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

Abstract

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⁻/Pi²⁻ and/or HADP²⁻/Pi²⁻ 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.