VDAC and BNIP3: a crucial interaction's role in delayed neuronal cell death in stroke

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Szelemej, Paul
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Stroke is currently the third-leading cause of death, and the primary cause of disability in Canada. In a stroke, the majority of neuron death is due to apoptosis triggered by stress from the ischemic insult. In theory, this means that those cells are not predestined to die, but rather program themselves to do so, making understanding apoptotic pathways crucial for potential therapeutic interventions in the future. Although there are countless apoptotic mechanisms and pathways, one important, caspase-independent pathway is that of BNIP3, a death inducing mitochondrial protein. It is currently known that BNIP3 somehow inserts into the mitochondrial membrane, and facilitates the mitochondrial release of apoptotic factors like Endonuclease G and Apoptosis Inducing Factor (AIF), thus further continuing the self-destruction of the cell. Our hypothesis is that the intermediate through which BNIP3 binds and communicates its pro-apoptotic message is VDAC (Voltage Dependent Anion Channels). This hypothesis is based on previous work showing a strong interaction between VDAC and BNIP3 using coimmunoprecipitation and GST pull-down assay techniques. The relationship between BNIP3 and Endo G release with/without VDAC inhibition in murine mitochondria was studied, and the preliminary results support the hypothesis, as EndoG release was significantly decreased upon inhibition of the VDAC receptors in fresh mitochondria, thus implying that VDAC is a significant intermediary between BNIP3 and EndoG in this apoptotic cascade. This could potentially have tremendous implications for the future, in which one might be able to minimize apoptotic neuronal loss after suffering stroke, through inhibition of VDAC.