Regulation of mitochondrial calcium signaling by Pannexin2

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** * 0* 0* 1* 242* 1382* 11* 3* 1621* 14.0* * * * * *** * Normal* 0* * * * * false* false* false* * EN-US* ZH-CN* X-NONE* * * * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * **** /* Style Definitions */*table.MsoNormalTable* {mso-style-name:"Table Normal";* mso-tstyle-rowband-size:0;* mso-tstyle-colband-size:0;* mso-style-noshow:yes;* mso-style-priority:99;* mso-style-parent:"";* mso-padding-alt:0cm 5.4pt 0cm 5.4pt;* mso-para-margin-top:0cm;* mso-para-margin-right:0cm;* mso-para-margin-bottom:10.0pt;* mso-para-margin-left:0cm;* text-align:justify;* text-justify:inter-ideograph;* text-indent:36.0pt;* mso-pagination:widow-orphan;* font-size:12.0pt;* font-family:"Times New Roman";* mso-ansi-language:EN-US;* mso-fareast-language:ZH-CN;}*******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. *** *