Ero1α Regulates Ca2+ Fluxes at the Endoplasmic Reticulum-Mitochondria Interface (MAM)

Aims: The endoplasmic reticulum (ER) is involved in many functions, including protein folding, redox homeostasis, and Ca2+ 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 Ero1 alpha, a key controller of oxidative folding and ER redox homeostasis, is enriched in MAM and regulates Ca2+ fluxes. Downregulation of Ero1 alpha by RNA interference inhibits mitochondrial Ca2+ fluxes and modifies the activity of mitochondrial Ca2+ uniporters. The overexpression of redox active Ero1 alpha increases passive Ca2+ efflux from the ER, lowering [Ca2+](ER) and mitochondrial Ca2+ fluxes in response to IP3 agonists. Innovation: The unexpected observation that Ca2+ fluxes are affected by either increasing or decreasing the levels of Ero1 alpha 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 Ero1 alpha coordinately regulate Ca2+ and redox homeostasis and signaling in the early secretory compartment. Antioxid. Redox Signal. 16, 1077-1087.