Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases.
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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.
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1546-170X
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Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (MR/R007446/1)
Wellcome Trust (101876/Z/13/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (212219/Z/18/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (RE/18/1/34212)
British Heart Foundation (RG/18/13/33946)
MRC (MC_UU_00006/1)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MR/N003284/1)
Medical Research Council (G1000143)
Medical Research Council (G0401527)
Medical Research Council (MC_UU_00015/7)
Medical Research Council (G0401527/1)
Cancer Research Uk (None)
Medical Research Council (MC_PC_13048)