Aminochrome Induces Irreversible Mitochondrial Dysfunction by Inducing Autophagy Dysfunction in Parkinson's Disease

摘要

Mitochondrial dysfunction in parkinson's disease In Parkinson's disease, mitochondrial complex I activity is diminished, and mitochondrial deoxyribonucleic acid (DNA) mutations accumulate (Zhang, 2013 ). The first evidence that mitochondrial dysfunction was involved in the pathogenesis of Parkinson's disease came from parkinsonism induced by the accidental exposure of drug users to 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), an inhibitor of the mitochondrial complex I of the electron transport chain (Langton et al., 1983 ; Esteves et al., 2011 ). Parker et al. ( 1989 ) found a significant reduction in the activity of complex I in platelet mitochondria purified from patients with idiopathic Parkinson's disease (Esteves et al., 2011 ). Further evidence for mitochondrial dysfunction in Parkinson's disease arose from studies developed in the substantia nigra of postmortem brains of patients with the disease, which showed deficiency of complex-I activity (Shapira et al., 1990 ; Esteves et al., 2011 ). Genes associated with familial form of the disease has been reported such as pink1, parkin, DJ-1, and CHCHD2 (Kazlauskaite and Muqit, 2015 ; Meng et al., 2017 ). Autophagy Macroautophagy is the most widely studied type of autophagy, where vacuoles with double membranes form, surround cellular elements (such as proteins, lipids, and organelles), and fuse with lysosomes, the enzymes of which degrade the autophagic cargo. Autophagy is controlled by proteins that are encoded by autophagy-related genes (ATGs), ATG1–ATG35. These proteins are organized into complexes that mediate the following steps in the autophagic process: initiation, elongation, maturation, and fusion and degradation (Tan et al., 2014 ). The pathways that control autophagy are primarily mTOR-dependent and mTOR-independent (mTOR: the mechanistic target of rapamycin, a serine/threonine kinase). mTOR is primarily an inhibitory signal, which participates upstream of the ATG proteins. In the mTOR-independent pathway the autophagy can be directly activated by AMPK [adenosine monophosphate (AMP)-activated protein kinase], leading to direct phosphorylation of ULK1 (serine-threonine-protein kinase that is encoded by the ULK1 gene) and beclin-1 (Tan et al., 2014 ). Mitophagy The degradation of mitochondria damaged by the autophagic pathway is known as mitophagy and constitutes one of the main mechanisms of cellular homeostasis (Zhang, 2013 ; Brady and Brady, 2016 ). Mitochondrial damage causes a decrease in mitochondrial membrane potential or an increase in mitochondrial fission, and both situations activate mitophagy (Brady and Brady, 2016 ). There are multiple mechanisms by which mitochondria are targeted for degradation in autophagosomes, but the best understood are the pathways of mitophagy induced by PINK/Parkin and BNIP3 (BCL2/adenovirus E1B 19 kDa protein-interacting protein 3), and NIX-dependent mitophagy (Nix: also known as BNIP3L, a BH3-only protein of the BCL-2 pro-apoptotic family). The mitochondrial protein PINK1 [phosphatase and tensin homolog (PTEN)-induced putative kinase 1], a serine-threonine kinase, is unstable due to presenilin-associated rhomboid-like protease activities (PARL). The decrease in mitochondrial membrane potential inhibits PINK1 degradation by PARL. In response to mitochondrial depolarization, PINK stabilizes, and accumulates in the outer mitochondrial membrane (OMM), where it phosphorylates ubiquitin in mitochondrial proteins to recruit autophagic cargo adapters, such as OPTN (Optineurin) and NDP52 (Nuclear dot protein 52 kDa), which directly bind to light chain 3 (LC3) in the autophagosome leading to degradation of mitochondria within autophagolysosomes (Springer and Macleod, 2016 ). PINK1 also recruits the E3 ubiquitin ligase Parkin and ubiquitin-specific substrates in the OMM, including VDAC (voltage-dependent anion-selective channel), Miro, and Mitofusin-2 to amplify the signal initiated by PINK (Springer and Macleod, 2016 ). Mutations in PARK2 (Parkin) and PARK6 (PINK1) have been independently linked to familial cases of Parkinson's disease, associating defects in mitophagy with the degeneration of dopaminergic neurons, a major feature of Parkinson's disease (Pikrell and Youle, 2015 ; Springer and Macleod, 2016 ). The clearance of mitochondria damaged by mitophagy prevents the accumulation of dysfunctional mitochondria and can also induce mitochondrial biogenesis, increasing cell survival. On the contrary, the decrease in mitophagy occurring during aging, for example, prevents both the removal of damaged mitochondria and alters mitochondrial biogenesis, which causes the progressive accumulation of dysfunctional mitochondria (Zhang, 2013 ; Palikaras et al., 2015 ). The dysfunction of the autophagic/lysosomal pathway is associated with mitochondrial dysfunction, which may be due to the decrease in the autophagic degradation of the dysfunctional mitochondria. For example, Wu et al. ( 2009 ) reported that deletion o