Mitochondrial DNA variants modulate proteostasis through N-formylmethionine

Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons are poorly understood. Undertaking an 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 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.Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR Cambridge Biomedical Research Centre (BRC 1215-20014)*. The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR Cambridge BRC (BRC-1215-20014)*. A complete list of the investigators and contributors to the INTERVAL trial is provided in Di Angelantonio E, et al. Lancet. 2017 Nov 25;390(10110):2360-2371. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome