{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T23:16:26Z","timestamp":1792278986641,"version":"4.4.0"},"reference-count":74,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"6769","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Science"],"published-print":{"date-parts":[[2025,10,9]]},"abstract":"<jats:p>\n            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 (\n            <jats:italic toggle=\"yes\">P<\/jats:italic>\n            &lt; 10\n            <jats:sup>\u22127<\/jats:sup>\n            ). 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.\n          <\/jats:p>","DOI":"10.1126\/science.adk7978","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T17:59:42Z","timestamp":1757008782000},"page":"164-172","update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":15,"title":["Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations"],"prefix":"10.1126","volume":"390","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8853-8379","authenticated-orcid":true,"given":"Huihui","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 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