Ischemia-induced ionic imbalance leads to the activation of numerous events including mitochondrial dysfunction and eventual cell death. Dysregulation of mitochondrial Ca(2+) (Ca(2+)(m)) plays a critical role in cell damage under pathological conditions including traumatic brain injury and stroke. High Ca(2+)(m) levels can induce the persistent opening of the mitochondrial permeability transition pore and trigger mitochondrial membrane depolarization, Ca(2+) release, cessation of oxidative phosphorylation, matrix swelling and eventually outer membrane rupture with release of cytochrome c and other apoptogenic proteins. Thus, the dysregulation of mitochondrial Ca(2+) homeostasis is now recognized to play a crucial role in triggering mitochondrial dysfunction and subsequent apoptosis. Recent studies show that some secondary active transport proteins, such as Na(+)-dependent chloride transporter and Na(+)/Ca(2+) exchanger, contribute to ischemia-induced dissipation of ion homeostasis including Ca(2+)(m).