Mitochondrial Calcium Overload Promotes Cell Hypertrophy And Energetic Dysfunction In Human Heart Failure.

Abstract

Introduction Impairment of intracellular Ca2+ homeostasis and bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. Mitochondrial calcium transport is mediated by the mitochondrial Ca2+ uniporter (MCU), and till now, the comprehension of its role in pathophysiology is limited by the complete lack of this molecular understanding. However, in light of the recent molecular identification of the MCU, new perspectives have been opened. Hypothesis In the failing human heart, increased energy demand triggers mitochondrial calcium overload through upregulation of the MCU, promoting energetic dysfunction. Methods Here, we measured the expression of MCU on failing human left ventricular tissue obtained at the time of orthotopic heart transplantation or left ventricular assist device (LVAD) insertion against non-failing heart tissue samples and after LVAD removal (post-LVAD). Moreover, we characterized the role of MCU in cardiac myoblast cells with reduced expression of MCU under angiotensin II-induced hypertrophy. In addition, mitochondrial function, mitochondrial biogenesis, and mitochondrial ROS production were assessed. T-Test and 1-way ANOVA were performed, N=3-27. This study followed all regulations and approvals from the Institutional Ethics Committee. Results Upregulated MCU (2.2 fold) was associated with poor prognosis in patients with HF. Moreover, the MCU expression positively correlated with the pathological remodeling in patients with HF, contrary to patients post-LVAD, where MCU expression decreases 40%. Furthermore, in cardiac myoblast cells, silencing MCU improved cell viability and prevents calcium retention capacity impairment when cells were insulted chronically with Angiotensin II (ANGII). Additionally, silencing MCU blocks the angiotensin II-dependent transversal hypertrophy and cell death. Mechanistically we found that this MCU-dependent anti-hypertrophic effect was mediated by preventing ANGII-induced mitochondrial ROS overproduction and the changes in the phosphorylation status of transcription factor A, preventing mitochondrial biogenesis and NFkB-dependent hypertrophic program. Conclusions Our findings suggest a novel insight for the mechanisms of energetic dysfunction and hypertrophy mediated by mitochondrial calcium and mitochondrial ROS production in Ca2+-mediated pathological remodeling that may provide a potential pharmacological target for heart failure. Impairment of intracellular Ca2+ homeostasis and bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. Mitochondrial calcium transport is mediated by the mitochondrial Ca2+ uniporter (MCU), and till now, the comprehension of its role in pathophysiology is limited by the complete lack of this molecular understanding. However, in light of the recent molecular identification of the MCU, new perspectives have been opened. In the failing human heart, increased energy demand triggers mitochondrial calcium overload through upregulation of the MCU, promoting energetic dysfunction. Here, we measured the expression of MCU on failing human left ventricular tissue obtained at the time of orthotopic heart transplantation or left ventricular assist device (LVAD) insertion against non-failing heart tissue samples and after LVAD removal (post-LVAD). Moreover, we characterized the role of MCU in cardiac myoblast cells with reduced expression of MCU under angiotensin II-induced hypertrophy. In addition, mitochondrial function, mitochondrial biogenesis, and mitochondrial ROS production were assessed. T-Test and 1-way ANOVA were performed, N=3-27. This study followed all regulations and approvals from the Institutional Ethics Committee. Upregulated MCU (2.2 fold) was associated with poor prognosis in patients with HF. Moreover, the MCU expression positively correlated with the pathological remodeling in patients with HF, contrary to patients post-LVAD, where MCU expression decreases 40%. Furthermore, in cardiac myoblast cells, silencing MCU improved cell viability and prevents calcium retention capacity impairment when cells were insulted chronically with Angiotensin II (ANGII). Additionally, silencing MCU blocks the angiotensin II-dependent transversal hypertrophy and cell death. Mechanistically we found that this MCU-dependent anti-hypertrophic effect was mediated by preventing ANGII-induced mitochondrial ROS overproduction and the changes in the phosphorylation status of transcription factor A, preventing mitochondrial biogenesis and NFkB-dependent hypertrophic program. Our findings suggest a novel insight for the mechanisms of energetic dysfunction and hypertrophy mediated by mitochondrial calcium and mitochondrial ROS production in Ca2+-mediated pathological remodeling that may provide a potential pharmacological target for heart failure.