Overexpressing GRP78 influences Ca2+ handling and function of mitochondria in astrocytes after ischemia-like stress

Ca2+ transfer from endoplasmic reticulum (ER) to mitochondria at contact sites between the organelles can induce mitochondrial dysfunction and programmed cell death after stress. The ER-localized chaperone glucose-regulated protein 78 kDa (GRP78/BiP) protects neurons against excitotoxicity and apoptosis. Here we show that overexpressing GRP78 protects astrocytes against ischemic injury, reduces net flux of Ca2+ from ER to mitochondria, increases Ca2+ uptake capacity in isolated mitochondria, reduces free radical production, and preserves respiratory activity and mitochondrial membrane potential after stress. We conclude that GRP78 influences ER-mitochondrial Ca2+ crosstalk to maintain mitochondrial function and protect astrocytes from ischemic injury.