Abstract 406: Loss of Sigmar1 Leads to Impaired Mitochondrial Respiration, Altered Mitochondrial Dynamics and Development of Cardiac Contractile Dysfunction

Abstract

Rationale: Studies involving different neuronal and cancer cell lines indicated that Sigma 1 receptor (Sigmar1) function as an inter-organelle signaling molecule and elicit cytoprotective functions. Though the presence of Sigmar1 in the heart was reported using ligand binding assay, all studies to date have been limited to pharmacological approaches using less selective ligands for Sigmar1. Despite all these studies, the physiological function of Sigmar1 in the heart remains unknown. Objective: We investigated the physiological function of Sigmar1 in the heart in regulating mitochondrial respiration, mitochondrial dynamics and cardiac contractility using the Sigmar1 knockout mouse (Sigmar1 -/- ). Methods and Results: Sigmar1 -/- hearts showed significantly increased hemodynamic parameters assessed by left ventricular (LV) catheterization both under basal conditions and after stimulation with increasing doses of the β 1 -adrenoceptor agonist. Noninvasive echocardiographic measurements showed the development of cardiac functional decline in Sigmar1 –/– hearts over aging indicated by decreased LV percent fraction shortening and percent ejection fraction. Histochemistry also showed significant cardiac fibrosis and increased expression of periostin in the Sigmar1 –/– hearts compared to wildtype (Wt) hearts. Ultrastructural analysis of Sigmar1 -/- cardiomyocytes showed irregularly shaped, highly fused mitochondrial network, and exhibited abnormal cristae. Mitochondrial size distribution in Sigmar1 -/- hearts showed an increased number of large mitochondria resulting in decreased numbers of mitochondria per microscopic field and also showed altered expression of mitochondrial dynamics regulatory proteins. Real-time oxygen consumption rates in isolated mitochondria showed reduced respiratory function in Sigmar1 -/- hearts compared with Wt hearts. Conclusions: All these data demonstrate a potential function of Sigmar1 in regulating normal mitochondrial organization and size in the heart. Knockdown of Sigmar1 evoked mitochondrial dysfunction, accumulation of abnormal mitochondria, enhanced adverse cardiac remodeling and resulting in cardiac contractile dysfunction.