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Cai, N. ; Gomez-Duran, A.* ; Yonova-Doing, E.* ; Kundu, K.* ; Burgess, A.I.* ; Golder, Z.J.* ; Calabrese, C.* ; Bonder, M.J.* ; Camacho, M.* ; Lawson, R.A.* ; Li, L.* ; Williams-Gray, C.H.* ; ICICLE-PD Study Group* ; di Angelantonio, E.* ; Roberts, D.J.* ; Watkins, N.A.* ; Ouwehand, W.H.* ; Butterworth, A.S.* ; Stewart, I.D.* ; Pietzner, M.* ; Wareham, N.J.* ; Langenberg, C.* ; Walter, K.* ; Rothwell, P.M.* ; Howson, J.M.M.* ; Stegle, O.* ; Chinnery, P.F.*

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

Nat. Med. 27, 1564-1575 (2021)
Publ. Version/Full Text DOI
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Differential Expression Analysis; Hereditary Optic Neuropathy; Oxidative-phosphorylation; Protein-synthesis; Point Mutation; Mtdna; Heteroplasmy; Population; Stress; Selection
ISSN (print) / ISBN 1078-8956
e-ISSN 1546-170X
Journal Nature medicine
Quellenangaben Volume: 27, Issue: 9, Pages: 1564-1575 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Helmholtz Pioneer Campus (HPC)
Grants Parkinson's UK
Cancer Research UK (CRUK)
British Heart Foundation (BHF)