TY - JOUR
T1 - Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
AU - Hong, Yun Soo
AU - Battle, Stephanie L.
AU - Shi, Wen
AU - Puiu, Daniela
AU - Pillalamarri, Vamsee
AU - Xie, Jiaqi
AU - Pankratz, Nathan
AU - Lake, Nicole J.
AU - Lek, Monkol
AU - Rotter, Jerome I.
AU - Rich, Stephen S.
AU - Kooperberg, Charles
AU - Reiner, Alex P.
AU - Auer, Paul L.
AU - Heard-Costa, Nancy
AU - Liu, Chunyu
AU - Lai, Meng
AU - Murabito, Joanne M.
AU - Levy, Daniel
AU - Grove, Megan L.
AU - Alonso, Alvaro
AU - Gibbs, Richard
AU - Dugan-Perez, Shannon
AU - Gondek, Lukasz P.
AU - Guallar, Eliseo
AU - Arking, Dan E.
N1 - Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-41785-7
DO - 10.1038/s41467-023-41785-7
M3 - Article
C2 - 37777527
AN - SCOPUS:85172827195
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6113
ER -
