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Highlights d Whole-genome sequences of 45 African killifish species d Relaxed selection leads to larger genomes in short-lived, annual killifish d Population bottlenecks affect the distribution of aging variants in fish and humans d Natural polg variants in annual killifish cause high rate of mtDNA mutations

Medeiros et al. show that mtDNA polymerase POLG controls mtDNA copy number in the context of autophagy-mediated metabolic homeostasis. After prolonged starvation, the mtDNA degradative activity of POLG is activated to adjust the increasing mtDNA copy number in WT cells, whereas in autophagy-deficient cells, POLG’s continued degradative activity causes mtDNA instability and respiratory dysfunction as a result of nucleotide insufficiency.