Neuronal Ca(2+) sensor-1 contributes to stress tolerance in cardiomyocytes via activation of mitochondrial detoxification pathways.

Identification of the molecules involved in cell death/survival pathways is important for understanding the mechanisms of cell loss in cardiac disease, and thus is clinically relevant. Ca(2+)-dependent signals are often involved in these pathways. Here, we found that neuronal Ca(2+)-sensor-1 (NCS-1), a Ca(2+)-binding protein, has an important role in cardiac survival during stress. Cardiomyocytes derived from NCS-1-deficient (Ncs1(-/-)) mice were more susceptible to oxidative and metabolic stress than wild-type (WT) myocytes. Cellular ATP levels and mitochondrial respiration rates, as well as the levels of mitochondrial marker proteins, were lower in Ncs1(-/-) myocytes. Although oxidative stress elevated mitochondrial proton leak, which exerts a protective effect by inhibiting the production of reactive oxygen species in WT myocytes, this response was considerably diminished in Ncs1(-/-) cardiomyocytes, and this would be a major reason for cell death. Consistently, H2O2-induced loss of mitochondrial membrane potential, a critical early event in cell death, was accelerated in Ncs1(-/-) myocytes. Furthermore, NCS-1 was upregulated in hearts subjected to ischemia-reperfusion, and ischemia-reperfusion injury was more severe in Ncs1(-/-) hearts. Activation of stress-induced Ca(2+)-dependent survival pathways, such as Akt and PGC-1α (which promotes mitochondrial biogenesis and function), was diminished in Ncs1(-/-) hearts. Overall, these data demonstrate that NCS-1 contributes to stress tolerance in cardiomyocytes at least in part by activating certain Ca(2+)-dependent survival pathways that promote mitochondrial biosynthesis/function and detoxification pathways.

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