Deleterious mitochondrial heteroplasmies exhibit increased longitudinal change in variant allele fraction

A common feature of human aging is the acquisition of somatic mutations, and mitochondria are particularly prone to mutation, leading to a state of mitochondrial DNA heteroplasmy. Cross-sectional studies have demonstrated that detection of heteroplasmy increases with participant age, a phenomenon that has been attributed to genetic drift. In this large-scale longitudinal study, we measured heteroplasmy in two prospective cohorts (combined <i>n</i> = 1404) at two time points (mean time between visits, 8.6 years), demonstrating that deleterious heteroplasmies were more likely to increase in variant allele fraction (VAF). We further demonstrated that increase in VAF was associated with increased risk of overall mortality. These results challenge the claim that somatic mtDNA mutations arise mainly due to genetic drift, instead suggesting a role for positive selection for a subset of predicted deleterious mutations at the cellular level, despite a negative impact of these mutations on overall mortality.

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Publication Details

Journal
iScience
Published
2025-05-06
DOI
https://doi.org/10.1016/j.isci.2025.112590
Citations
6
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
4.84

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article

Deleterious mitochondrial heteroplasmies exhibit increased longitudinal change in variant allele fraction

Wen Shi, Kent D. Taylor, Joyce B. J. van Meurs, Daniela Puiu et al.
6 citations
iScience
Mitochondrial Function and Pathology
4.84
article

Deleterious mitochondrial heteroplasmies exhibit increased longitudinal change in variant allele fraction

Wen Shi, Kent D. Taylor, Joyce B. J. van Meurs, Daniela Puiu, Jiaqi Xie, Joel S. Bader, Lieke M Kuiper, Dan E. Arking, Linda Broer, Charles Newcomb, Pascal Arp, Stephen S. Rich, Joost Verlouw, Eliseo Güallar, Yun Soo Hong, Jerome I. Rotter
article en
6 citations

Abstract

A common feature of human aging is the acquisition of somatic mutations, and mitochondria are particularly prone to mutation, leading to a state of mitochondrial DNA heteroplasmy. Cross-sectional studies have demonstrated that detection of heteroplasmy increases with participant age, a phenomenon that has been attributed to genetic drift. In this large-scale longitudinal study, we measured heteroplasmy in two prospective cohorts (combined <i>n</i> = 1404) at two time points (mean time between visits, 8.6 years), demonstrating that deleterious heteroplasmies were more likely to increase in variant allele fraction (VAF). We further demonstrated that increase in VAF was associated with increased risk of overall mortality. These results challenge the claim that somatic mtDNA mutations arise mainly due to genetic drift, instead suggesting a role for positive selection for a subset of predicted deleterious mutations at the cellular level, despite a negative impact of these mutations on overall mortality.

iScienceVol. 28(6)
Johns Hopkins University (US), Johns Hopkins Medicine (US), UCLA Medical Center (US), Erasmus MC (NL), National Institute for Public Health and the Environment (NL), Harbor–UCLA Medical Center (US), University of Virginia (US), New York University (US), Erasmus University Rotterdam (NL)
National Institute on Aging, NHLBI Division of Intramural Research
Zero hunger
Openalex Percentile: Top 5%
Mitochondrial Function and Pathology
4.84
DOIOpen Access PDFOpenAlex
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