Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases.
Cai N., Gomez-Duran A., Yonova-Doing E., Kundu K., Burgess AI., Golder ZJ., Calabrese C., Bonder MJ., Camacho M., Lawson RA., Li L., Williams-Gray CH., ICICLE-PD Study Group None., Di Angelantonio E., Roberts DJ., Watkins NA., Ouwehand WH., Butterworth AS., Stewart ID., Pietzner M., Wareham NJ., Langenberg C., Danesh J., Walter K., Rothwell PM., Howson JMM., Stegle O., Chinnery PF., Soranzo N.
Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis.