Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations
- 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
2025-09-04
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.