Figure 1.

MQC pathways and main regulatory molecules essential for mitochondrial function, maintenance and cell homeostasis (created with BioRender.com). Mt undergo fission and fusion, oscillating between globular and elongated morphology. Mitochondrial fission is essential for the proper distribution of Mt into the daughter cells during division and serves mitophagy by generating “edible” smaller units from injured Mt. Excessive fission is both a major sign and an inducing factor of cell stress, and is associated with deterioration of ATP production, extensive ROS generation, apoptosis, or necrotic death. The key component of mitochondrial fission is Drp1 which, upon induction of fragmentation, can translocate from the cytosol to the outer mitochondrial membrane (OMM). The opposite process, fusion, is catalyzed by the Mfn1 and Mfn2 in the OMM and OPA1 in the inner mitochondrial membrane (IMM). The maintenance of mitochondrial network integrity is orchestrated by the processes of mitophagy and mitochondrial biogenesis. Regulation of Mt biogenesis is coordinated by PGC1α, SIRT1 and AMPK, increasing the replication of MtDNA and the expression of mitochondrial proteins. The key mitophagy pathways are divided into receptor-mediated mitophagy and ubiquitin-mediated mitophagy. During receptor-mediated mitophagy, under mitochondrial stress (i.e., hypoxia or depolarization), mitophagy receptors localize to the OMM. Both major mitophagy receptors, FUNDC1 and BNIP3L/NIX, facilitate phagophore formation. Ubiquitin-dependent mitophagy is PINK1/Parkin-dependent, and phosphorylation of both Parkin and ubiquitin is conducted by PINK1. Under Mt stress, PINK1 and Parkin decorate Mt with phosphor-ubiquitin chains. Mt covered in ubiquitin are recognized by multiple autophagy receptors that assemble the autophagosomal machinery for degradation of damaged Mt. LC3 is involved in both ubiquitin-dependent and receptor-mediated mitophagy.