Tickled PINK1: mitochondrial homeostasis and autophagy in recessive Parkinsonism.
Dysregulation of mitochondrial structure and function has emerged as a central factor in the pathogenesis of Parkinson's disease and related parkinsonian disorders (PD). Toxic and environmental injuries and risk factors perturb mitochondrial complex I function, and gene products linked to familial PD often affect mitochondrial biology. Autosomal recessive mutations in PTEN-induced kinase 1 (PINK1) cause an L-DOPA responsive parkinsonian syndrome, stimulating extensive interest in the normal neuroprotective and mitoprotective functions of PINK1. Recent data from mammalian and invertebrate model systems converge upon interactions between PINK1 and parkin, as well as DJ-1, alpha-synuclein and leucine rich repeat kinase 2 (LRRK2). While all studies to date support a neuroprotective role for wild type, but not mutant PINK1, there is less agreement on subcellular compartmentalization of PINK1 kinase function and whether PINK1 promotes mitochondrial fission or fusion. These controversies are reviewed in the context of the dynamic mitochondrial lifecycle, in which mitochondrial structure and function are continuously modulated not only by the fission-fusion machinery, but also by regulation of biogenesis, axonal/dendritic transport and autophagy. A working model is proposed, in which PINK1 loss-of-function results in mitochondrial reactive oxygen species (ROS), cristae/respiratory dysfunction and destabilization of calcium homeostasis, which trigger compensatory fission, autophagy and biosynthetic repair pathways that dramatically alter mitochondrial structure. Concurrent strategies to identify pathways that mediate normal PINK1 function and to identify factors that facilitate appropriate compensatory responses to its loss are both needed to halt the aging-related penetrance and incidence of familial and sporadic PD.
Chu
Charleen T
CT
Department of Pathology (Division of Neuropathology), Center for Neuroscience and McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA, USA. ctc4@pitt.edu
D000818:Animals; D001343:Autophagy; D002454:Cell Differentiation; D006706:Homeostasis; D008928:Mitochondria / Q000201:enzymology*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000201:enzymology*; D011494:Protein Kinases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase