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

Lookup NU author(s): Dr Rachael LawsonORCiD



This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature, 2021.

For re-use rights please refer to the publisher's terms and conditions.


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.

Publication metadata

Author(s): Cai N, Gomez Duran A, Yonova Doing E, Kundu K, Burgess AI, Golder ZJ, Calabrese C, Bonder MJ, Camacho M, Lawson RA, Williams Gray CH, Di Angelantonio E, Roberts DJ, Watkins NA, Ouwehand WH, Butterworth AS, Stewart ID, Pietzner M, Wareham NJ, Langenberg C, Danesh J, Walter K, Rothwell WM, Howson JMM, Stegle O, Chinnery PF, Soranzo N

Publication type: Article

Publication status: Published

Journal: Nature Medicine

Year: 2021

Volume: 27

Pages: 1564-1575

Print publication date: 01/09/2021

Online publication date: 23/08/2021

Acceptance date: 15/06/2021

Date deposited: 15/06/2021

ISSN (print): 1078-8956

ISSN (electronic): 1546-170X

Publisher: Nature


DOI: 10.1038/s41591-021-01441-3


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