Fig. 11.

Regulation of mitochondrial respiration and redox state by ion handling. The Krebs cycle is stimulated by Ca²⁺ that enters mitochondria via the mitochondrial Ca²⁺ uniporter (MCU) and is exported by the mitochondrial Na⁺/Ca²⁺-exchanger (NCLX). The Krebs cycle produces NADH, which donates electrons to the electron transport chain (ETC). Sequential redox reactions along the ETC establish a proton gradient (ΔpH) across the inner mitochondrial membrane (IMM) which together with the electrical potential (ΔΨ_m) constitutes the proton motive force (Δμ_H), which is harnessed by the F₁/F_o-ATP synthase (ATPase) to regenerate ATP via oxidative phosphorylation of ADP. During respiration, superoxide (O₂⁻) is generated at complexes I and III, which are dismutated to hydrogen peroxide (H₂O₂) by the Mn²⁺-dependent superoxide dismutase (MnSOD). H₂O₂ is then eliminated by glutathione peroxidase (GPX) and the thioredoxin/peroxiredoxin system (not shown). GPX is regenerated by reduced glutathione (GSH), which in turn is reduced by the glutathione reductase (GR), which uses NADPH that is produced by NADP⁺-dependent isocitrate dehydrogenase (IDP_m) and the nicotinamide nucleotide transhydrogenase (NNT). Reactive oxygen species (ROS) from NADPH oxidases (Nox) 2 and 4, but also xanthine/xanthine oxidase (XO), nitric oxide synthase (NOS) or other mitochondria (Mitos) can activate redox-sensitive ion channels in the IMM, such as the permeability transition pore (PTP), the inner mitochondrial membrane anion channel (IMAC) or the ATP-sensitive K⁺-channel (K_ATP). Opening of these channels dissipates ΔΨ_m, requiring accelerated electron flux along the ETC to maintain ΔΨ_m. This oxidizes NADH and (via reverse-mode NNT) NADPH and thereby, the antioxidative capacity, limiting H₂O₂ elimination. ROS can leave mitochondria through the IMAC or PTP and trigger ROS release from neighboring mitochondria. Depending on the concentrations and durations of ROS elevations, ROS can serve protective roles, such as ischemic preconditioning, longevity and/or protein quality control, but at higher concentrations can deteriorate excitation-contraction coupling and induce epigenetic signaling, apoptosis and/or necrosis. When ΔΨ_m (transiently or permanently) dissipates, ATP production ceases, which activates sarcolemmal K_ATP channels, making the cell inexcitable. Heterogeneities of ΔΨ_m in different cardiac myocytes within the myocardium resemble “metabolic sinks” which can induce re-entry mechanisms to induce arrhythmias. In heart failure, elevated cytosolic [Na⁺]_i accelerates mitochondrial Ca²⁺ extrusion, which can be ameliorated by inhibiting the NCLX with CGP-37157 (CGP) or lowering [Na⁺]_i by inhibitors of the Na⁺/H⁺-exchanger (NHE), of late Na⁺ current (i.e., ranolazine) and as observed for Sodium/Glucose Co-transporter 2 (SGLT2)-inhibitors via inhibiting NHE and/or late Na⁺ current. CsA, cyclosporine A. GSSG, oxidized glutathione. CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; HDAC4, histone deacetylase 4; EC coupling, excitation-contraction coupling. Modified from [398].