Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality

Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplas...

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Published in:Nature communications Vol. 14; no. 1; pp. 6113 - 16
Main Authors: Hong, Yun Soo, Battle, Stephanie L., Shi, Wen, Puiu, Daniela, Pillalamarri, Vamsee, Xie, Jiaqi, Pankratz, Nathan, Lake, Nicole J., Lek, Monkol, Rotter, Jerome I., Rich, Stephen S., Kooperberg, Charles, Reiner, Alex P., Auer, Paul L., Heard-Costa, Nancy, Liu, Chunyu, Lai, Meng, Murabito, Joanne M., Levy, Daniel, Grove, Megan L., Alonso, Alvaro, Gibbs, Richard, Dugan-Perez, Shannon, Gondek, Lukasz P., Guallar, Eliseo, Arking, Dan E.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 30.09.2023
Nature Publishing Group
Nature Portfolio
Subjects:
631/208/721
631/67/1990/283
631/80/642/333
692/308/2056
Age related diseases
Biobanks
Cancer
Deoxyribonucleic acid
DNA
DNA, Mitochondrial - genetics
Genomes
Heterogeneity
Heteroplasmy
Humanities and Social Sciences
Humans
Leukemia
Leukemia - genetics
Mitochondria
Mitochondria - genetics
Mitochondrial DNA
Mortality
multidisciplinary
Mutation
Nucleotides
Science
Science (multidisciplinary)
Somatic cells
United Kingdom > UK
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia. Mitochondrial DNA is known to exhibit heterogeneity of variants, even within a single cell. Here, the authors assessed this heteroplasmy of mitochondrial DNA within the UK Biobank cohort and showed that the presence of heteroplasmy and a functional score generated from heteroplasmic SNVs were associated with all-cause mortality and certain cancers.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-41785-7