Lastly, we highlight new and emerging technologies that offer potential ways forward in increasing our understanding of somatic mtDNA mutagenesis in the aging process.

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FIGURE 1 Summary of genetic models reported to test the effects of mtDNA mutagenesis on aging. n. c. = no change, n. d. = not determined.
FIGURE 1 Summary of genetic models reported to test the effects of mtDNA mutagenesis on aging. n. c. = no change, n. d. = not determined.CC BY · PubMed Central
FIGURE 2 Bulk analysis of mtDNA mutations is unable to distinguish different scenarios with different physiological consequences. (A) Bulk sequencing of cells where left-25% of cells harbor a homoplasmic mutation (red) that causes OXPHOS dysfunction (orange/red-gradient) and the remainder contained only wild-type mtDNA (green) would have the same variant allele fraction (VAF) as bulk sequencing of a sample where Right-100% of cells contain a mutation that is, on average, at 25% heteroplasmy. In both cases, the apparent VAF would be 0.25, but the effect on tissue function would be different. Distinguishing between these two scenarios is only possible with single cell sequencing. (B) In this example, every cell is a clonal expansion harboring one of five possible homoplasmic mtDNA mutations (red, purple, grey, and cyan) that results in OXPHOS dysfunction. In bulk sequencing, no mutation would be seen to have a VAF >0.25, which is below the apparent phenotypic threshold.
FIGURE 2 Bulk analysis of mtDNA mutations is unable to distinguish different scenarios with different physiological consequences. (A) Bulk sequencing of cells where left-25% of cells harbor a homoplasmic mutation (red) that causes OXPHOS dysfunction (orange/red-gradient) and the remainder contained only wild-type mtDNA (green) would have the same variant allele fraction (VAF) as bulk sequencing of a sample where Right-100% of cells contain a mutation that is, on average, at 25% heteroplasmy. In both cases, the apparent VAF would be 0.25, but the effect on tissue function would be different. Distinguishing between these two scenarios is only possible with single cell sequencing. (B) In this example, every cell is a clonal expansion harboring one of five possible homoplasmic mtDNA mutations (red, purple, grey, and cyan) that results in OXPHOS dysfunction. In bulk sequencing, no mutation would be seen to have a VAF >0.25, which is below the apparent phenotypic threshold.CC BY · PubMed Central

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Metadata

Authors
Sanchez-Contreras, M., & Kennedy, S. R.
Venue
Frontiers in Aging
Publisher
Frontiers Media SA
Published
2022-01-10
Volume
2
ISSN
2673-6217
DOI
10.3389/fragi.2021.805126
PMC
PMC8896747
Cited by
60
References
28
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Human Genome Research Institute
  • National Cancer Institute
  • Congressionally Directed Medical Research Programs

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