Structural and Functional Alterations in Sinoatrial Node Mitochondria During Heart Failure

Abstract

Introduction: Sinoatrial node (SAN), the primary pacemaker in the heart, generates the electrical impulse that propagates throughout the heart. To accomplish such an energetically demanding process, it is composed of a dense network of mitochondria. Sinus node dysfunction is well documented in heart failure (HF); however, the exact molecular mechanisms remain incompletely understood. Since the mitochondria partake in multiple cellular processes that determine the life or death of a cell, we tested possible mitochondrial remodeling in SAN in HF that may contribute to SAN dysfunction. Methods: We subjected C57Bl/6J wild-type (WT) mice to either sham-operation or pressure-overload induced HF by transverse aortic constriction (TAC). After 8 weeks, mice underwent conscious echocardiography and ECG recordings, before their hearts were harvested for further mechanistic studies. Results: After 8 weeks, TAC mice exhibited impaired cardiac function, increased heart and lung weight to body weight ratios, and extensive fibrosis, relative to sham-operated mice. ECG recordings showed evidence of sinus node dysfunction in the TAC mice. Ultrastructural imaging using a transmission electron microscope (EM) revealed SAN cells isolated from TAC mice to have an elevated number of clusters of small mitochondria with abnormal cristae structure. Moreover, there was a loss of co-localization of mitofusin 1 and mitofusin 2 with the ryanodine receptor (RYR2) in SAN cells isolated from TAC mice. Functionally, mitochondria from TAC mice exhibited an impairment in Ca2+ handling and decreased membrane potential, which contributed to a reduction in energy production seen in SAN cells from TAC mice. Conclusion: Our findings suggest that impairment of mitochondria in the SAN could contribute to SAN dysfunction that occurs during HF. SAN-specific therapies that target the mitochondria could potentially provide a more comprehensive care in HF patients suffering from SAN dysfunction.