title: Neuroprotection of deferoxamine on rotenone-induced injury via accumulation of HIF-1 alpha and induction of autophagy in SH-SY5Y cells.
abstract: Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor that activates the transcription of genes and is responsible for progression of cell survival and proliferation. The synthesis of HIF-1 alpha can be stimulated via oxygen (O(2))-independent mechanisms; whereas, the degradation of HIF-1 alpha is regulated via Fe(2+) and/or O(2)-dependent enzyme prolyl hydroxylase (PHD). Aberrant iron accumulation, mitochondrial dysfunction and impairment of protein degradation system, such as autophagy, have been implicated in the pathogenesis of Parkinson's disease, among which, iron and mitochondrial dysfunction may enhance the enzyme activity of prolyl hydroxylase and cause the decrease of HIF-1 alpha. Recent reports have indicated that HIF-1 alpha may induce autophagy under hypoxic condition. Considering the metabolic characteristics of HIF-1 alpha under the pathogenesis of Parkinson's disease, we speculated that compounds that might stabilize HIF-1 alpha could prevent neuronal injury caused by excessive iron or mitochondrial injury under normoxic condition. Deferoxamine is one of iron chelators that may accumulate HIF-1 alpha due to the decreased degradation of HIF-1 alpha via inhibition of prolyl hydroxylase activity. In this study, we showed that the protein level of HIF-1 alpha was decreased in rotenone or MPP(+)-treated SH-SY5Y cell models of Parkinson's disease. We demonstrated that deferoxamine caused accumulation of HIF-1 alpha accompanied by the enhancement of autophagy in SH-SY5Y cells. When HIF-1 alpha gene was inhibited, deferoxamine-induced autophagy was suppressed accordingly, indicating that deferoxamine-induced autophagy was dependent on the expression of HIF-1 alpha. Our results also showed that deferoxamine attenuated rotenone-induced apoptosis, which was blocked when HIF-1 alpha or autophagy related gene Beclin 1 was suppressed. In summary, the present study indicated that the level of HIF-1 alpha was decreased under the situation when mitochondrial complex I was inhibited, and the neuroprotective role of deferoxamine in rotenone-induced apoptosis could be partially explained by its effects on the accumulation of HIF-1 alpha and HIF-1 alpha-mediated induction of autophagy.
authors.affiliation: Department of Neurology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China.
authors.forename: Yuncheng
authors.initials: Y
authors.lastname: Wu
authors.forename: Xinqun
authors.initials: X
authors.lastname: Li
authors.forename: Wenjie
authors.initials: W
authors.lastname: Xie
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
authors.forename: Tianhong
authors.initials: T
authors.lastname: Pan
mesh_terms: D000931:Antidotes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D015153:Blotting, Western; D002460:Cell Line; D003676:Deferoxamine / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018696:Neuroprotective Agents; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000517:prevention & control* / Q000523:psychology; D012402:Rotenone / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D014475:Uncoupling Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*
chemical_list: D000931:Antidotes; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D014475:Uncoupling Agents; D012402:Rotenone; D003676:Deferoxamine