Mitochondrial Function and Mitophagy in the Elderly: Effects of Exercise

Figure 1

Mitochondrial biogenesis, dynamics, and mitophagy process. Machinery regulating mitochondrial morphology dynamics can regulate mitophagy initiation, so mitophagy is inhibited by fusion process, mediated via Mfn1/2 and OPA1, and promoted by fission process, mediated via Drp1. Fission process generates polarized mitochondria, which is driven to fusion process, and depolarized mitochondria, which is targeted by mitophagy. In polarized mitochondria, PINK1 is imported into IMM and degraded via proteasome. In depolarized mitochondria, PINK1 is accumulated in OMM. There, PINK1 recruits Parkin from the cytosol by Mfn1 and Mfn2 phosphorylation and phosphorylates ubiquitin and ubiquitin-like domain of Parkin. Then, Parkin ubiquitinates OMM proteins, such as VDAC1, which recruit the p62/SQSTM1 autophagy cargo adaptor. This receptor simultaneously binds to LC3 localized in the nascent phagophore. Furthermore, mitochondrial biogenesis can promote the fusion process, blocking mitophagy, through PGC-1α, which stimulates Mfn2 expression; and mitophagy can inhibit mitochondrial biogenesis via Parkin, whose association with TFAM inhibits the expression of PGC-1α. On the other hand, upon expression, Bnip3 and Nix bind Bcl-2, broking the beclin1/Bcl-2 interaction, so that beclin1 can induce autophagy initiation. Moreover, Bnip3 and Nix are phosphorylated and form homodimers, which integrate in OMM and then bind to LC3. In both cases, the LC3 bond triggers mitochondria to autophagy.