Dynamin-related protein 1: A protein critical for mitochondrial fission, mitophagy, and neuronal death in Parkinson's disease. (January 2020)

• Record Type: Journal Article
• Authors: Feng, Si-Tong; Wang, Zhen-Zhen; Yuan, Yu-He; Wang, Xiao-Le; Sun, Hong-Mei; Chen, Nai-Hong; Zhang, Yi
• Is Part Of: Pharmacological research. Volume 151(2020)
• Publication Date: 2020-01
• Subjects: AMBRA1 activating molecule in Beclin1-regulated autophagy -- AMPK AMP-activated protein kinase -- ATAD3 AAA domain-containing protein 3 -- Atg autophagy-related protein -- ATP adenosine triphosphate -- Bcl-2 B-cell lymphoma 2 -- BNIP3 Bcl-2/adenovirus E1B 19-kDa interacting protein 3 -- Ca2+ calcium -- CaMKIα Ca2+/calmodulin-dependent kinase type I α -- CCCP carbonyl cyanide m-chlorophenylhydrazone -- CDK cyclin-dependent kinase -- Drp1 dynamin-related protein 1 -- ER endoplasmic reticulum -- ERK extracellular signal-regulated protein kinase -- Fis1 fission 1 -- FUNDC1 FUN14 domain containing 1 -- GABARAP GABA type A receptor-associated protein -- GSK-3β glycogen synthase kinase-3β -- GTPase guanosine triphosphatase -- IMM inner mitochondrial membrane -- IMS intermembrane space -- INF2 protein inverted formin-2 -- IRGM immunity related GTPase M -- LC3 light chain 3 -- LPS lipopolysaccharide -- LRRK2 leucine-rich repeat kinase-2 -- MAPK mitogen-activated protein kinase -- mdivi mitochondrial division inhibitor -- Mff mitochondrial fission factor -- Mfn1/2 mitofusin 1/2 -- MiD49/51 mitochondrial dynamic 49/51kDa protein -- MIRO1 mitochondrial rho 1 -- MitoQ 10-(4, 5-dimethoxy-2-methyl-3, 6-dioxo-1, 4-cyclohexadien-1-yl)decyl triphenylphosphonium -- MLKL mixed lineage kinase domain-like -- MPTP 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine -- MtCK mitochondrial isoform of creatine kinase -- mtDNA mitochondrial DNA -- mTOR mechanistic target of rapamycin -- NDP52 nuclear dot protein 52kDa -- NDPK-D nucleoside diphosphate kinase-D -- NF-κB nuclear transcription factor-kappa B -- NIX Nip-like protein x -- OMM outer mitochondrial membrane -- Opa1 optic atrophy 1 -- PARL presenilin-associated rhomboid-like protein -- PD Parkinson's disease -- PGAM5 phosphoglycerate mutase family member 5 -- PI3K phosphatidylinositide 3-kinase -- PINK1 PTEN-induced putative kinase 1 -- PKA protein kinase A -- PKB Akt/protein kinase B -- PKC protein kinase C -- PKI protein kinase I -- Rheb Ras homolog enriched in brain protein -- RIP1/3 receptor-interacting protein 1/3 -- RIPK1/3 receptor-interacting protein kinase 1/3 -- ROCK1 Rho-associated coiled-coil-containing protein kinase 1 -- ROS reactive oxygen species -- SIAH seven in absentia homolog -- SREBF1 sterol regulatory element‑binding transcription factor 1 -- TNF-α tumor necrosis factor-α -- TOM translocase of the outer membrane -- TRAF6 TNF receptor associated factor 6 -- ULK1 uncoordinated 51-like kinase 1 -- VDAC1 voltage-dependent anion channel 1 -- WIPI1 WD repeat domain, phosphoinositide interacting 1 -- α-syn α-synuclein -- ΔΨm mitochondrial membrane potential; Parkinson's disease -- Mitochondrial dysfunction -- Dynamin-related protein 1 -- Mitochondrial fission -- Mitophagy; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104553
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Parkinson's disease (PD) that afflicts millions of individuals worldwide is associated with deposits of aggregate-prone proteins (e.g., α-synuclein) and with mitochondrial dysfunction in neuronal cells. Mitochondria are the main source of reactive oxygen species, provide energy for neuronal cells, and are regarded as dynamic organelles that are determined by mitochondrial fission, fusion, and mitophagy to maintain mitochondrial homeostasis. Growing evidence reveals that several dynamics-related proteins, such as dynamin-related protein 1 (Drp1), mediate mitochondrial fission, fusion, and mitophagy, to protect against neurodegeneration in PD. More importantly, not only is Drp1-mediated fission required for mitophagy that exerts a protective effect on neurons, but abnormal mitochondrial fission and mitophagy can drive neuronal survival or cell death (i.e., autophagy, apoptosis, and necroptosis), suggesting that Drp1 may play a pivotal role in the pathogenesis of PD. Also, PD-related proteins such as α-synuclein, leucine-rich repeat kinase-2, PTEN-induced putative kinase 1, and Parkin have been proven to interact with Drp1, thus contributing to mitochondrial dynamics and clearance, as well as neuronal fate. Here, we review the roles of Drp1 in mitochondrial fission, dynamics, mitophagy, bulk autophagy, apoptosis, and necroptosis for a better understanding of mitochondrial disturbances in PD-associated neurodegeneration and summarize the advances of novel chemical compounds targeting Drp1 to provide new insight into potential PD therapies.