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Peer-reviewedCC BYNature

Mechanism of age-related accumulation of mtDNA mutations in human blood

  • Rahul Gupta1,2,3,4,5,6
  • Timothy Durham7,8,9
  • Grant Chau10,11,12
  • Masahiro Kanai13,11
  • Md Mesbah Uddin14,15,11
  • Wenhan Lu10,11,12
  • M. Austin Argentieri10,11,12
  • Konrad J. Karczewski10,16,11
  • Daniel P. Howrigan10,11,12
  • Pradeep Natarajan14,17,15,11
  • Wei Zhou11,18,12
  • Benjamin M. Neale19,20,21,22
1 more authors
  • Vamsi Krishna Mootha23,24,25,26
26 affiliations
  1. 1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected]
  2. 2Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. [email protected]
  3. 3Harvard Medical School, Boston, MA, USA. [email protected]
  4. 4Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA, USA. [email protected]
  5. 5Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  6. 6Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  7. 7Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
  8. 8Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA, USA
  9. 9Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  10. 10Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
  11. 11Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  12. 12Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  13. 13Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA
  14. 14Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
  15. 15Heart and Vascular Institute, Mass General Brigham, Boston, MA, USA
  16. 16Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  17. 17Harvard Medical School, Boston, MA, USA
  18. 18Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  19. 19Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected]
  20. 20Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  21. 21Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  22. 22Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  23. 23Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. [email protected]
  24. 24Harvard Medical School, Boston, MA, USA. [email protected]
  25. 25Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA, USA. [email protected]
  26. 26Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
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Abstract

Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing 1 . Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT , TCL1A and SMC4 , all of which have been linked to clonal haematopoiesis (CH) 2 . Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which ‘cryptic’ mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT , CH and observed accrual of mtDNA mutations.

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Cite

BibTeXRIS
BibTeX
@article{gupta2026mechanism,
  title = {{Mechanism of age-related accumulation of mtDNA mutations in human blood}},
  author = {Rahul Gupta and Timothy Durham and Grant Chau and Masahiro Kanai and Md Mesbah Uddin and Wenhan Lu and M. Austin Argentieri and Konrad J. Karczewski and Daniel P. Howrigan and Pradeep Natarajan and Wei Zhou and Benjamin M. Neale and Vamsi Krishna Mootha},
  journal = {Nature},
  year = {2026},
  month = may,
  doi = {10.1038/s41586-026-10569-6},
  url = {https://doi.org/10.1038/s41586-026-10569-6},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Mechanism of age-related accumulation of mtDNA mutations in human blood
AU  - Rahul Gupta
AU  - Timothy Durham
AU  - Grant Chau
AU  - Masahiro Kanai
AU  - Md Mesbah Uddin
AU  - Wenhan Lu
AU  - M. Austin Argentieri
AU  - Konrad J. Karczewski
AU  - Daniel P. Howrigan
AU  - Pradeep Natarajan
AU  - Wei Zhou
AU  - Benjamin M. Neale
AU  - Vamsi Krishna Mootha
PY  - 2026
DA  - 2026/05/27
JO  - Nature
DO  - 10.1038/s41586-026-10569-6
UR  - https://doi.org/10.1038/s41586-026-10569-6
AB  - Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing 1 . Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT , TCL1A and SMC4 , all of which have been linked to clonal haematopoiesis (CH) 2 . Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which ‘cryptic’ mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT , CH and observed accrual of mtDNA mutations.
SN  - 0028-0836
SN  - 1476-4687
ER  -