Autophagy functions in mitochondrial DNA maintenance and copy number regulation Tânia Medeiros1, Ryan Thomas1, Ruben Ghillebert1, and Martin Graef1,2* 1Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany 2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany *Correspondence to Martin Graef: email@example.com Mitochondria evolved from endosymbiotic proteobacteria and maintained a highly reduced genome. Reduction of size and coding capacity of the mitochondrial genome (mtDNA) was accompanied by an increase in mtDNA copy number, which creates genetic redundancy that allows the buffering of otherwise deleterious mutations in mitochondrial genes essential for cellular functions. How mtDNA copy number is maintained and regulated has remained largely elusive. Here, we provide insights into the remarkable dynamics of mtDNA copy number in yeast cells transitioning into starvation and into the role of autophagy in maintaining metabolic homeostasis and its role in mtDNA copy number regulation during nutrient stress. We identified how defects in autophagy impinge upon mitochondrial function and describe the underlying causes driving the active degradation of mtDNA in non-dividing autophagy-deficient cells. Importantly, we discovered the intra-mitochondrial degradative mechanisms that are responsible for mtDNA copy number adjustment in wild type and mtDNA instability in autophagy-deficient cells. In summary, our data reveal an intimate link between the homeostatic functions of autophagy and mitochondria, which play an essential role for copy number regulation and the stability of the mitochondrial genome.
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