在这里，该研究团队表明短暂的损伤会引起持续性mtDNA突变的爆发，从而损害对未来损伤的恢复能力。mtDNA突变抑制了能量密集型核苷酸代谢。腺苷的补充，而不是其他核苷酸，恢复ATP的生成，这需要一个核编码嘌呤生物合成酶，腺苷酸激酶4 （AK4）。对369,912名UK Biobank参与者的分析显示，突变负担与慢性肾脏疾病严重程度之间存在分级关联，以及未来急性肾损伤事件风险的独立增加（p < 107）。因此，异质性mtDNA突变可能反映了代谢活跃细胞急性损伤的累积效应，以一种适合核控制嘌呤生物合成的方式损害主要功能。
据介绍，体细胞获得性线粒体DNA突变随着年龄的增长而积累，但其机制和后果尚不清楚。
附：英文原文
Title: Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations
Author: 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
Issue&Volume: 2025-09-04
Abstract: Somatically acquired mitochondrial DNA mutations accumulate with age, but the mechanisms and consequences 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 ATP 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 < 107). 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.
DOI: adk7978
Source: https://www.science.org/doi/10.1126/science.adk7978