title: Mitochondrial uncoupling protein-2 (UCP2) mediates leptin protection against MPP+ toxicity in neuronal cells.
abstract: Mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Uncoupling proteins (UCPs) delink ATP production from biofuel oxidation in mitochondria to reduce oxidative stress. UCP2 is expressed in brain, and has neuroprotective effects under various toxic insults. We observed induction of UCP2 expression by leptin in neuronal cultures, and hypothesize that leptin may preserve neuronal survival via UCP2. We showed that leptin preserved cell survival in neuronal SH-SY5Y cells against MPP+ toxicity (widely used in experimental Parkinsonian models) by maintaining ATP levels and mitochondrial membrane potential (MMP); these effects were accompanied by increased UCP2 expression. Leptin had no effect in modulating reactive oxygen species levels. Stable knockdown of UCP2 expression reduced ATP levels, and abolished leptin protection against MPP+-induced mitochondrial depolarization, ATP deficiency, and cell death, indicating that UCP2 is critical in mediating these neuroprotective effects of leptin against MPP+ toxicity. Interestingly, UCP2 knockdown increased UCP4 expression, but not of UCP5. Our findings show that leptin preserves cell survival by maintaining MMP and ATP levels mediated through UCP2 in MPP+-induced toxicity.
authors.affiliation: Division of Neurology, University Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.
authors.forename: Philip Wing-Lok
authors.initials: PW
authors.lastname: Ho
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Liu
authors.forename: Jessica Wing-Man
authors.initials: JW
authors.lastname: Ho
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Zhang
authors.forename: Andrew Chi-Yuen
authors.initials: AC
authors.lastname: Chu
authors.forename: Ken Hon-Hung
authors.initials: KH
authors.lastname: Kwok
authors.forename: Xuan
authors.initials: X
authors.lastname: Ge
authors.forename: Koon-Ho
authors.initials: KH
authors.lastname: Chan
authors.forename: David Boyer
authors.initials: DB
authors.lastname: Ramsden
authors.forename: Shu-Leong
authors.initials: SL
authors.lastname: Ho
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D020738:Leptin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000494:pharmacology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D000071245:Mitochondrial Uncoupling Proteins; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D006540:Herbicides; D007473:Ion Channels; D020738:Leptin; D026901:Membrane Transport Proteins; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D000071245:Mitochondrial Uncoupling Proteins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C117577:SLC25A27 protein, human; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D015655:1-Methyl-4-phenylpyridinium