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

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 signalinghubs. How these multiple functions are integrated with one another in living cells remains unclear.Results: Here we show that Ero1a, a key controller of oxidative folding and ER redox homeostasis, is enriched inMAM and regulates Ca2+ fluxes. Downregulation of Ero1a by RNA interference inhibits mitochondrial Ca2+fluxes and modifies the activity of mitochondrial Ca2+ uniporters. The overexpression of redox active Ero1aincreases passive Ca2+ efflux from the ER, lowering [Ca2+]ER and mitochondrial Ca2+ fluxes in response to IP3agonists. Innovation: The unexpected observation that Ca2+ fluxes are affected by either increasing or decreasingthe levels of Ero1a reveals a pivotal role for this oxidase in the early secretory compartment and implies a strictcontrol of its amounts. Conclusions: Taken together, our results indicate that the levels, subcellular localization,and activity of Ero1a coordinately regulate Ca2+ and redox homeostasis and signaling in the early secretorycompartment. Antioxid. Redox Signal. 16, 1077–1087.