How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

Abstract

Mitochondria are indispensable cellular organelles providing ATP and numerous other essential metabolites to ensure cell survival. Reactive oxygen species (ROS), which are formed as side reactions during oxidative phosphorylation or by external agents, induce molecular damage in mitochondrial proteins, lipids/ membranes and DNA. To cope with this and other sorts of organellar stress, a multi-level quality control system exists to maintain cellular homeostasis. One critical level of mitochondrial quality control is the removal of damaged mitochondria by mitophagy. This process utilizes parts of the general autophagy machinery, e.g. for the formation of autophagosomes but also employs mitophagy-specific factors. Depending on the proteins utilized mitophagy is divided into receptor-mediated and ubiquitin-mediated mitophagy. So far, at least seven receptor proteins are known to be required for mitophagy under different experimental conditions. In contrast to receptor-mediated pathways, the Pink-Parkin-dependent pathway is currently the best characterized ubiquitin-mediated pathway. Recently two additional ubiquitin-mediated pathways with distinctive similarities and differences were unraveled. We will summarize the current state of knowledge about these multiple pathways, explain their mechanism, and describe the regulation and crosstalk between these pathways. Finally, we will review recent evidence for the evolutionary conservation of ubiquitin-mediated mitophagy pathways.

Quantitative analysis of the mitochondrial proteome in human ovarian carcinomas

“…This current study identified those proteins too, even though few of them appeared to have changing expression patterns ( Table 2). The results were consistent with previous studies, for those proteins activated downstream mitophagy by post-translational modifications (Zimmermann & Reichert 2017). A peroxisome is a kind of organelle in nearly all eukaryotic cells.…”

“…In autophagosomes, mitochondrion, proteins or peroxisome were usually observed. Autophagosomes fuse with lysosomes and emit high-energy substances, including fatty acid and amino acid (Zimmermann & Reichert 2017). In this progress, mitophagy is dependent on the general autophagy machinery and relies on a growing cadre of 'mitophagy adaptors' and regulatory molecules, such as FUNDC1, BNIP3L(NIX), PGAM5, CK, OPA1, prohibitin2, OPTN, TBK1, p62 and Bcl2-L13 (Drake et al 2017).…”

Mitochondria, lysosomes, and dysfunction: their meaning in neurodegeneration

“…Ubiquitin‐dependent mitophagy utilizes the serine/threonine‐protein kinase PTEN‐induced putative kinase 1/parkin RBR E3 ubiquitin protein ligase (PINK1/PARKIN) system to ubiquitylate outer mitochondria membrane proteins which recruit adaptor proteins to initiate the engulfment of mitochondria via microtubule‐associated protein 1 light chain 3‐α (LC3) interaction on the phagophore membrane. In contrast, during receptor‐mediated mitophagy outer mitochondrial membrane receptors are activated to increase their affinity to LC3, for example, by phosphorylation (BCL2‐Interacting Protein 3 Like, BCL2‐Interacting Protein 3 (BNIP3), and BCL2 Like 1 (BCL2L)) or other, so far unknown activators (Autophagy And Beclin 1 Regulator 1 and SMAD‐Specific E3 Ubiquitin Protein Ligase 1 [for review see (Zimmermann and Reichert )].…”

Gp78 E3 ubiquitin ligase mediates both basal and damage-induced mitophagy

“…Mitophagy, mitochondrial autophagy, is a process by which mitochondria are selectively targeted for autophagy and lysosomal degradation (1)(2)(3). Mitophagy plays a critical role in cellular health by controlling mitochondrial mass and eliminating damaged or dysfunctional mitochondria (4).…”

“…PINK1dependent, Parkin-independent mitophagy pathways include the synphilin/SIAH1 and the Mulan pathways (15,16,19). However, synphilin is primarily expressed in brain and whether Mulan functions downstream of or independently of PINK1 remains to be determined (1). Nevertheless, PINK1 remains, to date, a unique sensor of mitochondrial damage (20,21).…”