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

被引：42

作者：

Cai, Na ^{[1
,2
,3
]}

Gomez-Duran, Aurora ^{[4
,5
,6
]}

Yonova-Doing, Ekaterina ^{[7
,8
]}

Kundu, Kousik ^{[1
]}

Burgess, Annette, I ^{[9
]}

Golder, Zoe J. ^{[4
,5
]}

Calabrese, Claudia ^{[4
,5
]}

Bonder, Marc J. ^{[2
,10
]}

Camacho, Marta ^{[4
]}

Lawson, Rachael A. ^{[11
]}

Li, Lixin ^{[9
]}

Williams-Gray, Caroline H. ^{[4
]}

Di Angelantonio, Emanuele ^{[7
,12
,13
,14
,15
]}

Roberts, David J. ^{[13
,16
,17
]}

Watkins, Nick A. ^{[18
]}

Ouwehand, Willem H. ^{[1
,12
,18
,19
]}

Butterworth, Adam S. ^{[7
,12
,13
,14
,15
]}

Stewart, Isobel D. ^{[20
]}

Pietzner, Maik ^{[20
]}

Wareham, Nick J. ^{[20
]}

Langenberg, Claudia ^{[20
]}

Danesh, John ^{[1
,7
,12
,13
,14
,15
]}

Walter, Klaudia ^{[1
]}

Rothwell, Peter M. ^{[9
]}

Howson, Joanna M. M. ^{[7
,8
]}

Stegle, Oliver ^{[2
,10
,21
]}

Chinnery, Patrick F. ^{[4
,5
]}

Soranzo, Nicole ^{[1
,12
,13
,19
,22
]}

机构：

[1] Wellcome Sanger Inst WT, Human Genet Dept, Hinxton, England

[2] European Bioinformat Inst EMBL EBI, Hinxton, England

[3] Helmholtz Zentrum Munchen, Helmholtz Pioneer Campus, Neuherberg, Germany

[4] Univ Cambridge, Sch Clin Med, Dept Clin Neurosci, Cambridge Biomed Campus, Cambridge, England

[5] Univ Cambridge, Med Res Council Mitochondrial Biol Unit, Cambridge Biomed Campus, Cambridge, England

[6] Consejo Super Invest Cient CIB CSIC, Ctr Invest Biol Margarita Salas, Madrid, Spain

[7] Univ Cambridge, British Heart Fdn Cardiovasc Epidemiol Unit, Dept Primary Publ Hlth & Primary Care, Cambridge, England

[8] Novo Nordisk Res Ctr Oxford, Dept Genet, Oxford, England

[9] Univ Oxford, John Radcliffe Hosp, Wolfson Ctr Prevent Stroke & Dementia, Nuffield Dept Clin Neurosci, Oxford, England

[10] German Canc Res Ctr, Div Computat Genom & Syst Genet, Heidelberg, Germany

[11] Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[12] Univ Cambridge, British Heart Fdn Ctr Res Excellence, Cambridge, England

[13] Univ Cambridge, Natl Inst Hlth Res Blood & Transplant Res Unit Do, Cambridge, England

[14] Wellcome Genome Campus, Hlth Data Res UK Cambridge, Cambridge, England

[15] Univ Cambridge, Cambridge, England

[16] John Radcliffe Hosp, NHS Blood & Transplant Oxford Ctr, Oxford, England

[17] Univ Oxford, Radcliffe Dept Med, Oxford, England

[18] Cambridge Biomed Campus, NHS Blood & Transplant, Cambridge, England

[19] Univ Cambridge, Dept Haematol, Cambridge, England

[20] Univ Cambridge, MRC Epidemiol Unit, Cambridge, England

[21] European Mol Biol Lab, Heidelberg, Germany

[22] Human Technopole, Genom Res Ctr, Milan, Italy

来源：

NATURE MEDICINE | 2021年 / 27卷 / 09期

基金：

英国医学研究理事会; 英国经济与社会研究理事会; 英国惠康基金; 英国工程与自然科学研究理事会;

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; HEREDITARY OPTIC NEUROPATHY; OXIDATIVE-PHOSPHORYLATION; PROTEIN-SYNTHESIS; POINT MUTATION; MTDNA; HETEROPLASMY; POPULATION; STRESS; SELECTION;

D O I：

10.1038/s41591-021-01441-3

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The association between certain mitochondrial DNA variants and increased risk of late-onset diseases in humans could be explained by a direct role of mitochondrial DNA in the regulation of cellular proteostasis. 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.

引用

页码：1564 / +

页数：27

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