Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER\u2013mitochondria communication during the early phase of ER stress

Roberto Bravo-Sagua,Carolina Ortiz-Sandoval,Mario Navarro-Marquez,Valentina Parra,Nasser Tahbaz,Andrea E Rodríguez,Joseph A Hill,Thomas Simmen,Mariana Cifuentes,Carlos Sanhueza,Sergio Lavandero,Andrew F G Quest,Natalia Diaz-Valdivia,Beverly A Rothermel,Camila Lopez-Crisosto

doi:10.1038/s41418-018-0197-1

Abstract

Close contacts between endoplasmic reticulum and mitochondria enable reciprocal Ca2+ exchange, a key mechanism in the regulation of mitochondrial bioenergetics. During the early phase of endoplasmic reticulum stress, this inter-organellar communication increases as an adaptive mechanism to ensure cell survival. The signalling pathways governing this response, however, have not been characterized. Here we show that caveolin-1 localizes to the endoplasmic reticulum–mitochondria interface, where it impairs the remodelling of endoplasmic reticulum–mitochondria contacts, quenching Ca2+ transfer and rendering mitochondrial bioenergetics unresponsive to endoplasmic reticulum stress. Protein kinase A, in contrast, promotes endoplasmic reticulum and mitochondria remodelling and communication during endoplasmic reticulum stress to promote organelle dynamics and Ca2+ transfer as well as enhance mitochondrial bioenergetics during the adaptive response. Importantly, caveolin-1 expression reduces protein kinase A signalling, as evidenced by impaired phosphorylation and alterations in organelle distribution of the GTPase dynamin-related protein 1, thereby enhancing cell death in response to endoplasmic reticulum stress. In conclusion, caveolin-1 precludes stress-induced protein kinase A-dependent remodelling of endoplasmic reticulum–mitochondria communication.

Highlights

Communication between the endoplasmic reticulum (ER) and mitochondria is essential to coordinate cellular responses [1, 2]
These data indicate that CAV1 prevents the mitochondrial response to early ER stress by modulating both mitochondrial bioenergetics and ER–mitochondria communication
Stress, while CAV1 silencing has the opposite effect. These results partially agree with Sala-Vila et al showing that mitochondriaassociated ER membranes (MAM) from CAV1-knockout mice have elevated cholesterol levels [16], which exacerbate the function of the respiratory chain [18]

Summary

Introduction

Communication between the endoplasmic reticulum (ER) and mitochondria is essential to coordinate cellular responses [1, 2]. We showed that disruption of the ER protein folding capacity, termed ER stress, during its early stage increases the ER–mitochondria contacts, leading to an adaptive increase in mitochondrial ATP production [7]. This appears to be a generic response to acute stress, as we observed such changes upon inhibition of the nutrient-sensing kinase mammalian target of rapamycin complex 1 (mTORC1) [8]. Alterations in ER–mitochondria contacts have been reported in various models of chronic disease [9,10,11,12].

Methods

Results

Conclusion