Persistent injury-induced mtDNA mutations compromise organ fitness by suppressing nucleotide biosynthesis

The mitochondrial genome is present at thousands of copies/cell in metabolically active tissues. In organs such as the kidney that are exposed to frequent sublethal insults, the impact on mitochondrial DNA (mtDNA) quality is unknown. Here we show that acute kidney injury induces a burst of persistent random mtDNA mutations (mtDNA) that impair mitochondrial function, induce fibrosis, and increase subsequent injury risk in cells, mice, and humans, implicating a feed-forward loop of accumulating mtDNA mutations driving chronic disease. Multi-omic interrogation of mtDNA settings implicates marked reduction of energy-intensive nucleotide biosynthesis. Strikingly, repletion of adenosine, but not other nucleosides, restores ATP and ameliorates injury risk via the purine biosynthetic enzyme adenylate kinase 4. mtDNA may therefore be a durable remnant of acute injuries that compromise future health and both a genetic and tissue-based indicator of organ fitness. Augmented purine biosynthesis may protect vulnerable organs from acute insults.