Fig. 1

The molecular mechanism behind mitophagy after stroke. PINK, Parkin, NIX, BNIP3, and the newly-found FUNDC1 are mitophagy receptors in mammalian cells. Mitophagy regulated by PINK1-Parkin-mediated pathway is a multi-step process. Briefly, PINK1 is accumulated on the outer membrane of dysfunctional mitochondria, subsequently to recruit parkin by activating parkin’s cytosolic E3 ubiquitin ligase, then proteins on the outer mitochondrial membrane such as VDAC1 and Mfn1/2 are ubiquitinated by parkin to induce mitophagy. Adapter proteins including p62 are accumulated in the outer mitochondrial membrane after the ubiquitination, leading to ubiquitylated cargo recruited into autophagosomes by binding to LC3. BNIP3 and NIX are related multi-functional outer mitochondrial membrane proteins. Bnip3 and NIX activated mitophagy by binding to Bcl-2 family proteins (including BCL2 and BCL-xL), and also by repressing mTOR or regulating the production of ROS. The molecular mechanism of FUNDC1-mediated mitophagy has not been reported in the pathologies of stroke so far. FUNDC1 phosphorylated at serine 17 under hypoxia stress, thereby to interacting with LC3 and promoting mitophagy. Bcl-xL can inhibit LC-3II conversion, thereby suppressing FUNDC1-mediated mitophagy. In response to the stress of stroke (both of ischemic and hemorrhagic stroke), mitophagy is activated as a stress adaptation to removing dysfunctional mitochondria. Elongated mitochondria were divided into pieces, of which the process is preceded by mitochondrial fission, then autophagosomes, double-membrane vesicles are formed, and sequester targeted cell constituents and mitochondria. The mature autophagosomes then fuse with a lysosome to form the autophagolysosomes, where the mitochondria are subsequently degraded