A autofagia é necessária para a segregação de DNA mitocondrial no Fígado

Abstract

Mutations in the mitochondrial genome (mtDNA) are ubiquitous in humans and can lead to a broad spectrum of disorders. However, due to the presence of multiple mtDNA molecules in the cell, coexistence of mutant and wild-type mtDNAs (termed heteroplasmy) can mask disease phenotype unless a threshold of mutant molecules is reached. Importantly, mutant mtDNA level can change across lifespan as mtDNA segregates in an allele- and tissue-specific fashion, potentially leading to disease. Mitochondrial segregation is most evident in hepatic cells, which positively select for mtDNA mutations, including mutations potentially affecting protein sequence. Using Atg7 knockout and heteroplasmic mice with a deleterious mtDNA we show here that this phenotype relies on autophagy, implicating mtDNA degradation as a driving force of mtDNA segregation in the liver. The Atg7 gene is an E1-like enzyme, responsible for activating the two main conjugation systems required for elongation of the autophagosome, and its knockout results in the block of autophagy. Based on this model, we suggest that the accumulation of age-dependent mutant mtDNA in the liver of heteroplasmic individuals is a consequence of the selective clearance of the alternative mtDNA variant.