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

Authors :
Medical Research Council (UK)
Engineering and Physical Sciences Research Council (UK)
Economic and Social Research Council (UK)
Department of Health & Social Care (UK)
Wellcome Trust
University of Cambridge
European Commission
NIHR Biomedical Research Centre (UK)
Cai, Na [0000-0001-7496-2075]
Gómez-Durán, Aurora [0000-0002-5895-6860]
Kundu, Kousik [0000-0002-1019-8351]
Burgess, Annette I. [0000-0003-3442-8083]
Calabrese, Claudia [0000-0002-8941-2620]
Camacho, Marta [0000-0002-1490-5703]
Lawson, Rachael A. [0000-0003-2608-8285]
Williams-Gray, Caroline H. [0000-0002-2648-9743]
Di Angelantonio, Emanuele [0000-0001-8776-6719]
Butterworth, Adam S. [0000-0002-6915-9015]
Pietzner, Maik [0000-0003-3437-9963]
Wareham, Nicholas J. [0000-0003-1422-2993]
Langenberg, Claudia [0000-0002-5017-7344]
Danesh, John [0000-0003-1158-6791]
Walter, Klaudia [0000-0003-4448-0301]
Rothwell, Peter M. [0000-0001-9739-9211]
Howson, Joanna M. M. [0000-0001-7618-0050]
Stegle, Oliver [0000-0002-8818-7193]
Chinnery, Patrick F. [0000-0002-7065-6617]
Soranzo, Nicole [0000-0003-1095-3852]
Cai, Na
Gómez-Durán, Aurora
Yonova-Doing, Ekaterina
Kundu, Kousik
Burgess, Annette I.
Golder, Zoe J.
Calabrese, Claudia
Bonder, Marc J.
Camacho, Marta
Lawson, Rachael A.
Li, Lixin
Williams-Gray, Caroline H.
ICICLE-PD Study Group
Di Angelantonio, Emanuele
Roberts, David J.
Watkins, Nick A.
Ouwehand, Willem H.
Butterworth, Adam S.
Stewart, Isobel D.
Pietzner, Maik
Wareham, Nicholas J.
Langenberg, Claudia
Danesh, John
Walter, Klaudia
Rothwell, Peter M.
Howson, Joanna M. M.
Stegle, Oliver
Chinnery, Patrick F.
Soranzo, Nicole
Medical Research Council (UK)
Engineering and Physical Sciences Research Council (UK)
Economic and Social Research Council (UK)
Department of Health & Social Care (UK)
Wellcome Trust
University of Cambridge
European Commission
NIHR Biomedical Research Centre (UK)
Cai, Na [0000-0001-7496-2075]
Gómez-Durán, Aurora [0000-0002-5895-6860]
Kundu, Kousik [0000-0002-1019-8351]
Burgess, Annette I. [0000-0003-3442-8083]
Calabrese, Claudia [0000-0002-8941-2620]
Camacho, Marta [0000-0002-1490-5703]
Lawson, Rachael A. [0000-0003-2608-8285]
Williams-Gray, Caroline H. [0000-0002-2648-9743]
Di Angelantonio, Emanuele [0000-0001-8776-6719]
Butterworth, Adam S. [0000-0002-6915-9015]
Pietzner, Maik [0000-0003-3437-9963]
Wareham, Nicholas J. [0000-0003-1422-2993]
Langenberg, Claudia [0000-0002-5017-7344]
Danesh, John [0000-0003-1158-6791]
Walter, Klaudia [0000-0003-4448-0301]
Rothwell, Peter M. [0000-0001-9739-9211]
Howson, Joanna M. M. [0000-0001-7618-0050]
Stegle, Oliver [0000-0002-8818-7193]
Chinnery, Patrick F. [0000-0002-7065-6617]
Soranzo, Nicole [0000-0003-1095-3852]
Cai, Na
Gómez-Durán, Aurora
Yonova-Doing, Ekaterina
Kundu, Kousik
Burgess, Annette I.
Golder, Zoe J.
Calabrese, Claudia
Bonder, Marc J.
Camacho, Marta
Lawson, Rachael A.
Li, Lixin
Williams-Gray, Caroline H.
ICICLE-PD Study Group
Di Angelantonio, Emanuele
Roberts, David J.
Watkins, Nick A.
Ouwehand, Willem H.
Butterworth, Adam S.
Stewart, Isobel D.
Pietzner, Maik
Wareham, Nicholas J.
Langenberg, Claudia
Danesh, John
Walter, Klaudia
Rothwell, Peter M.
Howson, Joanna M. M.
Stegle, Oliver
Chinnery, Patrick F.
Soranzo, Nicole
Publication Year :
2021

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.

Details

Database :
OAIster
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1286581034
Document Type :
Electronic Resource