TY - JOUR
T1 - Neuroprotection of deferoxamine on rotenone-induced injury via accumulation of HIF-1α and induction of autophagy in SH-SY5Y cells
AU - Wu, Yuncheng
AU - Li, Xinqun
AU - Xie, Wenjie
AU - Jankovic, Joseph
AU - Le, Weidong
AU - Pan, Tianhong
N1 - Funding Information:
This work was supported by Diana Helis Henry Medical Research Foundation (2007–2010), Carolyn Weiss Law seed funding (2008–2009). It was also supported by the funding for Excellent Young Medical Talent of Shanghai First People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine. We also thank the National Parkinson Foundation of their support of the NPF Center of Excellence at Baylor College of Medicine. We thank Institutional Core Grant #CA16672 High Resolution Electron Microscopy facility, UTMDACC and appreciate the hard work by Kenneth Dunner.
PY - 2010/10
Y1 - 2010/10
N2 - Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that activates the transcription of genes and is responsible for progression of cell survival and proliferation. The synthesis of HIF-1α can be stimulated via oxygen (O2)-independent mechanisms; whereas, the degradation of HIF-1α is regulated via Fe2+ and/or O2-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-1α Recent reports have indicated that HIF-1α may induce autophagy under hypoxic condition. Considering the metabolic characteristics of HIF-1α under the pathogenesis of Parkinson's disease, we speculated that compounds that might stabilize HIF-1α could prevent neuronal injury caused by excessive iron or mitochondrial injury under normoxic condition. Deferoxamine is one of iron chelators that may accumulate HIF-1α due to the decreased degradation of HIF-1α via inhibition of prolyl hydroxylase activity. In this study, we showed that the protein level of HIF-1α was decreased in rotenone or MPP+-treated SH-SY5Y cell models of Parkinson's disease. We demonstrated that deferoxamine caused accumulation of HIF-1α accompanied by the enhancement of autophagy in SH-SY5Y cells. When HIF-1α gene was inhibited, deferoxamine-induced autophagy was suppressed accordingly, indicating that deferoxamine-induced autophagy was dependent on the expression of HIF-1α Our results also showed that deferoxamine attenuated rotenone-induced apoptosis, which was blocked when HIF-1α or autophagy related gene Beclin 1 was suppressed. In summary, the present study indicated that the level of HIF-1α 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-1α and HIF-1α-mediated induction of autophagy.
AB - Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that activates the transcription of genes and is responsible for progression of cell survival and proliferation. The synthesis of HIF-1α can be stimulated via oxygen (O2)-independent mechanisms; whereas, the degradation of HIF-1α is regulated via Fe2+ and/or O2-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-1α Recent reports have indicated that HIF-1α may induce autophagy under hypoxic condition. Considering the metabolic characteristics of HIF-1α under the pathogenesis of Parkinson's disease, we speculated that compounds that might stabilize HIF-1α could prevent neuronal injury caused by excessive iron or mitochondrial injury under normoxic condition. Deferoxamine is one of iron chelators that may accumulate HIF-1α due to the decreased degradation of HIF-1α via inhibition of prolyl hydroxylase activity. In this study, we showed that the protein level of HIF-1α was decreased in rotenone or MPP+-treated SH-SY5Y cell models of Parkinson's disease. We demonstrated that deferoxamine caused accumulation of HIF-1α accompanied by the enhancement of autophagy in SH-SY5Y cells. When HIF-1α gene was inhibited, deferoxamine-induced autophagy was suppressed accordingly, indicating that deferoxamine-induced autophagy was dependent on the expression of HIF-1α Our results also showed that deferoxamine attenuated rotenone-induced apoptosis, which was blocked when HIF-1α or autophagy related gene Beclin 1 was suppressed. In summary, the present study indicated that the level of HIF-1α 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-1α and HIF-1α-mediated induction of autophagy.
KW - Autophagy
KW - HIF-1α
KW - Iron chelator
KW - Neuroprotection
KW - Parkinson's disease
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UR - http://www.scopus.com/inward/citedby.url?scp=77955094939&partnerID=8YFLogxK
U2 - 10.1016/j.neuint.2010.05.008
DO - 10.1016/j.neuint.2010.05.008
M3 - Article
C2 - 20546814
AN - SCOPUS:77955094939
SN - 0197-0186
VL - 57
SP - 198
EP - 205
JO - Neurochemistry International
JF - Neurochemistry International
IS - 3
ER -