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

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Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases
Nature Medicine ( IF 82.9 ) Pub Date : 2021-08-23 , DOI: 10.1038/s41591-021-01441-3
Na Cai _{1,

2,

3} , Aurora Gomez-Duran _{4,

5,

6} , Ekaterina Yonova-Doing _{7,

8} , Kousik Kundu ₁ , Annette I Burgess ₉ , Zoe J Golder _{4,

5} , Claudia Calabrese _{4,

5} , Marc J Bonder _{2,

10} , Marta Camacho ₄ , Rachael A Lawson ₁₁ , Lixin Li ₉ , Caroline H Williams-Gray ₄ , , Emanuele Di Angelantonio _{7,

12,

13,

14} , David J Roberts _{13,

15,

16} , Nick A Watkins ₁₇ , Willem H Ouwehand _{1,

12,

17,

18} , Adam S Butterworth _{7,

12,

13,

14} , Isobel D Stewart ₁₉ , Maik Pietzner ₁₉ , Nick J Wareham ₁₉ , Claudia Langenberg ₁₉ , John Danesh _{1,

7,

12,

13,

14} , Klaudia Walter ₁ , Peter M Rothwell ₉ , Joanna M M Howson _{7,

8} , Oliver Stegle _{2,

10,

20} , Patrick F Chinnery _{4,

5} , Nicole Soranzo _{1,

12,

13,

18,

21}

Affiliation

Human Genetics Department, Wellcome Sanger Institute (WT), Hinxton, UK.
European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
Helmholtz Pioneer Campus, Helmholtz Zentrum München, Neuherberg, Germany.
Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CIB-CSIC), Madrid, Spain.
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Primary Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK.
Wolfson Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
NHS Blood and Transplant-Oxford Centre, John Radcliffe Hospital, Oxford, UK.
Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
Department of Haematology, University of Cambridge, Cambridge, UK.
MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
European Molecular Biology Laboratory, Heidelberg, Germany.
Genomics Research Centre, Human Technopole, Milan, Italy.

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.

中文翻译：

线粒体 DNA 变异调节 N-甲酰甲硫氨酸、蛋白质稳态和迟发性人类疾病的风险

线粒体 DNA (mtDNA) 变异会影响迟发性人类疾病的风险，但其原因知之甚少。对 16,220 名健康供体中具有 mtDNA 变异的 5,689 种血液衍生生物标志物进行无假设分析，我们在这里表明定义 mtDNA 单倍群 Uk 和 H4 的变异调节循环N的水平-甲酰甲硫氨酸 (fMet)，启动线粒体蛋白质翻译。在人细胞质杂交（cybrid）细胞系中，fMet 通过转录、翻译后修饰和 N-degron 途径的蛋白水解，在多个水平上调节线粒体和胞质蛋白，从而消除 mtDNA 单倍群之间的已知差异。在另外 11,966 人中，fMet 水平导致全因死亡率和几种常见心血管疾病的疾病风险。总之，这些发现表明 fMet 通过对细胞蛋白质稳态的多效性作用在常见的年龄相关疾病中发挥关键作用。

更新日期：2021-08-23

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