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.