| Title: | Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations |
| Journal: | Science |
| Published: | 4 Sep 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40906782/ |
| DOI: | https://doi.org/10.1126/science.adk7978 |
| URL: | https://pmc.ncbi.nlm.nih.gov/articles/PMC12892176/ |
Publication 19565
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Abstract
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 (P < 10-7). 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.</p>
16 Keywords
- Adenosine
- Adenosine Triphosphate
- Adenylate Kinase
- Aged
- Aging
- DNA, Mitochondrial
- Energy Metabolism
- Female
- Heteroplasmy
- Humans
- Male
- Middle Aged
- Mitochondria
- Mutation
- Purines
- Renal Insufficiency, Chronic
23 Authors
- Huihui Huang
- Yi Wang
- Zsuzsanna K. Zsengeller
- Joshua M. Gorham
- Vamsidhara Vemireddy
- Amanda J. Clark
- Hui Pan
- Jonathan M. Dreyfuss
- Vasantha Jotwani
- Michael G. Shlipak
- Mark J. Sarnak
- Chirag R. Parikh
- Heather Thiessen-Philbrook
- Ronit Katz
- Sushrut S. Waikar
- Nicole J. Lake
- Monkol Lek
- Wen Shi
- Daniela Puiu
- Yun Soo Hong
- Jonathan G. Seidman
- Dan E. Arking
- Samir M. Parikh
1 Application
| Application ID | Title |
|---|---|
| 17731 | A phenome-wide association study of copy number variation |
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