| Literature DB >> 34426706 |
Na Cai1,2,3, Aurora Gomez-Duran4,5,6, Ekaterina Yonova-Doing7,8, Kousik Kundu1, Annette I Burgess9, Zoe J Golder4,5, Claudia Calabrese4,5, Marc J Bonder2,10, Marta Camacho4, Rachael A Lawson11, Lixin Li9, Caroline H Williams-Gray4, Emanuele Di Angelantonio7,12,13,14, David J Roberts13,15,16, Nick A Watkins17, Willem H Ouwehand1,12,17,18, Adam S Butterworth7,12,13,14, Isobel D Stewart19, Maik Pietzner19, Nick J Wareham19, Claudia Langenberg19, John Danesh1,7,12,13,14, Klaudia Walter1, Peter M Rothwell9, Joanna M M Howson7,8, Oliver Stegle20,21,22, Patrick F Chinnery23,24, Nicole Soranzo25,26,27,28,29.
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.Entities:
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Year: 2021 PMID： 34426706 DOI： 10.1038/s41591-021-01441-3
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 87.241