title: Neuronal Ca2+sensor-1 contributes to stress tolerance in cardiomyocytes via activation of mitochondrial detoxification pathways.
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. Ca2+-dependent signals are often involved in these pathways. Here, we found that neuronal Ca2+-sensor-1 (NCS-1), a Ca2+-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 Ca2+-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 Ca2+-dependent survival pathways that promote mitochondrial biosynthesis/function and detoxification pathways.
authors.affiliation: Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan. Electronic address: tomoen@ri.ncvc.go.jp.
authors.forename: Tomoe Y
authors.initials: TY
authors.lastname: Nakamura
authors.affiliation: Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Nakao
authors.affiliation: Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan; Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Wakabayashi
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019069:Cell Respiration; D002470:Cell Survival; D002478:Cells, Cultured; D055786:Gene Knockout Techniques; D008658:Inactivation, Metabolic; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051580:Neuronal Calcium-Sensor Proteins / Q000235:genetics* / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D024101:Mitochondrial Proteins; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; C101464:frequenin calcium sensor proteins; D000255:Adenosine Triphosphate
keywords: Ca(2+) sensor; Cardiomyocytes; Ischemia-reperfusion; Mitochondria; Stress tolerance