Regulation of PRKN-independent mitophagy

Abstract

Mitochondria are dynamic, multifunctional cellular organelles that play a fundamental role in maintaining cellular homeostasis. Keeping the quality of mitochondria in check is of essential importance for functioning and survival of the cells. Selective autophagic clearance of flawed mitochondria, a process termed mitophagy, is one of the most prominent mechanisms through which cells maintain a healthy mitochondrial pool. The best-studied pathway through which mitophagy is exerted is the PINK1-PRKN pathway. However, an increasing number of studies have shown an existence of alternative pathways, where different proteins and lipids are able to recruit autophagic machinery independently of PINK1 and PRKN. The significance of PRKN-independent mitophagy pathways is reflected in various physiological and pathophysiological processes, but many questions regarding the regulation and the interplay between these pathways remain open. Here we review the current knowledge and recent progress made in the field of PRKN-independent mitophagy. Particularly we focus on the regulation of various receptors that participate in targeting impaired mitochondria to autophagosomes independently of PRKN.Abbreviations: AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BH: BCL2 homology; CCCP: Carbonyl cyanide m-chlorophenylhydrazone; CL: cardiolipin; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-trifluoromethoxyphenylhydrazone; IMM: inner mitochondrial membrane; IMS: mitochondrial intermembrane space; LIR: LC3-interacting region; MDVs: mitochondrial-derived vesicles; MTORC1: mechanistic target of rapamycin kinase complex 1; OMM: outer mitochondrial membrane; OXPHOS: oxidative phosphorylation; PD: Parkinson disease; PtdIns3K: phosphatidylinositol 3-kinase; RGC: retinal ganglion cell; RING: really interesting new gene; ROS: reactive oxygen species; SUMO: small ubiquitin like modifier; TBI: traumatic brain injury; TM: transmembrane.

Keywords: Autophagy receptors; mitochondria; mitochondrial dysfunction; mitophagy; selective autophagy.

Figure 1.

Molecular mechanisms of PRKN-independent mitophagy. De novo autophagosome formation can take place near the ER from various membrane sources or at/around the cargo. Autophagy initiation requires the activation of ULK1 complex that is tightly regulated by MTORC1 and AMPK and series of phosphorylation events triggered by growth signals, nutrient availability and cellular energy and oxygen levels. Phosphorylation of BECN1 by ULK1 further activates the class III PtdIns3K complex, leading to PtdIns3P synthesis and phagophore formation/nucleation. PtdIns3P binds to WIPI proteins, which further recruit the ubiquitin-like conjugation system (E1-E3) that facilitates conjugation of Atg8-family proteins to phosphatidylethanolamine (PE) (Atg8-II), leading to phagophore elongation. Mitophagy receptors such as BNIP3, BNIP3L, FUNDC1, BCL2L13, FKBP8 and PHB2 can directly bind to lipidated LC3 and GABARAP-family members at the phagophore membrane. Phagophore closure around the tagged mitochondria will form the double-membrane autophagosome (mitophagosome) that later fuses with the lysosome (mitolysosome) where mitochondria and cargo receptors are degraded and recycled by the action of lysosomal hydrolases.

Figure 2.

Ceramide and CL mediate PRKN independent mitophagy upon mitochondrial damage. (A) Ceramide at the OMM can bind LC3B-II: targeting autophagosomes to the mitochondria to initiate mitophagy. Ceramide signaling induces BECN1 expression guiding LC3B lipidation and autophagy. DNM1L expression influences ceramide distribution at the OMM, contributing to its interaction with LC3B-II. (B) CL is mainly found in mitochondrial membranes and its translocation from IMM to OMM triggers mitophagy. PLSCR3 is responsible for CL transport from IMM to OMM and its depletion leads to reduced distribution of CL at the OMM and lower levels of mitophagy. CL in the OMM can directly bind LC3 and BECN1 and has a strong binding affinity for DNM1L.

Figure 3.

Schematic representation of the domains of proteins involved in the PRKN-independent mitophagy. Domain structures are shown schematically with sizes of proteins roughly in scale. Abbreviations: LIR: LC3-interacting region; TM: transmembrane domain; BH: BCL2 homology domain; RING: RING domain; IMS: mitochondrial intermembrane space; SIAH: SIAH zinc finger domain; IBR: IBR zinc finger domain; UBA: ubiquitin-associated like domain; WD: WD repeats.