TY - JOUR
T1 - Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases
AU - ICICLE-PD Study Group
AU - Cai, Na
AU - Gomez-Duran, Aurora
AU - Yonova-Doing, Ekaterina
AU - Kundu, Kousik
AU - Burgess, Annette I.
AU - Golder, Zoe J.
AU - Calabrese, Claudia
AU - Bonder, Marc J.
AU - Camacho, Marta
AU - Lawson, Rachael A.
AU - Li, Lixin
AU - Williams-Gray, Caroline H.
AU - Di Angelantonio, Emanuele
AU - Roberts, David J.
AU - Watkins, Nick A.
AU - Ouwehand, Willem H.
AU - Butterworth, Adam S.
AU - Stewart, Isobel D.
AU - Pietzner, Maik
AU - Wareham, Nick J.
AU - Langenberg, Claudia
AU - Danesh, John
AU - Walter, Klaudia
AU - Rothwell, Peter M.
AU - Howson, Joanna M.M.
AU - Stegle, Oliver
AU - Chinnery, Patrick F.
AU - Soranzo, Nicole
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85114631926&partnerID=8YFLogxK
U2 - 10.1038/s41591-021-01441-3
DO - 10.1038/s41591-021-01441-3
M3 - Article
C2 - 34426706
AN - SCOPUS:85114631926
SN - 1078-8956
VL - 27
SP - 1564
EP - 1575
JO - Nature Medicine
JF - Nature Medicine
IS - 9
ER -
