Free Radical Research, August 2012; 46(8): 1011–1018 ORIGINAL ARTICLE MAO-B elevation decreases parkin’s ability to efﬁciently clear damaged mitochondria: protective effects of rapamycin ALMAS SIDDIQUI, INGRID HANSON & JULIE K. ANDERSEN Buck Institute for Research in Aging, Novato, CA, USA (Received date: 15 December 2011; Accepted date: 25 January 2012) 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 turno- ver and decreased mitochondrial function, although this did not inhibit parkin’s ability to translocation to damaged mito- chondria. 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. Keywords: parkin, mTOR, rapamycin, oxidative stress, monoamine oxidase-B, mitophagy Introduction Studies in both post-mortem patient tissues and Par- kinsonian animal models have provided strong evi- dence supporting the involvement of oxidative stress in the progression of Parkinson’s disease (PD). One possible source of increased oxidative stress are eleva- tions in brain monoamine oxidase B (MAO-B) levels, which have been demonstrated to increase with age and in association with neurodegenerative disease both in humans and in mice [12,13]. Substrate oxi- dation by MAO-B is accompanied by the stoichio- metric reduction of oxygen to hydrogen peroxide (H2O2) [5,17]. It has been postulated that age-related increases in MAO-B activity may contribute to cel- lular neurodegeneration in the brain due to corre- sponding increases in H2O2 production [10]. MAO-B catalysed ROS production has also been suggested to contribute to age-related increases in mitochondrial damage, particularly in the substantia nigra (SN), a brain region, which displays preferential neurodegen- eration in PD [19]. Mitochondrial dysfunction has long been implicated in the pathogenesis of idio- pathic PD [8]. In order to assess the potential role of MAO-B- induced ROS in associated mitochondrial dysfunc- tion, we created both PC12 cell lines [23] and transgenic mice in which MAO-B levels could be spe- ciﬁcally induced [20]. We discovered that elevations in MAO-B activity in these models at concentrations found to be associated with aging and disease resulted in signiﬁcantly increases in levels of mitochondrial dysfunction as a consequence of increased H2O2 gen- eration [8,18]. However, the possible mechanisms involved were not fully elucidated. Parkin is ubiquitin E3 ligase, which has recently been reported to be recruited to impaired mito- chondria and to promote their autophagic degrada- tion via the lysosome [3]. When parkin becomes dysfunctional, the clearance of damaged mitochon- dria is prevented resulting in overall cellular mito- chondrial dysfunction [4]. Mutations in the parkin (PARK2) gene in certain forms of familial PD have Correspondence: Julie K. Andersen, Buck Institute for Research in Aging, 8001 Redwood Blvd, Novato, CA 94945, Tel: 415-209-2070. Fax: 415-209-2231. E-mail: jandersen@buckinstitute.org ISSN 1071-5762 print/ISSN 1029-2470 online © 2012 Informa UK, Ltd. DOI: 10.3109/10715762.2012.662277