Neuronal Ca2+ sensor-1 contributes to stress tolerance in cardiomyocytes via activation of mitochondrial detoxification pathways. (October 2016)

• Record Type: Journal Article
• Authors: Nakamura, Tomoe Y.; Nakao, Shu; Wakabayashi, Shigeo
• Is Part Of: Journal of molecular and cellular cardiology. Volume 99(2016:Oct.)
• Page Start: 23
• Page End: 34
• Publication Date: 2016-10
• Subjects: Akt protein kinase B -- AMPK AMP-activated protein kinase -- ATP adenosine triphosphate -- CaMKII Ca2+/calmodulin-dependent protein kinase II -- FCCP carbonyl cyanide-p-trifluoromethoxyphenylhydrazone -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- GSK3β glycogen synthase kinase 3 beta -- H2O2 hydrogen peroxide -- I/R ischemia-reperfusion -- LDH lactate dehydrogenase -- NMVM neonatal mouse ventricular myocyte -- NCS-1 neuronal calcium sensor-1 -- OCR oxygen consumption rate -- PGC-1α peroxisome proliferator-activated receptor gamma-1 coactivator -- ROS reactive oxygen species -- TMRE tetramethylrhodamine ethyl ester -- TTC triphenyltetrazolium chloride; Ca2+ sensor -- Cardiomyocytes -- Mitochondria -- Stress tolerance -- Ischemia-reperfusion; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.08.013
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: 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, H2 O2 -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. Highlights: NCS-1 knockout rendered mouse hearts more susceptible to oxidative/metabolic stress. Re-expression of NCS-1 partially rescued cardiomyocytes from H2 O2 -induced toxicity ATP levels, mitochondrial respiration and protein levels were lower in KO myocytes. NCS-1 expression reversed early ΔΨm loss in KO myocytes induced by H2 O2 . Stress-induced cardioprotective pathways were inhibited in KO hearts and myocytes.