title: Potential roles of PINK1 for increased PGC-1α-mediated mitochondrial fatty acid oxidation and their associations with Alzheimer disease and diabetes.
abstract: Down-regulation of PINK1 and PGC-1α proteins is implicated in both mitochondrial dysfunction and oxidative stress potentially linking metabolic abnormality and neurodegeneration. Here, we report that PGC-1α and PINK1 expression is markedly decreased in Alzheimer disease (AD) and diabetic brains. We observed a significant down-regulation of PGC-1α and PINK1 protein expression in H2O2-treated cells but not in those cells treated with N-acetyl cysteine. The protein levels of two key enzymes of the mitochondrial β-oxidation machinery, acyl-coenzyme A dehydrogenase, very long chain (ACADVL) and mitochondrial trifunctional enzyme subunit α are significantly decreased in AD and diabetic brains. Moreover, we observed a positive relationship between ACADVL and 64 kDa PINK1 protein levels in AD and diabetic brains. Overexpression of PGC-1α decreases lipid-droplet accumulation and increases mitochondrial fatty acid oxidation; down-regulation of PINK1 abolishes these effects. Together, these results provide new insights into potential cooperative roles of PINK1 and PGC-1α in mitochondrial fatty acid oxidation, suggesting possible regulatory roles for mitochondrial function in the pathogenesis of AD and diabetes.
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, MD 21201, USA; Veterans Affairs Medical Center, Baltimore, MD 21201, USA. Electronic address: jochoi@som.umaryland.edu.
authors.forename: Joungil
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, MD 21201, USA; Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
authors.forename: Avinash
authors.initials: A
authors.lastname: Ravipati
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, MD 21201, USA; Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
authors.forename: Vamshi
authors.initials: V
authors.lastname: Nimmagadda
authors.affiliation: National Institute of Neurological Disorders and Stroke, Baltimore, MD 21201, USA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert
authors.affiliation: Department of Pathology, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Rudolph J
authors.initials: RJ
authors.lastname: Castellani
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, MD 21201, USA; Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Russell
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology; D005227:Fatty Acids / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011494:Protein Kinases; D014157:Transcription Factors; D000099202:PTEN-Induced Putative Kinase; C486497:PPARGC1A protein, human; C485290:Ppargc1a protein, mouse
keywords: Alzheimer disease; Diabetes; Mitochondria; PGC-1α; PINK1