Deleterious Heteroplasmic Mitochondrial Mutations are associated With an increased Risk of Overall and Cancer-Specific Mortality

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

Publication Date

9-30-2023

Journal

Nature Communications

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.

Keywords

Humans, Mitochondria, DNA, Mitochondrial, Heteroplasmy, Leukemia, Mutation