title: Mao-B elevation decreases parkin's ability to efficiently clear damaged mitochondria: protective effects of rapamycin.
abstract: Increased oxidative stress in the Parkinsonian substantia nigra is believed to contribute to neurodegeneration, in part due to regionally elevated levels of the enzyme monoamine oxidase B (MAO-B). Increased oxidative stress has also been reported to be associated with the inhibition of E3 ligase activity of the Parkinson's disease-related protein parkin. In an inducible MAO-B cell model, losses in parkin E3 ligase activity were found to occur in conjunction with reduced mitochondrial turnover and decreased mitochondrial function, although this did not inhibit parkin's ability to translocation to damaged mitochondria. The mTOR inhibitor rapamycin was found to restore both mitophagy and mitochondrial function in these cells. These data suggest that MAO-B induction can interfere with mitochondrial quality control via losses in parkin activity that in turn impact on mitochondrial turnover. Rapamycin may be an effective means of counteracting the effects of lost parkin function by independently enhancing autophagic removal of damaged mitochondria.
authors.affiliation: Buck Institute for Research in Aging, Novato, CA, USA.
authors.forename: Almas
authors.initials: A
authors.lastname: Siddiqui
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hanson
authors.forename: Julie K
authors.initials: JK
authors.lastname: Andersen
mesh_terms: D000818:Animals; D001343:Autophagy; D002454:Cell Differentiation; D002470:Cell Survival; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D016716:PC12 Cells; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D008995:Monoamine Oxidase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D004318:Doxycycline; D020123:Sirolimus