Fluvoxamine rescues mitochondrial Ca^{2 +} transport and ATP production through σ₁-receptor in hypertrophic cardiomyocytes

Aims We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor with high affinity for the σ₁-receptor (σ₁R), ameliorates cardiac hypertrophy and dysfunction via σ₁R stimulation. Although σ₁R on non-cardiomyocytes interacts with the IP₃ receptor (IP₃R) to promote mitochondrial Ca^{2 +} transport, little is known about its physiological and pathological relevance in cardiomyocytes. Main methods Here we performed Ca^{2 +} imaging and measured ATP production to define the role of σ₁Rs in regulating sarcoplasmic reticulum (SR)-mitochondrial Ca^{2 +} transport in neonatal rat ventricular cardiomyocytes treated with angiotensin II to promote hypertrophy. Key finding These cardiomyocytes exhibited imbalances in expression levels of σ₁R and IP₃R and impairments in both phenylephrine-induced mitochondrial Ca^{2 +} mobilization from the SR and ATP production. Interestingly, σ₁R stimulation with fluvoxamine rescued impaired mitochondrial Ca^{2 +} mobilization and ATP production, an effect abolished by treatment of cells with the σ₁R antagonist, NE-100. Under physiological conditions, fluvoxamine stimulation of σ₁Rs suppressed intracellular Ca^{2 +} mobilization through IP₃Rs and ryanodine receptors (RyRs). In vivo, chronic administration of fluvoxamine to TAC mice also rescued impaired ATP production. Significance These results suggest that σ₁R stimulation with fluvoxamine promotes SR-mitochondrial Ca^{2 +} transport and mitochondrial ATP production, whereas σ₁R stimulation suppresses intracellular Ca^{2 +} overload through IP₃Rs and RyRs. These mechanisms likely underlie in part the anti-hypertrophic and cardioprotective action of the σ₁R agonists including fluvoxamine.