Calcium is a major regulator of neuronal metabolism. Calcium transients are associated with energy demands which are met by mitochondrial OXPHOS through  ADP-dependent increases in neuronal respiration and/or via calcium signaling in mitocondria. It has been widely assumed that Ca2+-actions require its uptake by the mitochondrial calcium uniporter (MCU), but other pathways modulated by cytosolic Ca2+ such as the malate aspartate shuttle (MAS) also play this role. The MAS component Aralar, the mitocondrial aspartate-glutamate carrier, harbors EFhand Ca2+ binding motifs facing the intermembrane space and is thus able to sense cytosolic Ca2+.   Selective disruption of MCU or Aralar in neurons using glucose has shown that Aralar-MAS, but not MCU,  participates in the maintenance of basal respiration exerted through Ca2+- fluxes between ER and mitocondria. Aralar/ MAS pathway,  provides in fact  redox equivalents and pyruvate, fueling respiration. Upon neuronal activation, neurons upregulate OXPHOS, cytosolic pyruvate production and glycolysis, together with glucose uptake, in a Ca2+-dependent way. This  upregulation is partially  dependent on the increase in ATP demand caused by Ca2+ fluxes but also on Ca2+ signaling in mitochondria via Aralar-MAS but not MCU.  Ca2+ activation of Aralar/MAS, by increasing cytosolic NAD+/NADH provides Ca2+-dependent increases in glycolysis and cytosolic pyruvate production priming respiration as a feed-forward mechanism in response to workload. The interrelation between  MCU and Aralar/MAS pathways under stronger stimulation conditions will be discussed.

More information:

• https://www.cbm.uam.es/es/investigacion/programas/procesos-fisiologicos-y-patologicos/redes-metabolicas-y-senalizadoras-en-la-enfermedad/senalizacion-mitocondrial-del-calcio-y-senalizacion-de-insulina-leptina-en-envejecimiento