Cardiac Dysfunction in the Sigma 1 Receptor Knockout Mouse Associated With Impaired Mitochondrial Dynamics and Bioenergetics

Abstract

Background The Sigma 1 receptor (Sigmar1) functions as an interorganelle signaling molecule and elicits cytoprotective functions. The presence of Sigmar1 in the heart was first reported on the basis of a ligand‐binding assay, and all studies to date have been limited to pharmacological approaches using less‐selective ligands for Sigmar1. However, the physiological function of cardiac Sigmar1 remains unknown. We investigated the physiological function of Sigmar1 in regulating cardiac hemodynamics using the Sigmar1 knockout mouse (Sigmar1 −/− ). Methods and Results Sigmar1 −/− hearts at 3 to 4 months of age showed significantly increased contractility as assessed by left ventricular catheterization with stimulation by increasing doses of a β 1 ‐adrenoceptor agonist. Noninvasive echocardiographic measurements were also used to measure cardiac function over time, and the data showed the development of cardiac contractile dysfunction in Sigmar1 −/− hearts as the animals aged. Histochemistry demonstrated significant cardiac fibrosis, collagen deposition, and increased periostin in the Sigmar1 −/− hearts compared with wild‐type hearts. Ultrastructural analysis of Sigmar1 −/− cardiomyocytes revealed an irregularly shaped, highly fused mitochondrial network with abnormal cristae. Mitochondrial size was larger in Sigmar1 −/− hearts, resulting in decreased numbers of mitochondria per microscopic field. In addition, Sigmar1 −/− hearts 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 wild‐type hearts. Conclusions We demonstrate a potential function of Sigmar1 in regulating normal mitochondrial organization and size in the heart. Sigmar1 loss of function led to mitochondrial dysfunction, abnormal mitochondrial architecture, and adverse cardiac remodeling, culminating in cardiac contractile dysfunction.

Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function

“…Following 4 weeks of "binge and crash" METH administration, we assessed the cardiac dimensions and function using M-mode echocardiography (Fig. 3) 32,[35][36][37][38] . Cardiac systolic parameters, i.e., percent fractional shortening (%FS) ( Fig.…”

“…Recently, activation of Sigmar1 using the Sigmar1 agonist PRE-084 has been shown to limit METHinduced dopamine efflux in dopaminergic neurons, attenuate METH-induced locomotion, and motivate behavior and the drug-seeking brain reward function 29 . We have previously reported that Sigmar1 is highly expressed in the heart 30,31 , and that the genetic loss of Sigmar1 causes altered cardiac mitochondrial morphology and dysfunction, leading to cardiac contractile dysfunction 32 . Despite all these studies suggesting Sigmar1's potential role in cardiac physiology and also serve as a direct target of METH, to our knowledge, no studies to date explored the direct involvement of Sigmar1 in the development of METH-associated cardiac pathology.…”

Sirt3 Deficiency Shortens Life Span and Impairs Cardiac Mitochondrial Function Rescued by Opa1 Gene Transfer

“…It is worth mentioning that deacetylation of OPA1-but not of other mitochondrial proteins including SOD2-maintained in the long term in Sirt3 -/animals, corrected cardiac dysfunction and fibrosis, demonstrating this maneuvre's previously unanticipated potential for cardiac protection. Studies have shown that mitochondrial dysfunction in cardiomyocytes critically contributes to the development of age-associated cardiac fibrosis by impairing bioenergetics and reducing cell survival (1,28,49). Furthermore, based on the recent evidence that Complex I inhibition is sufficient to promote the development of fibrosis in the lung, it is tempting to infer that the normalization of Complex I activity through mutOpa1 gene transfer contributes to the amelioration of cardiac fibrosis (30).…”

Mitochondrial Ca2+ regulation in the etiology of heart failure: physiological and pathophysiological implications

“…Recent findings have also identified several molecular chaperones, including calnexin [ 108 ], syntaxin-17 and sigma-1 receptor (Sig-1R) at MAMs, which are involved in the regulation of information exchange, such as Ca 2+ ions between the ER and mitochondria. Sig-1R is a chaperone located in MAMs that regulates Ca 2+ transfer between mitochondria and ER by binding with IP3R3 [ 109 ]. Upon the induction of ER stress, Sig-1R is separated from BIP, and IP3R3 is stabilized to accelerate Ca 2+ influx from the ER into mitochondria to increase the production of ATP.…”

“…Upon the induction of ER stress, Sig-1R is separated from BIP, and IP3R3 is stabilized to accelerate Ca 2+ influx from the ER into mitochondria to increase the production of ATP. It has been suggested that Sig-1R knockout leads to mitochondrial dysfunction and HF [ 109 ]. In addition, it has been suggested that syntaxin-17 interacts with Drp1 and regulates the calcium concentration in the ER and cytoplasm [ 110 ].…”