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

Abstract

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.

• Authors: Yun Soo Hong, Stephanie L Battle, Wen Shi, Daniela Puiu, Vamsee Pillalamarri, Jiaqi Xie, Nathan Pankratz, Nicole J Lake, Monkol Lek, Jerome I Rotter, Stephen S Rich, Charles Kooperberg, Alex P Reiner, Paul L Auer, Nancy Heard-Costa, Chunyu Liu, Meng Lai, Joanne M Murabito, Daniel Levy, Megan L Grove, Alvaro Alonso, Richard Gibbs, Shannon Dugan-Perez, Lukasz P Gondek, Eliseo Guallar, Dan E Arking
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 6113 (09 30 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 37777527 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. Springer Nature Limited.

Chemical References

• DNA, Mitochondrial

Topics

• Humans
• Mitochondria (genetics)
• DNA, Mitochondrial (genetics)
• Heteroplasmy
• Leukemia (genetics)
• Mutation