SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca(2+) buffering.
Ca(2+)-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-Mg(2-)/Pi(2-) and/or HADP(2-)/Pi(2-) uptake into the mitochondria after an increase in cytosolic [Ca(2+)]. ATP and ADP contribute to Ca(2+) 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 Ca(2+) buffering capacity and sensitized cells to mPT-mediated necrotic death triggered by oxidative stress and Ca(2+) overload. These findings revealed that SCaMC-1 exerts a negative feedback control between cellular Ca(2+) overload and mPT-dependent cell death, suggesting that the carrier might represent a novel target for cancer therapy.
Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa UAM-CSIC, CIBER de Enfermedades Raras, Universidad Autónoma, Madrid, Spain.
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J
Traba
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A
Del Arco
M R
MR
Duchen
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G
Szabadkai
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J
Satrústegui
D000244:Adenosine Diphosphate / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002522:Chlorocebus aethiops; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D018384:Oxidative Stress / Q000235:genetics; D010539:Permeability
D002135:Calcium-Binding Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002118:Calcium