Figure 3.

The scheme of mitochondrial dynamics and mitophagy. Mitochondrial fusion and fission processes are responsible for a healthy mitochondrial network through the segregation and subsequent degradation of damaged mitochondria. Mitochondrial fusion is a two-step process. The fusion of the outer mitochondrial membrane is regulated by Mfn1 (Mitofusin 1) and Mfn2 (Mitofusin 2), whereas fusion of the inter mitochondrial membrane is mediated by OPA1 (optic dominant atrophy 1) and mitochondria-specific cardiolipin (CL). Mitochondrial fission is mediated predominantly by Drp1 (a dynamin superfamily GTPase) and recruited to scission sites by resident outer-membrane proteins including Mff (mitochondrial fission factors) and Fis1 (mitochondrial fission 1 protein). The fission process generates fragmented mitochondria, which are conducive to the sequestration of injured fragments for subsequent degradation through mitophagy. PTEN-induced kinase 1 (PINK1) and the Parkin pathway regulate the initiation of mitophagy. Mitochondrial damage results in the accumulation of PINK1 on the outer mitochondrial membrane, where it phosphorylates polyubiquitin chains linked to mitochondrial outer membrane proteins. Next, phospho-S65-ubiquitin binds to Parkin, recruiting it from the cytosol and activating Parkin’s E3 ubiquitin ligase activity. This complex is identified by ubiquitin-SQSTM1(multifunctional adaptor protein sequestosome 1)-LC3 (microtubule-associated protein 1 light chain 3) autophagosome targeting and is degraded following lysosomal fusion.