Biomarker of cardiovascular disease
MtDNA-CN has proven to be a biomarker of cardiovascular disease in several large epidemiological studies, with studies often assuming that such relationships are attributable to pathological processes including mitochondrial dysfunction, oxidative stress and inflammation.
Consistent with previous GWAS findings, our genetic analyses confirm that mtDNA-CN indeed reflects specific mitochondrial functions, but perhaps not the ones commonly attributable to mtDNA-CN. Primarily, differences in mtDNA-CN reflect mitochondrial processes related to dNTP metabolism and the replication, maintenance, and organization of mtDNA.
Secondarily, genes involved in mitochondrial biogenesis, metabolism, oxidative phosphorylation, and protein homeostasis were also identified but do not represent the main constituents. The observed enrichment in common variant associations within mtDNA depletion genes further reinforces the notion that differences in mtDNA-CN first and foremost reflect perturbations in mtDNA-related processes.