The Role of Autophagy and Mitophagy in Mitochondrial Diseases

Abstract Mitochondrial diseases are a group of rare genetic disorders with a very heterogeneous origin caused by total or partial dysfunction of mitochondria, the organelles that produce most of the energy of the cell. ATP shortage and excess production of ROS are the main pathogenic factors that cause most of the clinical manifestations of mitochondrial diseases. Recent reports have demonstrated that these pathological signals promote the induction of bulk autophagy and/or mitophagy in different models of mitochondrial disease. The term “autophagy” is used to describe lysosomal-mediated degradation of intracellular contents including damaged or excessive organelles through the formation of a double-membrane structure known as the autophagosome. In contrast, mitophagy refers to the selective degradation of mitochondria by autophagy and normally needs complementary factors as low mitochondrial membrane potential and Parkin translocation to mitochondria. Most of the investigators hypothesize that both bulk autophagy and mitophagy have a protective role in mitochondrial disease, since the accumulation of damaged mitochondria and other toxic aggregates causes a worsening of cell pathophysiology. Indeed, mitophagy could modulate the percentage of heteroplasmy of the mitochondrial DNA (mtDNA) mutations, which is directly related with the pathophysiology of the disease. However, regulation of autophagy and mitophagy in the cell appears to be essential for the balance between survival and cell death, since autophagy is a catabolic process that could potentially be used by the cell to its self-destruction, as well as massive mitophagy can suppose an extensive loss of mitochondrial mass resulting in the bioenergetics collapse of the cell.