The ATPMg/Pi carrier has been described as a putative regulator of gluconeogenesis and the urea cycle, as well as being responsible for the uptake of nucleotides that takes place after birth in newborn liver mitochondria. In addition, recent work has implicated the carrier in mitochondrial calcium homoeostasis and as a regulator of susceptibility to calciumoverload stimuli. In the present work we have studied the function of SCaMC3, the paralog of the mitochondrial ATPMg/Pi carrier found in brain and liver, through the characterization of a mouse model deficient for the protein. Our results indicate that absence of the protein increases the level of liver injury markers in blood and decreases the plasma concentration of urea. In addition, we show that SCaMC3 can favour coupling between electron transport chain activity and oxidative phosphorylation in adenine nucleotidedepleted mitochondria, a situation similar to the one observed in newborn liver mitochondria, through a mechanism dependent on extramitochondrial calcium that does not require calcium entry in the mitochondria. We have also described that SCaMC3 is a target of glucagon signalling, being responsible for the uptake of nucleotides by liver mitochondria and the stimulation of respiration observed after its administration. Finally, we show that lack of SCaMC3 renders mice more susceptible to kainic acidinduced seizures and astrogliosis, but more resistant to ischemia/reperfusion injury both in vivo, with smaller infarct volume after middle cerebral arterial occlusion, and in vitro, with reduced cell death after oxygen and glucose deprivation.
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