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.

GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics through ER-mitochondria cholesterol transport

“…In support of this, cholesterol oxidase-based quantification of mitochondrial cholesterol revealed a similar increase of mitochondrial cholesterol in GRAMD1C KO cells compared to control cells (Figure 6c). At the same time, loss of GRAMD1C caused a reduction of ER cholesterol levels, as seen through an increase in SREBP target gene expression (Supplementary figure 4d), in line with a previous observations 40 . Additionally, the abundance of cholesterol-associated proteins (STARD9, ERLIN, SQLE, NPC2, and APOB) in GRAMD1C depleted cells were altered as seen through proteomic analysis of siGRAMD1C treated cells (Supplementary figure 4e, Table II).…”

Regulation of mitochondrial cargo-selective autophagy by posttranslational modifications

“…In addition to the PINK1/parkin-dependent mitophagy pathway described above, alternative parkin-independent pathways can recruit LC3 to mitochondria and promote their selective autophagic elimination ( 122 , 123 ). Two different parkin-independent mechanisms can be distinguished: (1) receptor-mediated or (2) ubiquitin-mediated mitophagy ( Fig.…”

“…Cardiolipin is a phospholipid normally residing at the MIM, which can be externalized under mitochondrial stress conditions by phospholipid scramblase-3. Such relocalization to the MOM allows cardiolipin to directly bind to LC3 ( 43 ), thus acting as a lipid kind of autophagy receptor in the regulation of parkin-independent mitophagy ( 122 ) ( Fig. 3 A ).…”

The dynamics of mitochondrial autophagy at the initiation stage

“…In the case of ubiquitin-independent pathways, a number of mitophagy receptors are recruited to damaged mitochondria (or exposed on their surface) to mediate interaction with the autophagic machinery [ 2 , 56–58 ]. BNIP3 and BNIP3L (or NIX) are two such receptors which regulate mitophagy under hypoxic conditions with BNIP3L also being essential for mitochondrial clearance during erythrocyte maturation and somatic cell reprogramming [ 2 , 56 ]. Both BNIP3 and BNIP3L contain oligopeptide domains that interact with ATG8 family proteins (LIR domains) and this is the mechanism for autophagosome recruitment.…”

“…Another receptor involved in mitophagy independently of a ubiquitin ‘eat me' signal is FUNDC1, a transmembrane protein of the outer mitochondrial membrane that has been implicated in homeostatic pathways of cardiac cells. Interaction of FUNDC1 with the autophagic machinery during hypoxic conditions involves both a LIR domain exposed on the cytosolic side as well as binding to the ULK1 kinase [ 2 , 56 ]. All of these interactions between receptors and ATG8 family members are regulated by phosphorylation cascades thus modulating receptor affinity for the forming autophagosomal membrane.…”