The multi-tissue landscape of somatic mtDNA mutations indicates tissue-specific accumulation and removal in aging
Abstract
Accumulation of somatic mutations in the mitochondrial genome (mtDNA) has long been proposed as a possible mechanism of mitochondrial and tissue dysfunction that occurs during aging. A thorough characterization of age-associated mtDNA somatic mutations has been hampered by the limited ability to detect low-frequency mutations. Here, we used Duplex Sequencing on eight tissues of an aged mouse cohort to detect >89,000 independent somatic mtDNA mutations and show significant tissue-specific increases during aging across all tissues examined which did not correlate with mitochondrial content and tissue function. G→A/C→T substitutions, indicative of replication errors and/or cytidine deamination, were the predominant mutation type across all tissues and increased with age, whereas G→T/C→A substitutions, indicative of oxidative damage, were the second most common mutation type, but did not increase with age regardless of tissue. We also show that clonal expansions of mtDNA mutations with age is tissue- and mutation type-dependent. Unexpectedly, mutations associated with oxidative damage rarely formed clones in any tissue and were significantly reduced in the hearts and kidneys of aged mice treated at late age with elamipretide or nicotinamide mononucleotide. Thus, the lack of accumulation of oxidative damage-linked mutations with age suggests a life-long dynamic clearance of either the oxidative lesions or mtDNA genomes harboring oxidative damage.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 17, 2023
- Source ID
- 10.7554/elife.83395
Entities
People
- Brendan F Kohrn
- David J. Marcinek
- Hyeon Jeong Kim
- James B. Hurley
- Jeanne Fredrickson
- Jeremy A Whitson
- Kristine Tsantilas
- Mariya T. Sweetwyne
- Matthew D Campbell
- Megan M Nguyen
- Michael J. Hipp
- Monica Sanchez-Contreras
- Peter S. Rabinovitch
- Scott R. Kennedy
Organizations
- Congressionally Directed Medical Research Programs
- National Cancer Institute
- National Human Genome Research Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute on Aging
- University of Washington