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

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 and Dan E. Arking ()
Additional contact information
Yun Soo Hong: Johns Hopkins University School of Medicine
Stephanie L. Battle: Johns Hopkins University School of Medicine
Wen Shi: Johns Hopkins University School of Medicine
Daniela Puiu: Johns Hopkins University
Vamsee Pillalamarri: Johns Hopkins University School of Medicine
Jiaqi Xie: Johns Hopkins University School of Medicine
Nathan Pankratz: University of Minnesota
Nicole J. Lake: Yale School of Medicine
Monkol Lek: Yale School of Medicine
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Stephen S. Rich: University of Virginia
Charles Kooperberg: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
Alex P. Reiner: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
Paul L. Auer: Division of Biostatistics, Institute for Health & Equity, and Cancer Center, Medical College of Wisconsin
Nancy Heard-Costa: Boston University Chobanian & Avedisian School of Medicine
Chunyu Liu: Framingham Heart Study
Meng Lai: Boston University
Joanne M. Murabito: Boston University Chobanian & Avedisian School of Medicine
Daniel Levy: National Heart, Lung, and Blood Institute, NIH
Megan L. Grove: The University of Texas Health Science Center at Houston
Alvaro Alonso: Emory University
Richard Gibbs: Human Genome Sequencing Center, Baylor College of Medicine
Shannon Dugan-Perez: Human Genome Sequencing Center, Baylor College of Medicine
Lukasz P. Gondek: Johns Hopkins University
Eliseo Guallar: Johns Hopkins University Bloomberg School of Public Health
Dan E. Arking: Johns Hopkins University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41785-7

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