Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations
Somatically acquired mitochondrial DNA (mtDNA) mutations accumulate with age, but the mechanisms and consequences of this accumulation are poorly understood. Here we show that transient injuries induce a burst of persistent mtDNA mutations that impair resilience to future injuries. mtDNA mutations suppressed energy-intensive nucleotide metabolism. Repletion of adenosine, but not other nucleotides, restored adenosine triphosphate generation, which required a nuclear-encoded purine biosynthetic enzyme, adenylate kinase 4 (AK4). Analysis of 369,912 UK Biobank participants revealed a graded association between mutation burden and chronic kidney disease severity as well as an independent increase in the risk of future acute kidney injury events (<i>P</i> < 10<sup>-7</sup>). Heteroplasmic mtDNA mutations may therefore reflect the cumulative effect of acute injuries to metabolically active cells, impairing major functions in a fashion amenable to nuclear-controlled purine biosynthesis.
Authors
- Joshua Gorham (ORCID: https://orcid.org/0000-0001-5969-4690)
- Vamsidhara Vemireddy (ORCID: https://orcid.org/0000-0001-7068-6640)
- Wen Shi (ORCID: https://orcid.org/0000-0002-2886-2361)
- Amanda J. Clark (ORCID: https://orcid.org/0000-0002-6550-730X)
- Heather Thiessen‐Philbrook (ORCID: https://orcid.org/0000-0003-2067-0514)
- Jonathan G. Seidman (ORCID: https://orcid.org/0000-0002-9082-3566)
- Monkol Lek (ORCID: https://orcid.org/0000-0003-1227-6293)
- Ronit Katz (ORCID: https://orcid.org/0000-0001-7723-7469)
- Samir M. Parikh (ORCID: https://orcid.org/0000-0002-1038-981X)
- Daniela Puiu (ORCID: https://orcid.org/0000-0002-2386-9265)
- Chirag R. Parikh (ORCID: https://orcid.org/0000-0001-9051-7385)
- Zsuzsanna K. Zsengellér (ORCID: https://orcid.org/0000-0002-4540-5728)
- Dan E. Arking (ORCID: https://orcid.org/0000-0001-8980-8695)
- Sushrut S. Waikar (ORCID: https://orcid.org/0000-0003-4004-326X)
- Vasantha Jotwani (ORCID: https://orcid.org/0000-0003-1913-3957)
- Nicole J. Lake (ORCID: https://orcid.org/0000-0003-4103-6387)
- Michael G. Shlipak (ORCID: https://orcid.org/0000-0002-9559-204X)
- Jonathan M. Dreyfuss (ORCID: https://orcid.org/0000-0001-7242-3991)
- Yun Soo Hong (ORCID: https://orcid.org/0000-0002-2438-5641)
- Hui Pan (ORCID: https://orcid.org/0000-0001-5748-7217)
- Yi Wang (ORCID: https://orcid.org/0000-0002-0291-5314)
- Huihui Huang (ORCID: https://orcid.org/0000-0002-8853-8379)
- Mark J. Sarnak
Institutions
- Boston Medical Center (US)
- Boston Children's Hospital (US)
- Tufts Medical Center (US)
- Joslin Diabetes Center (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Johns Hopkins University (US)
- University of California, San Francisco (US)
- University of Washington (US)
- Johns Hopkins Medicine (US)
- Yale University (US)
- San Francisco VA Health Care System (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Science
- Published
- 2025-09-04
- DOI
- https://doi.org/10.1126/science.adk7978
- Citations
- 3
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 2.42