Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases.

DOI: http://doi.org/10.1038/s41591-021-01441-3 Journal: Nat Med E-pub date: 1 Sep 2021 Authors: N Cai, A Gomez-Duran, E Yonova-Doing, K Kundu, AI Burgess, ZJ Golder, C Calabrese, MJ Bonder, M Camacho, RA Lawson, L Li, CH Williams-Gray, ICICLE-PD Study Group, E Di Angelantonio, DJ Roberts, NA Watkins, WH Ouwehand, AS Butterworth, ID Stewart, M Pietzner, NJ Wareham, C Langenberg, J Danesh, K Walter, PM Rothwell, JMM Howson, O Stegle, PF Chinnery, N Soranzo

Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases.

Abstract:

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.