Aims: The endoplasmic reticulum (ER) is involved in many functions, including protein folding, redox homeostasis and Ca2+ storage and signalling. To perform these multiple tasks, the ER is composed of distinct, specialised subregions, amongst which mitochondrial associated ER membranes (MAM) emerge as key signalling 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 Ca2+ fluxes. Downregulation of Ero1α by RNA interference inhibits mitochondrial Ca2+ fluxes and modifies the activity of mitochondrial Ca2+ uniporters. The over-expression of redox active Ero1α 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 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 co-ordinately regulate Ca2+ and redox homeostasis and signalling in the early secretory compartment.
Ero1α Regulates Ca2+ Fluxes at the Endoplasmic Reticulum-Mitochondria Interface (MAM).
BERGAMELLI, Leda;RIMESSI, Alessandro;PINTON, Paolo;
2012
Abstract
Aims: The endoplasmic reticulum (ER) is involved in many functions, including protein folding, redox homeostasis and Ca2+ storage and signalling. To perform these multiple tasks, the ER is composed of distinct, specialised subregions, amongst which mitochondrial associated ER membranes (MAM) emerge as key signalling 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 Ca2+ fluxes. Downregulation of Ero1α by RNA interference inhibits mitochondrial Ca2+ fluxes and modifies the activity of mitochondrial Ca2+ uniporters. The over-expression of redox active Ero1α 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 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 co-ordinately regulate Ca2+ and redox homeostasis and signalling in the early secretory compartment.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
