Ero1α regulates Ca(2+) fluxes at the endoplasmic reticulum-mitochondria interface (MAM)

Anelli, Tiziana and Bergamelli, Leda and Margittai, Eva and Rimessi, Alessandro and Fagioli, Claudio and Malgaroli, Antonio and Pinton, Paolo and Ripamonti, Maddalena and Rizzuto, Rosario and Sitia, Roberto (2012) Ero1α regulates Ca(2+) fluxes at the endoplasmic reticulum-mitochondria interface (MAM). Antioxidants & redox signaling, 16 (10). pp. 1077-1087. ISSN 1557-7716

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Abstract

AIMS The endoplasmic reticulum (ER) is involved in many functions, including protein folding, redox homeostasis, and Ca(2+) storage and signaling. To perform these multiple tasks, the ER is composed of distinct, specialized subregions, amongst which mitochondrial-associated ER membranes (MAM) emerge as key signaling hubs. How these multiple functions are integrated with one another in living cells remains unclear. RESULTS Here we show that Ero1α, a key controller of oxidative folding and ER redox homeostasis, is enriched in MAM and regulates Ca(2+) fluxes. Downregulation of Ero1α by RNA interference inhibits mitochondrial Ca(2+) fluxes and modifies the activity of mitochondrial Ca(2+) uniporters. The overexpression of redox active Ero1α increases passive Ca(2+) efflux from the ER, lowering [Ca(2+)](ER) and mitochondrial Ca(2+) fluxes in response to IP3 agonists. INNOVATION The unexpected observation that Ca(2+) fluxes are affected by either increasing or decreasing the levels of Ero1α reveals a pivotal role for this oxidase in the early secretory compartment and implies a strict control of its amounts. CONCLUSIONS Taken together, our results indicate that the levels, subcellular localization, and activity of Ero1α coordinately regulate Ca(2+) and redox homeostasis and signaling in the early secretory compartment.

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