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

Abstract

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.

Keywords: Ca(2+) signaling; Computational modeling; Energetic adaptation; Intracellular sodium; Oxidative stress; Redox signaling.

Figure 1.. Conceptual 3D representation of changes in redox stress (ROS emission) as a function of Ca²⁺_m concentration and RE.

ROS emitted (diffusion of H₂O₂ from mitochondria into the cytoplasmic compartment) as a function of Ca²⁺ concentration and RE. Ca²⁺_m concentration (blue arrow in the x-axis) is determined by the Na⁺_i (green arrow in x-axis) through the Na⁺/Ca²⁺ exchanger in the inner mitochondrial membrane, which is sensitive to the accumulation of matrix Na⁺. The latter, is in part determined by the activity of the F₁F_o ATP synthase that carries Na⁺ in addition to K⁺ and H⁺, enabling the accumulation of Ca²⁺ through NCX_mito inhibition. The red arrow is pointing toward larger (more negative) RE. This conceptual representation includes an approximate depiction of modeling results that simulate the two, “oxidized” and “reduced”, scenarios discussed throughout this work.

Figure 2.. Simulation results showing comparatively the ROS emission (A) and ATP synthase (B) fluxes.

The plot displays the relationship of the average mitochondrial Ca²⁺_m, RE, and rate of H₂O₂ emission from mitochondria (panel A) or ATP synthesis rate (panel B). The points plotted correspond to the averages of the pulses of Ca²⁺ and ADP, during the simulation described in the text. The lines color indicates the “reduced” (yellow), and the “oxidized” (red) scenarios.

Figure 3.. Simplified scheme of the main processes considered in the model in relation to cytoplasmic Na⁺.

Na⁺_i is transported across the inner mitochondrial membrane through three paths: the F₁F_o ATP synthase, the Na⁺/H⁺ exchanger (NHE_mito), and the Na⁺/Ca²⁺ exchanger (NCX_mito). The latter is involved in determining the Ca²⁺_m concentration that, in turn, affects NADH levels through the activity of mitochondrial dehydrogenases, including pyruvate, isocitrate and α ketoglutarate dehydrogenases. NADH plays a key role in the two scenarios, transferring the electrons either toward the respiratory chain and ROS generation (yellow arrow) or to replenish the NADPH pool, which acts as the electron donor for the antioxidant defense systems, GSH and thioredoxin (red arrow). According to conditions, the increase in Ca²⁺_m will rather relatively increase the flow of electrons toward ROS generation (“reduced” scenario) or to replenish the antioxidant defenses (“oxidized” scenario).