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

Na Cai^#^{1

2

3}, Aurora Gomez-Duran^#^{4

5

6}, Ekaterina Yonova-Doing^{7

8}, Kousik Kundu¹, Annette I Burgess⁹, Zoe J Golder^{4

5}, Claudia Calabrese^{4

5}, Marc J Bonder^{2

10}, Marta Camacho⁴, Rachael A Lawson¹¹, Lixin Li⁹, Caroline H Williams-Gray⁴; ICICLE-PD Study Group; Emanuele Di Angelantonio^{7

12

13

14}, David J Roberts^{13

15

16}, Nick A Watkins¹⁷, Willem H Ouwehand^{1

12

17

18}, Adam S Butterworth^{7

12

13

14}, Isobel D Stewart¹⁹, Maik Pietzner¹⁹, Nick J Wareham¹⁹, Claudia Langenberg¹⁹, John Danesh^{1

7

12

13

14}, Klaudia Walter¹, Peter M Rothwell⁹, Joanna M M Howson^{7

8}, Oliver Stegle^{20

21

22}, Patrick F Chinnery^{23

24}, Nicole Soranzo^{25

26

27

28

29}

Affiliations

¹ Human Genetics Department, Wellcome Sanger Institute (WT), Hinxton, UK.
² European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
³ Helmholtz Pioneer Campus, Helmholtz Zentrum München, Neuherberg, Germany.
⁴ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
⁵ Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
⁶ Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CIB-CSIC), Madrid, Spain.
⁷ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Primary Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁸ Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK.
⁹ Wolfson Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
¹⁰ Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
¹² British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
¹³ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
¹⁴ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹⁵ NHS Blood and Transplant-Oxford Centre, John Radcliffe Hospital, Oxford, UK.
¹⁶ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁷ NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
¹⁸ Department of Haematology, University of Cambridge, Cambridge, UK.
¹⁹ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
²⁰ European Bioinformatics Institute (EMBL-EBI), Hinxton, UK. o.stegle@dkfz-heidelberg.de.
²¹ Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. o.stegle@dkfz-heidelberg.de.
²² European Molecular Biology Laboratory, Heidelberg, Germany. o.stegle@dkfz-heidelberg.de.
²³ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. pfc25@cam.ac.uk.
²⁴ Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. pfc25@cam.ac.uk.
²⁵ Human Genetics Department, Wellcome Sanger Institute (WT), Hinxton, UK. ns6@sanger.ac.uk.
²⁶ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK. ns6@sanger.ac.uk.
²⁷ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK. ns6@sanger.ac.uk.
²⁸ Department of Haematology, University of Cambridge, Cambridge, UK. ns6@sanger.ac.uk.
²⁹ Genomics Research Centre, Human Technopole, Milan, Italy. ns6@sanger.ac.uk.

^# Contributed equally.

PMID: 34426706
DOI: 10.1038/s41591-021-01441-3

Free article

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

Na Cai et al. Nat Med. 2021 Sep.

Free article

. 2021 Sep;27(9):1564-1575.

doi: 10.1038/s41591-021-01441-3. Epub 2021 Aug 23.

Authors

Affiliations

¹ Human Genetics Department, Wellcome Sanger Institute (WT), Hinxton, UK.
² European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
³ Helmholtz Pioneer Campus, Helmholtz Zentrum München, Neuherberg, Germany.
⁴ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
⁵ Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
⁶ Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CIB-CSIC), Madrid, Spain.
⁷ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Primary Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁸ Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK.
⁹ Wolfson Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
¹⁰ Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
¹² British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
¹³ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
¹⁴ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹⁵ NHS Blood and Transplant-Oxford Centre, John Radcliffe Hospital, Oxford, UK.
¹⁶ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁷ NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
¹⁸ Department of Haematology, University of Cambridge, Cambridge, UK.
¹⁹ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
²⁰ European Bioinformatics Institute (EMBL-EBI), Hinxton, UK. o.stegle@dkfz-heidelberg.de.
²¹ Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. o.stegle@dkfz-heidelberg.de.
²² European Molecular Biology Laboratory, Heidelberg, Germany. o.stegle@dkfz-heidelberg.de.
²³ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. pfc25@cam.ac.uk.
²⁴ Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. pfc25@cam.ac.uk.
²⁵ Human Genetics Department, Wellcome Sanger Institute (WT), Hinxton, UK. ns6@sanger.ac.uk.
²⁶ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK. ns6@sanger.ac.uk.
²⁷ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK. ns6@sanger.ac.uk.
²⁸ Department of Haematology, University of Cambridge, Cambridge, UK. ns6@sanger.ac.uk.
²⁹ Genomics Research Centre, Human Technopole, Milan, Italy. ns6@sanger.ac.uk.

^# Contributed equally.

PMID: 34426706
DOI: 10.1038/s41591-021-01441-3

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.

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Comment in

A role for mitochondrial DNA in cellular proteostasis.
Barranco C. Barranco C. Nat Rev Genet. 2021 Nov;22(11):690. doi: 10.1038/s41576-021-00418-9. Nat Rev Genet. 2021. PMID: 34518658 No abstract available.
The subtle long-lasting burden of mitochondrial DNA variants.
Hasegawa S, Inagi R. Hasegawa S, et al. Nat Rev Nephrol. 2022 Jan;18(1):4-5. doi: 10.1038/s41581-021-00500-9. Nat Rev Nephrol. 2022. PMID: 34663981 No abstract available.

References

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1. Giles, R. E., Blanc, H., Cann, H. M. & Wallace, D. C. Maternal inheritance of human mitochondrial DNA. Proc. Natl Acad. Sci. USA 77, 6715–6719 (1980). - PubMed - PMC - DOI
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Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases

Affiliations

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

Authors

Affiliations

Abstract

Comment in

References

Publication types

MeSH terms

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Grants and funding

LinkOut - more resources

Full Text Sources