*2.4. Mitophagy*

Mitophagy, a mitochondrion-specific type of autophagy, is responsible for removing damaged mitochondria and protecting cells from injury. PTEN-induced putative protein kinase 1 (PINK1) and Parkin are key players in the regulation of ubiquitin-dependent mitophagy [19]. In healthy mitochondria, PINK1 is transported into the inner mitochondrial membrane (IMM), where it is processed and cleaved by several proteases [20,21]. The truncated form of PINK1 is degraded by the ubiquitin–proteasome system [20,21]. Following the loss of the mitochondrial membrane potential, mitochondrial import is prevented, facilitating PINK1 stabilization on the outer mitochondrial membrane (OMM) [20–22]. PINK1 is activated by auto-phosphorylation leading to the translocation of Parkin to the mitochondrial surface. In this process, MITOL plays a role in the initial step in Parkin recruitment to mitochondria, resulting in ubiquitination of its substrate [23]. Although the physiological significance of this is still unclear, it has also been shown that MITOL is transferred to other organelles during mitophagy [24]. We have actually observed translocation to other organelles as well. Several mitochondrial proteins, including Nix/BNIP3L, BNIP3, FUNDC1, Optineurin, NDP52, and Bcl2-L-13, have been reported as mitophagy receptors in mammalian cells [19]. In particular, FUNDC1 is thought to be involved in mitophagy through its interaction with LC3 (yeast Atg8 ortholog) and ULK1 (yeast Atg1 ortholog) through hypoxic stress and inhibitory treatment of oxidative phosphorylation [25]. MITOL has been shown to regulate mitophagy by ubiquitinating FUNDC1 for degradation during hypoxic stress [26], suggesting that MITOL also acts as a regulator of such dynamic mitochondrial quality control. These observations sugges<sup>t</sup> that MITOL may determine mitochondrial fate in response to a variety of mitochondrial stresses.
