ER membrane reorganisation negatively regulates BH3 mimetic mediated mitochondrial fission, outer membrane permeabilisation and apoptosis Govinda Yedida1, Mateus Milani1, Gerald M. Cohen1,2 and Shankar Varadarajan1,2 Departments of 1Molecular and Clinical Cancer Medicine and 2Pharmacology, Institute of Translational Medicine, University of Liverpool, UK
We have previously identified an evolutionarily conserved form of cellular stress response characterised by a striking, but reversible, reorganisation of ER membranes that occurred independently of the canonical Unfolded Protein Response (UPR). Moreover, using connectivity mapping, we identified several structurally diverse chemicals that can induce this novel form of ER membrane reorganisation. Now, we report that such ER membrane reorganisation occurs at the level of ER tubes and not sheets, and yet significantly affecting several ER functions, such as ER-golgi trafficking and global protein synthesis. Since the ER tubular architecture facilitates its association with other organelles, such as mitochondria, endosomes and peroxisomes, thus regulating homeostasis, cell survival and proliferation, it is possible that ER membrane reorganisation could affect the structural and functional integrity of these organelles. In this study, we focus on mitochondrial structure and function, and report that induction of ER membrane reorganisation disrupted mitochondrial fission, mediated by BH3 mimetics (apoptosis inducers) and CCCP (mitochondrial uncoupler/ autophagy inducer) in the non-small cell lung carcinoma cell line, H1299. Furthermore, the reorganised ER tubes also inhibited BH3 mimetic-mediated mitochondrial outer membrane permeabilisation (characterised by the release of mitochondrial cytochrome c) and phosphatidylserine externalisation in several cell lines. These results highlight the requirement of 'untangled' ER tubes for the onset of mitochondrial fission, outer membrane permeabilisation and apoptosis in cancer cells.
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