Superoxide signals for the mitophagy of dysfunctional mitochondria to maintain quality control

The mechanism of selecting dysfunctional mitochondria for mitophagy is only partially understood. Evidence suggests the mechanism involves reactions of superoxide (O₂^-•), hydrogen peroxide (H₂O₂), nitric oxide (NO•), peroxynitrite (ONOO^-), carbonate radicals (•CO₃^-), nitrogen dioxide radicals (•NO₂), hydroxyl radicals (•OH), oxygen (•O₂• or O₂), and carbon dioxide (CO₂). However, the larger picture of how these reactions are organized to induce mitophagy is unclear. Extensive evidence suggests that increased mitochondrial matrix O₂^-• is associated with the mitophagy of dysfunctional organelles. In most cells, mitochondrial O₂^-• is mainly produced by the reaction of O₂ with free radical intermediate forms of coenzyme Q (CoQ) and flavins, which are generated in substantial amounts in the inner membrane and matrix space of dysfunctional mitochondria. Mitochondrial O₂^-• plays two key roles in orchestrating mitophagy. First, it is dismutated by mitochondrial matrix superoxide dismutase 2 (SOD2) to H₂O₂. This diffusible messenger directs the nuclear and cytoplasmic compartments to prepare for mitophagy, including the generation of cytoplasmic NADPH and glutathione and the increased synthesis of membrane-diffusible NO•. Second, mitochondrial matrix space O₂^-• readily reacts with NO• to form ONOO^-, which initiates a cascade of free radical reactions culminating in mitochondrial membrane depolarization and PINK1 and Parkin-driven mitophagy. Compelling observations that support the proposed mechanism are given. This mechanism could be targeted for the treatment of diseases characterized by dysfunctional mitophagy, such as Parkinson's disease. Because of the central role of mitochondrial O₂^-• as a sentinel for selective mitophagy, we have named this hypothesis the superoxide sentinel hypothesis of mitochondrial quality control.