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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.* ; Soranzo, N.*

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

Nat. Med. 27, 1564-1575 (2021)
Postprint DOI PMC
Open Access Green
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Differential Expression Analysis; Hereditary Optic Neuropathy; Oxidative-phosphorylation; Protein-synthesis; Point Mutation; Mtdna; Heteroplasmy; Population; Stress; Selection
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 1078-8956
e-ISSN 1546-170X
Zeitschrift Nature medicine
Quellenangaben Band: 27, Heft: 9, Seiten: 1564-1575 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Pioneer Campus (HPC)
POF Topic(s) 30202 - Environmental Health
Forschungsfeld(er) Pioneer Campus
PSP-Element(e) G-510007-001
Förderungen Parkinson's UK
Cancer Research UK (CRUK)
British Heart Foundation (BHF)
DOI 10.1038/s41591-021-01441-3
WOS ID WOS:000687518700003
Scopus ID 85114631926
PubMed ID 34426706
Erfassungsdatum 2021-10-01
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