Molecular mechanisms involved in mitochondrial calcium homeostasis and their relationship with mitochondrial dynamics in in vitro models of cerebral ischemia

The mitochondrial influx and efflux calcium pathways play a relevant role in cytosolic and mitochondrial calcium homeostasis and contribute to the regulation of mitochondrial functions. The mitochondrial Na+/Ca2+ exchanger, first hypothesized, in 1974, has been primarily investigated from a functional point of view. So far, however, its identity and its localization in mitochondria are still unknown. In the first step of the present study we examined (a) whether the nuclear encoded NCX family proteins are present on mitochondria and, if they are, (b) where they are localized, (c) what might be their contribution to mitochondrial Ca2+ handling and, finally, (d) whether NCX activity on mitochondria is controlled by AKAP121, a member of the AKAP family proteins in the outer mitochondrial membrane (Carlucci et al 2008; Livigni et al 2006). Collectively, the results of this study suggest that NCX3 regulates mitochondrial calcium handling from the outer mitochondrial membrane through an AKAP121-anchored signalling complex, thus promoting cell survival. A second step of the study was addressed to investigate the molecular mechanisms that regulate mitochondrial biogenesis in cellular models of cerebral ischemia with particular regard to mitochondrial fusion and fission events and to verify the role of NCX3 and the putative interaction between this protein and AKAP121 in mitochondrial fission and fusion during ischemia.