SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca2+ buffering

Ca2+-mediated mitochondrial permeability transition (mPT) is the final common pathway of stress-induced cell death in many major pathologies, but its regulation in intact cells is poorly understood. Here we report that the mitochondrial carrier SCaMC-1/SLC25A24 mediates ATP-Mg2-/Pi(2-) and/or HADP(2-)/Pi(2-) uptake into the mitochondria after an increase in cytosolic [Ca2+]. ATP and ADP contribute to Ca2+ buffering in the mitochondrial matrix, resulting in desensitization of the mPT. Comprehensive gene expression analysis showed that SCaMC-1 overexpression is a general feature of transformed and cancer cells. Knockdown of the transporter led to vast reduction of mitochondrial Ca2+ buffering capacity and sensitized cells to mPT-mediated necrotic death triggered by oxidative stress and Ca2+ overload. These findings revealed that SCaMC-1 exerts a negative feedback control between cellular Ca2+ overload and mPT-dependent cell death, suggesting that the carrier might represent a novel target for cancer therapy. Cell Death and Differentiation (2012) 19, 650-660; doi:10.1038/cdd.2011.139; published online 21 October 2011