Regulation of mitochondrial calcium signaling by Pannexin2

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Pannexins are channel proteins that are related to the connexin family of gap junction proteins. Unlike connexins, pannexins do not from a link between two adjacent cells but connect directly to the external environment of the cells. However, we recently showed that one member of the pannexins, Panx2, is restricted to the interior of the cell. Most importantly, it is closely associated with mitochondria, the energy powerhouse of the cell. Defects in mitochondria are implicated in brain disorders including Alzheimer’s and Parkinson’s disease. Since pannexin channels have been reported to be permeable to calcium ions, we hypothesize that under normal conditions Panx2 channel activity regulate mitochondrial energy production by regulating mitochondrial calcium levels. In contrast, under pathological conditions, dysregulation of Panx2 channel activity triggers mitochondrial calcium overload leading to cell death. We propose to test this hypothesis in three interrelated aims. In Aim 1, we will examine whether alteration of mitochondrial energy production will lead to changes in Panx2 expression and distribution. If an increase in Panx2 is related to mitochondrial dysfunction, we will determine whether Panx2 modulates the production of energy molecule ATP in Aim 2. After confirming the critical role of Panx2 in mitochondrial signaling, we will investigate whether Panx2 activity influences the level mitochondrial calcium in Aim 3. Findings from our proposal will reveal novel strategies to curtail mitochondrial dysfunction and lay the foundation of possible therapeutic interventions in brain diseases.