Role of the mitochondrial sodium/calcium exchanger in neuronal physiology and in the pathogenesis of neurological diseases

In neurons, as in other excitable cells, mitochondria extrude Ca2+ ions from their matrix in exchange with cytosolic Na+ ions. This exchange is mediated by a specific transporter located in the inner mitochondrial membrane, the mitochondrial Na+/Ca2+ exchanger (NCXmito). The stoichiometry of NCXmito-operated Na+/Ca2+ exchange has been the subject of a long controversy, but evidence of an electrogenic 3 Na+/1 Ca2+ exchange is increasing. Although the molecular identity of NCXmito is still undetermined, data obtained in our laboratory suggest that besides the long-sought and as yet unfound mitochondrial-specific NCX, the three isoforms of plasmamembrane NCX can contribute to NCXmito in neurons and astrocytes. NCXmito has a role in controlling neuronal Ca2+ homeostasis and neuronal bioenergetics. Indeed, by cycling the Ca2+ ions captured by mitochondria back to the cytosol, NCXmito determines a shoulder in neuronal [Ca2+]c responses to neurotransmitters and depolarizing stimuli which may then outlast stimulus duration. This persistent NCXmito-dependent Ca2+ release has a role in post-tetanic potentiation, a form of short-term synaptic plasticity. By controlling [Ca2+]m NCXmito regulates the activity of the Ca2+-sensitive enzymes pyruvate-, α-ketoglutarate- and isocitrate-dehydrogenases and affects the activity of the respiratory chain. Convincing experimental evidence suggests that supraphysiological activation of NCXmito contributes to neuronal cell death in the ischemic brain and, in epileptic neurons coping with seizure-induced ion overload, reduces the ability to reestablish normal ionic homeostasis. These data suggest that NCXmito could represent an important target for the development of new neurological drugs.