Deleterious heteroplasmic mitochondrial mutations increase risk of overall and cancer-specific mortality

Mitochondria are involved in energetic, biosynthetic, and homeostatic processes in eukaryotic cells. Mitochondria carry their own circular genome and disruption of the quantity or quality of mitochondrial genome is associated with various aging-related diseases1-3. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1,000s to 10,000s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbor a particular variant. We used MitoHPC, a bioinformatics pipeline, to accurately quantify mtDNA heteroplasmy from whole genome sequencing data in 194,871 participants in the UK Biobank. We found that the presence of heteroplasmy is associated with an increased risk of all-cause mortality (adjusted hazard ratio [aHR] 1.50-fold; 95% confidence interval [CI] 1.14, 1.98, when comparing participants with 4 or more heteroplasmies to those without any heteroplasmy). In addition, we functionally characterized mtDNA single nucleotide variants (SNVs) using a novel constraint-based score, Mitochondrial local constraint (MLC) score sum (MSS), which demonstrated that SNVs at highly constrained sites were strongly associated with all-cause mortality (aHR for a 1-unit increase in MSS 1.28; 95% CI 1.20, 1.37) and cancer-related mortality (aHR 1.36; 95% CI 1.24,1.49), particularly lung and breast cancers, lymphoma, and leukemia. MSS was also associated with prevalence and incidence of lung cancer, lymphoma, and leukemia. Moreover, among individuals with prevalent leukemia, high MSS was strongly associated with leukemia mortality (adjusted HR 4.03; 95% CI 1.34, 12.11). These results indicate that mitochondria may have a functional role in certain cancers and mitochondrial heteroplasmic SNVs have the potential to serve as a prognostic markers for cancer incidence and outcome, especially for leukemia.