Signaling pathways regulating mitochondrial calcium efflux - a commentary on Rozenfeld et al. "Essential role of the mitochondrial Na(+)/Ca(2+) exchanger NCLX in mediating PDE2-dependent neuronal survival and learning"

Mitochondrial calcium ((m)Ca(2+)) is a critical regulator of neuronal cell death, bioenergetics, and signaling pathways. Although the regulatory machinery governing (m)Ca(2+) uptake via the mitochondrial calcium uniporter (mtCU) has been identified and functionally characterized, regulation of the mitochondrial Na(+)/Ca(2+) exchanger (NCLX), the primary means of (m)Ca(2+) efflux, is poorly understood. Rozenfeld et al. report that inhibition of phosphodiesterase 2 (PDE2) enhances (m)Ca(2+)efflux via increased NCLX phosphorylation by protein kinase A (PKA) [1]. The authors demonstrate that enhancing NCLX activity by pharmacologic inhibition of PDE2 improves neuronal survival in response to excitotoxic insult in vitro and enhances cognitive performance. Here we contextualize this discovery within existing literature and provide conjecture to add clarity to the proposed novel regulatory mechanism.