Mitochondrial Ca2+, redox environment and ROS emission in heart failure: Two sides of the same coin?

• Published in: Journal of molecular and cellular cardiology 2021-02, Vol.151, p.113-125
• Main Authors: Cortassa, Sonia, Juhaszova, Magdalena, Aon, Miguel A., Zorov, Dmitry B., Sollott, Steven J.
• Format: Article
• Language: English
• Subjects: Ca2+ signaling; Computational modeling; Energetic adaptation; Intracellular sodium; Oxidative stress; Redox signaling
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2020.11.013

Heart failure (HF) is a progressive, debilitating condition characterized, in part, by altered ionic equilibria, increased ROS production and impaired cellular energy metabolism, contributing to variable profiles of systolic and diastolic dysfunction with significant functional limitations and risk of premature death. We summarize current knowledge concerning changes of intracellular Na+ and Ca2+ control mechanisms during the disease progression and their consequences on mitochondrial Ca2+ homeostasis and the shift in redox balance. Absent existing biological data, our computational modeling studies advance a new ‘in silico’ analysis to reconcile existing opposing views, based on different experimental HF models, regarding variations in mitochondrial Ca2+ concentration that participate in triggering and perpetuating oxidative stress in the failing heart and their impact on cardiac energetics. In agreement with our hypothesis and the literature, model simulations demonstrate the possibility that the heart’s redox status together with cytoplasmic Na+ concentrations act as regulators of mitochondrial Ca2+ levels in HF and of the bioenergetics response that will ultimately drive ATP supply and oxidative stress. The resulting model predictions propose future directions to study the evolution of HF as well as other types of heart disease, and to develop novel testable mechanistic hypotheses that may lead to improved therapeutics. [Display omitted] •Heart failure exhibits altered cytoplasmic and mitochondrial Na+, Ca2+ and redox.•Modeling shows how redox and Na+ shape matrix Ca2+ and oxidative stress in HF.•Redox and Na+ govern divergent Ca2+ impacts on oxidative stress, energetics in HF.•Different redox scenarios may reconcile conflicting results in distinct HF animal models.