Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps

Abstract

Mitophagy, a conserved intracellular process by which mitochondria are eliminated via the autophagic machinery, is a quality control mechanism which facilitates maintenance of a functional mitochondrial network and cell homeostasis, making it a key process in development and longevity. Mitophagy has been linked to multiple human disorders, especially neurodegenerative diseases where the long-lived neurons are relying on clearance of old/damaged mitochondria to survive. During the past decade, the availability of novel tools to study mitophagy both in vitro and in vivo has significantly advanced our understanding of the molecular mechanisms governing this fundamental process in normal physiology and in various disease models. We here give an overview of the known mitophagy pathways and how they are induced, with a particular emphasis on the early events governing mitophagosome formation.

Hyperoxia exposure arrests alveolarization in neonatal rats via PTEN‑induced putative kinase 1‑Parkin and Nip3‑like protein X‑mediated mitophagy disorders

“…After clarifying the overall protein expression levels of PINK1 and Parkin during lung development, the co-localisation between the mitochondrial marker protein COX4 and autophagy marker protein LC3B was evaluated in primary AT-II cells in the postnatal period. A hallmark of the mitophagy process is the co-localisation of mitochondria with autophagosomes for elimination ( 28 ). Immunofluorescence revealed higher LC3B protein levels in the model group compared with in the control group, reaching a peak at P7 ( Fig.…”

The Impact of Mitochondrial Fission-Stimulated ROS Production on Pro-Apoptotic Chemotherapy

“…Upon mild stress, mitochondrial fragments compromised by deteriorating mitochondrial membrane potential are selectively pinched off the continuous mitochondrial network reticulum by the action of the mitochondrial fission machinery [ 63 ]. Subsequently, fragmented mitochondria are selectively recognized by the mitophagy machinery through receptor binding between OMM and the growing membranous structure termed the phagophore [ 64 ]. Following further extension, phagophore ultimately encapsulates the damaged mitochondrion into a new structure called the mitophagosome [ 65 ].…”

“…In this configuration, the adapter protein contacts LC3 through its LC3-interacting region (LIR) and binds to ubiquitin through its ubiquitin-binding domain (UBD) [ 69 ]. In the ubiquitin-independent pathway, LC3 directly interacts with specific OMM receptors such as Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and NIX (also known as BNIP3L) [ 64 ].…”

The function of apolipoproteins L (APOLs): relevance for kidney disease, neurotransmission disorders, cancer and viral infection

“…APOLs could control the initiation of isolation membranes by Golgi‐derived vesicles, owing to their effect on PI(4)P synthesis by PI4KB [8], which is key to autophagy initiation [56,166]. In addition, APOLs could contribute to the process by which mitochondria donate their membranes to phagophores [146,168], owing to their association with both the autophagy receptors PHB and autophagy factors LC3/GABARAP, together with their common binding to cardiolipin [8,117,137,143,162]. Since Golgi‐derived PI4KB‐containing vesicles play a part in the fission of mitochondrial membranes at MERCs [59], where autophagy and mitophagy are initiated [174], the succession between the initiation and elongation processes depicted here can be envisaged (dotted arrow).…”