Regulation of mitochondrial ATP synthesis by neuronal Cav1

Mitochondria are fundamental cell components because they enable effective energy production. They are also involved in many important biochemical pathways and provide essential cellular signaling molecules and metabolites. Therefore, mitochondria represent crucial organelles for most cell types, including nerve cells. In addition, mitochondria also harbor key elements of programmed cell death (apoptosis), which puts them center stage in neurodegenerative mechanisms. Energy production and metabolism of mitochondria are regulated by intracellular and/or intramitochondrial Ca2+, which also plays a central role in the induction of apoptosis. Neurodegenerative mitochondrial effects have been widely attributed to Ca2+-influx via glutamate receptors of the so called NMDA-type. Other routes of Ca2+ rises in neurons, such as the one provided by voltage-gated calcium channels of the L-type (LTCC), were considered less harmful. Nevertheless, it has been proposed that LTCC-mediated Ca2+-influx may exert detrimental effects under certain conditions. Indeed, elevated levels of LTCC activity were suggested to contribute to the pathogenesis of Parkinsons disease and to play a precipitating role in epileptogenesis. However, in contrast to the proposed role in neuropathology, evidence was also presented that LTCC-mediated Ca2+-influx exerts beneficial effects and promotes neuronal survival. It remained unclear whether mitochondria were involved in such LTCC-dependent neuroprotective mechanisms, too. One of our recent findings may help to shed light on this issue: w e were able to show that LTCC- mediated Ca2+-influx affects mitochondrial function in opposite manners, which depends on the size of the Ca2+-elevation. LTCC-mediated Ca2+-influx that is brought about by stimulation of neuronal activity was found to promote mitochondrial ATP production. However, under conditions of extensive LTCC availability, mitochondria turned into ATP consumers rather than producing this energy carrier. Hence, LTCC-mediated Ca2+-influx may stand at the crossroads of neuroprotective and neurodegenerative mitochondrial processes. Therefore, the mechanistic details underlying the regulatory link between LTCC and mitochondria shall be investigated in future studies proposed in this grant proposal. The overall aim of this project will be to contribute to molecular and functional identification of interactions between LTCC and mitochondria that lead to promotion of ATP production. The results of this project can be envisaged to enable development of new therapeutic strategies for the treatment of neuronal diseases.

No additional funding sources recorded.