Neuronal Mitophagy in Neurodegenerative Diseases

Abstract

Neuronal homeostasis depends on the proper functioning of different quality control systems. All intracellular components are subjected to continuous turnover through the coordinated synthesis, degradation and recycling of their constituent elements. Autophagy is the catabolic mechanism by which intracellular cytosolic components, including proteins, organelles, aggregates and any other intracellular materials, are delivered to lysosomes for degradation. Among the different types of selective autophagy described to date, the process of mitophagy involves the selective autophagic degradation of mitochondria. In this way, mitophagy is responsible for basal mitochondrial turnover, but can also be induced under certain physiological or pathogenic conditions to eliminate unwanted or damaged mitochondria. Dysfunctional cellular proteolytic systems have been linked extensively to neurodegenerative diseases (ND) like Alzheimer's disease (AD), Parkinson's disease (PD), or Huntington's disease (HD), with autophagic failure being one of the main factors contributing to neuronal cell death in these diseases. Neurons are particularly vulnerable to autophagic impairment as well as to mitochondrial dysfunction, due mostly to their particular high energy dependence and to their post-mitotic nature. The accurate and proper degradation of dysfunctional mitochondria by mitophagy is essential for maintaining control over mitochondrial quality and quantity in neurons. In this report, I will review the role of mitophagy in neuronal homeostasis and the consequences of its dysfunction in ND.

Keywords: Alzheimer disease; Parkinson’s disease; autophagy; mitophagy; neurodegeneration.

Figure 1

Autophagy and endocytosis can delivery substrates to lysosome for degradation. Autophagy is a tightly regulated process by which certain intracellular components are recycled through lysosomal degradation. Various types of autophagy are present in mammalian cells: microautophagy involves the sequestration and degradation of complete regions of the through invaginations of the lysosomal membrane. Macroautophagy (commonly referred as “autophagy”) consists in the engulfment of intracellular components in a double membrane vesicle called autophagosome. This vesicle is then fused with lysosomes to form an autophagoslysosome and the lysosomal hydrolytic enzymes complete the degradation. Under some conditions, macroautophagy can be a selective mechanism where specific substrates are recognized by distinct autophagic receptors and eliminated. Among the different types of selective (macro)autophagy, mitophgay consists in selective degradation of mitochondria. Chaperone-mediated autophagy (CMA) is a proteolytic pathway where specific cytosolic proteins containing a CMA-motif are recognized by chaperones and directly translocated into the lysosome through the CMA receptor formed by LAMP-2A protein. Extracellular components can also be degraded by endocytosis when late endosome fuse with lysosomes or alternatively, first with an autophagosomes and later on with a lysosome. Intracellular proteins can also be degraded by the ubquitin proteasomal system (UPS). All degradative pathways work coordinated and simultaneously to maintain cellular homeostasis.

Figure 2

Mitochondrial degradation. Whole mitochondria can be degraded by mitophagy (upper panels) under different physiological and stress-induced situations. Different mitophagy receptors link the mitochondria with the pre-autophagosome structure (PAS) through the direct intercation with light chain 3 (LC3)-II (in purple). These receptor can be mitochondrial components (A) o non-mitochondrial proteins (B) that bind both the phosphorylated ubiquitin (P-UB) chains on the mitochondria surface and LC3-II. Mitochondria can also be partially degraded (lower panel) through the formation of mitochondrial-derived vesicles (MDVs) that can directly be fused with lysosomes (C). Some outer mitochondrial membrane (OMM) proteins can be degraded by the UPS (D) after mitochondrial depolarization with the recruitment of the 26S proteasome on the mitochondrial surface. Internally, the mitochondrial unfolded protein response (UPR^mt) is a quality control system formed by molecular chaperones and proteases (D).