Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations

• 成果类型: Article
• 署名作者: Huang, Huihui; Wang, Yi; Zsengeller, Zsuzsanna K.; Gorham, Joshua M.; Vemireddy, Vamsidhara; Clark, Amanda J.; Pan, Hui; Dreyfuss, Jonathan M.; Jotwani, Vasantha; Shlipak, Michael G.; Sarnak, Mark J.; Parikh, Chirag R.; Thiessen-Philbrook, Heather; Katz, Ronit; Waikar, Sushrut S.; Lake, Nicole J.; Lek, Monkol; Shi, Wen; Puiu, Daniela; Hong, Yun Soo; Seidman, Jonathan G.; Arking, Dan E.; Parikh, Samir M.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Joslin Diabetes Center, Inc.; University of California System; University of California San Francisco; Tufts Medical Center; Johns Hopkins University; Johns Hopkins Medicine; University of Washington; University of Washington Seattle; Boston Medical Center; Boston University; Yale University; Johns Hopkins University; Johns Hopkins Medicine
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adk7978
• 发表日期: 2025-10-09
• 页码: 164-172
• 关键词: mitochondrial-dna mutations; ACUTE KIDNEY INJURY; adenylate kinase; point mutations; genome; metabolism; CREATININE

摘要

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.