Abstract
Abstract FATE1 (fetal and adult testis expressed 1), also known as the cancer-testis antigen BJ-HCC-2, is expressed in testis and tumor tissues. FATE1 was recently described as a major survival factor in tumor cells of various origins, by mediating the degradation of the pro-apoptotic BH3-only protein Bik (Maxfield et al., in Nat Commun 2015 Nov 16;6:8840) and through ER-mitochondrial uncoupling (Doghman-Bouguerra et al., in EMBO Rep 2016 Sep;17(9):1264-80). Interestingly, FATE1 shares high sequence homology with the mitochondrial Drp1 receptor MFF (mitochondrial fission factor). We thus investigated a possible role of FATE1 impact on mitochondrial morphology following the stimulation of apoptosis in cancer cells. We found that, similar to MFF, FATE1 is localized to outer mitochondrial membranes and, unlike MFF, additionally localized to the endoplasmic reticulum. Importantly, in contrast to MFF, FATE1 overexpression does not recruit Drp1 to mitochondria, and instead promotes hyperfusion of mitochondrial networks. Co-immunoprecipitation experiments and reconstitution of Mfn2 or Mfn1 in double knockout mouse embryonic fibroblasts indicate a role for the mitochondrial fusion protein Mfn2, but not Mfn1. As FATE1 overexpressing cancer cells were more resistant to mitochondrial fragmentation in response to TNF and valinomycin treatments, we propose FATE1 as a novel regulator of mitochondrial morphology changes occurring during apoptosis, with possible implications in FATE1-mediated resistance of cancer cells to chemotherapy. Citation Format: Anne Hamacher-Brady, Verena Lang, Nathan R. Brady. FATE1 promotes mitochondrial hyperfusion and supports maintenance of mitochondrial networks following apoptosis stimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3324. doi:10.1158/1538-7445.AM2017-3324
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