期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1802, 期 1, 页码 20-28出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2009.06.012
关键词
PINK1; Parkin; Autophagy; Kinase; Mitochondria; Neurodegeneration; Oxidative stress; Parkinson's disease; Mitochondrial fission; Calcium dysregulation; Electron transport chain; Cristae
资金
- National Institutes of Health [AG026389, AG026389-03S1, NS053777, DC009120]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS053777] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG026389] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS [K18DC009120] Funding Source: NIH RePORTER
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 PINKI 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 PINKI 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. (C) 2009 Elsevier B.V. All rights reserved.
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