FATE1 antagonizes calcium‐ and drug‐induced apoptosis by uncoupling ER and mitochondria. (11th July 2016)

• Record Type: Journal Article
• Authors: Doghman‐Bouguerra, Mabrouka; Granatiero, Veronica; Sbiera, Silviu; Sbiera, Iuliu; Lacas‐Gervais, Sandra; Brau, Frédéric; Fassnacht, Martin; Rizzuto, Rosario; Lalli, Enzo
• Is Part Of: EMBO reports. Volume 17:Number 9(2016:Sep.)
• Page Start: 1264
• Page End: 1280
• Publication Date: 2016-07-11
• Subjects: adrenal cortex -- apoptosis -- endocrine cancer -- MAM -- mitochondria; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201541504
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Several stimuli induce programmed cell death by increasing Ca 2+ transfer from the endoplasmic reticulum (ER) to mitochondria. Perturbation of this process has a special relevance in pathologies as cancer and neurodegenerative disorders. Mitochondrial Ca 2+ uptake mainly takes place in correspondence of mitochondria‐associated ER membranes (MAM), specialized contact sites between the two organelles. Here, we show the important role of FATE1, a cancer‐testis antigen, in the regulation of ER–mitochondria distance and Ca 2+ uptake by mitochondria. FATE1 is localized at the interface between ER and mitochondria, fractionating into MAM. FATE1 expression in adrenocortical carcinoma (ACC) cells under the control of the transcription factor SF‐1 decreases ER–mitochondria contact and mitochondrial Ca 2+ uptake, while its knockdown has an opposite effect. FATE1 also decreases sensitivity to mitochondrial Ca 2+ ‐dependent pro‐apoptotic stimuli and to the chemotherapeutic drug mitotane. In patients with ACC, FATE1 expression in their tumor is inversely correlated with their overall survival. These results show that the ER–mitochondria uncoupling activity of FATE1 is harnessed by cancer cells to escape apoptotic death and resist the action of chemotherapeutic drugs. Synopsis: This study shows that FATE1, a cancer‐testis antigen, is localized at the interface between the ER and mitochondria where it modulates the coupling of the two organelles and apoptotic cell death. FATE1 is a cancer‐testis antigen. FATE1 levels are a prognostic indicator in adrenocortical carcinoma patients. Abstract : This study shows that FATE1, a cancer‐testis antigen, is localized at the interface between the ER and mitochondria where it modulates the coupling of the two organelles and apoptotic cell death.