title: Rescue of PINK1 protein null-specific mitochondrial complex IV deficits by ginsenoside Re activation of nitric oxide signaling.
abstract: PINK1, linked to familial Parkinson's disease, is known to affect mitochondrial function. Here we identified a novel regulatory role of PINK1 in the maintenance of complex IV activity and characterized a novel mechanism by which NO signaling restored complex IV deficiency in PINK1 null dopaminergic neuronal cells. In PINK1 null cells, levels of specific chaperones, including Hsp60, leucine-rich pentatricopeptide repeat-containing (LRPPRC), and Hsp90, were severely decreased. LRPPRC and Hsp90 were found to act upstream of Hsp60 to regulate complex IV activity. Specifically, knockdown of Hsp60 resulted in a decrease in complex IV activity, whereas antagonistic inhibition of Hsp90 by 17-(allylamino) geldanamycin decreased both Hsp60 and complex IV activity. In contrast, overexpression of the PINK1-interacting factor LRPPRC augmented complex IV activity by up-regulating Hsp60. A similar recovery of complex IV activity was also induced by coexpression of Hsp90 and Hsp60. Drug screening identified ginsenoside Re as a compound capable of reversing the deficit in complex IV activity in PINK1 null cells through specific increases of LRPPRC, Hsp90, and Hsp60 levels. The pharmacological effects of ginsenoside Re could be reversed by treatment of the pan-NOS inhibitor L-NG-Nitroarginine Methyl Ester (L-NAME) and could also be reproduced by low-level NO treatment. These results suggest that PINK1 regulates complex IV activity via interactions with upstream regulators of Hsp60, such as LRPPRC and Hsp90. Furthermore, they demonstrate that treatment with ginsenoside Re enhances functioning of the defective PINK1-Hsp90/LRPPRC-Hsp60-complex IV signaling axis in PINK1 null neurons by restoring NO levels, providing potential for new therapeutics targeting mitochondrial dysfunction in Parkinson's disease.
authors.affiliation: Department of Brain and Cognitive Sciences, College of Pharmacy, Brain Disease Research Institute, Ewha Womans University, 120-750 Seoul, South Korea.
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Karen
authors.initials: K
authors.lastname: Song
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Yoon
authors.forename: Omer
authors.initials: O
authors.lastname: Shehzad
authors.forename: Yeong-Shik
authors.initials: YS
authors.lastname: Kim
authors.forename: Jin H
authors.initials: JH
authors.lastname: Son
mesh_terms: D000818:Animals; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism*; D036145:Ginsenosides / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000099202:PTEN-Induced Putative Kinase
chemical_list: D018834:Chaperonin 60; D003576:Electron Transport Complex IV; D036145:Ginsenosides; D018841:HSP90 Heat-Shock Proteins; D009363:Neoplasm Proteins; D009569:Nitric Oxide; D010936:Plant Extracts; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C486222:Lrpprc protein, mouse; C049864:ginsenoside Re