MTORC1 inhibitor rapamycin and ER stressor tunicamycin induce differential patterns of ER-mitochondria coupling

Roberto Bravo-Sagua, Camila López-Crisosto, Valentina Parra, Marcelo Rodriguez-Peña, Beverly A. Rothermel, Andrew F G Quest, Sergio Lavandero

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Abstract

Efficient mitochondrial Ca2+ uptake takes place at contact points between the ER and mitochondria, and represents a key regulator of many cell functions. In a previous study with HeLa cells, we showed that ER-to-mitochondria Ca2+ transfer increases during the early phase of ER stress induced by tunicamycin as an adaptive response to stimulate mitochondrial bioenergetics. It remains unknown whether other types of stress signals trigger similar responses. Here we observed that rapamycin, which inhibits the nutrient-sensing complex mTORC1, increased ER-mitochondria coupling in HeLa cells to a similar extent as did tunicamycin. Interestingly, although global responses to both stressors were comparable, there were notable differences in the spatial distribution of such changes. While tunicamycin increased organelle proximity primarily in the perinuclear region, rapamycin increased organelle contacts throughout the entire cell. These differences were paralleled by dissimilar alterations in the distribution of regulatory proteins of the ER-mitochondria interface, heterogeneities in mitochondrial Ca2+ uptake, and the formation of domains within the mitochondrial network with varying mitochondrial transmembrane potential. Collectively, these data suggest that while increasing ER-mitochondria coupling appears to represent a general response to cell stress, the intracellular distribution of the associated responses needs to be tailored to meet specific cellular requirements.

Original languageEnglish (US)
Article number36394
JournalScientific Reports
Volume6
DOIs
StatePublished - Nov 3 2016

ASJC Scopus subject areas

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    Bravo-Sagua, R., López-Crisosto, C., Parra, V., Rodriguez-Peña, M., Rothermel, B. A., Quest, A. F. G., & Lavandero, S. (2016). MTORC1 inhibitor rapamycin and ER stressor tunicamycin induce differential patterns of ER-mitochondria coupling. Scientific Reports, 6, [36394]. https://doi.org/10.1038/srep36394