Cross Talk of Proteostasis and Mitostasis in Cellular Homeodynamics, Ageing, and Disease

Figure 3

Pathways for the removal of damaged mitochondria. Unrepaired mitochondrial damage or reduced membrane potential () prompts the removal of mitochondria by autophagy. Autophagy starts (upper left) with the upstream complex ULK1 which is composed from Unc-51-Like Kinase 1 protein (ULK1), ATG13, mTOR kinase, and RB1-inducibile Coiled-Coil 1 (RB1CC1). Inhibition of the mTOR kinase leads to the generation of the Beclin1-Vacuolar Protein Sorting (VPS) 34-VPS15 complex. B-cell lymphoma 2 (BCL-2) blocks the induction of autophagy by binding to Beclin1 and to the Activating Molecule in Beclin1-Regulated Autophagy (AMBRA1). Displacement by BH3-only proteins activates Beclin1-VPS 34-VPS15 and induces the phagophore generation. The phagophore is elongated by the autophagy proteins ATG12-ATG5 creating the ATG16L complex, which then conjugates phosphatidylethanolamine (PE) to the procures of microtubule-associated protein 1 Light Chain 3 (LC3) to generate the LC3 II receptor. Finally, the membrane engulfs the cargo, closes its ends, and fuses with lysosomes in order to degrade its content. Mitophagy can also occur in a PINK1/Parkin dependent pathway (lower left; upper right): PINK1 is exposed at the outer membrane, where it recruits the E3 ubiquitin ligase Parkin to mitochondria. Parkin ubiquitinates outer membrane proteins, such as Mfns and Voltage-Dependent Anion Channel (VDAC), which are then degraded by the 26S proteasome. Similarly, p62/SQSTM1 (Sequestosome 1) interacts with ubiquitinated mitochondrial proteins and recruits the autophagosome through its interaction with the LC3 receptor. An alternative PINK1/Park dependent pathway is the formation of cargo-selective vesicles (lower left) which are released from mitochondria (Mitochondria-Derived Vesicles, MDV) and fuse with lysosomes. The formation of MDV is induced by increased ROS levels and does not require mitochondrial depolarization and/or LC3 or ATG5 proteins. Mitophagy in a Parkin-independent way (lower right) may also occur since (a) the autophagy receptors NIX and BNIP3 can directly interact with the autophagosome through the LC3 receptor; (b) AMBRA1 if overexpressed in the mitochondria outer membrane interacts with the LC3 receptor and can induce autophagy by both Parkin dependent and Parkin-independent pathways; and (c) PINK1 phosphorylates the ubiquitin chains in mitochondria promoting the recruitment of NDP52 [also known as Calcium binding and Coil-Coil domain protein 2, (CALCOCO2)] and optineurin autophagy receptors; subsequently, ND52 and optineurin recruit the upstream machinery of autophagy and trigger mitophagy.