BimEL up‐regulation potentiates AIF translocation and cell death in response to MPTP

Abstract

This study attempted to elucidate the signaling mechanism underlying dopaminergic cell death in the MPP+ model for Parkinson's disease. In neuronal-differentiated PC12 cells, through the regulation by activated JNK and c-jun, BimEL expression was markedly increased in response to MPP+ treatment, which led to the cell degeneration. In lieu of Smac translocation as seen in other paradigms, up-regulation of BimEL effected an increase in calpain I activity that, in turn, mediated AIF release from the mitochondria. In support, we found that knocking down BimEL expression resulted in a decrease in calpain I activity, as well as AIF release from the mitochondria and cell death. Finally, inhibition of calpain activity mitigated AIF release from the mitochondria and cell death. Under cell-free conditions, activated purified calpain I could induce the release of AIF from isolated mitochondria without the participation of BimEL or activated JNK, suggesting that AIF release is a direct consequence of calpain I activity. In concert, the results suggest a novel signaling pathway for dopaminergic cell degeneration, in which MPP+ induces the up-regulation of BimEL, which in turn potentiates an elevation in calpain I activity that mediates AIF release and cell death in a caspase-independent manner.

Cavitation of embryoid bodies requires optimal oxidative phosphorylation and AIF

“…These cells are identifiable as macrophages by their stereotypic distribution and enormous size, and by doubly labeling for Croquemort (Figure 1e), a macrophage-specific cell surface marker. 11,12 Identical results were obtained using the mitochondrial marker TMRE (not shown).…”

“…10 In mammalian cells, removal of AIF can reduce apoptosis in some particular settings, although there is no general apoptosis defect. 2,8,9 Thus, knockdown of AIF protects differentiated PC12 cells against the neurotoxin 1-methyl-4-phenylpyridinium, 12 Jurkat T lymphoma cells against a combination of g-irradiation and phytosphingosin, 13 16 and Raji B lymphoma cells against UV irradiation. 17 Microinjection of AIF-neutralizing antibodies can also reduce the neurotoxic effects of NMDA in primary murine cortical cultures, 18 the lethal effects of PARP-1 activators in several cellular systems, 19 as well as the proapoptotic effects of staurosporin on non-small cell lung carcinoma cells.…”

3,4-Dihydroxyphenylacetic acid (DOPAC) modulates the toxicity induced by nitric oxide in PC-12 cells via mitochondrial dysfunctioning

“…8a and b). In fact, several studies suggest that in this neurodegenerative disease the neurons can die by a caspase-independent cell death (Graeber et al, 1999;Han et al, 2003;Chu et al, 2005;Liou et al, 2005).…”

Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia

“…27 Knock down of AIF with small interfering RNAs (siRNAs) protects primary cultures of hippocampal neurons and HT22 cells from glutamate toxicity 16 and differentiated PC12 cells against the neurotoxin 1-methyl-4-phenylpyridinium. 28 In vivo excitotoxic studies using kainic acid-induced seizures revealed that Hq mice had significantly less hippocampal damage than Wt littermates. 13 In addition, the brains of adult Hq mice are particularly resistant to focal ischemia.…”