Figure 7. Summary of the role of mCa²⁺ in the chain of events underlying cellular contractile/bioenergetic/redox dysfunction in HF.

Insufficient mCa²⁺ accumulation in HF occurs due to impaired Ca²⁺ release into the diadic/mitochondrial microdomain and acceleration of Ca²⁺ extrusion via NCLX as a result of cytosolic Na⁺ overload. Impaired mCa²⁺ signaling renders the HF cell unable to upregulate NAD(P)H production to meet cellular energy demands, compromising mitochondrial energy production (via NADH) and antioxidant capacity (via NADPH). Increased ROS emission increases RyR-mediated SR Ca²⁺ leak, resulting in cellular Ca²⁺ depletion via sarcolemmal NCX. The inability to maintain SR Ca²⁺ stores further exacerbates the mCa²⁺ insufficiency in a vicious cycle. MCU overexpression (MCU-OE) restores mitochondrial redox balance, decreases SR Ca²⁺ leak, increases SR Ca²⁺ load, and improves frequency- or b-adrenergic- dependent inotropy to prevent or reverse heart failure. AOS, anti-oxidant system; OxPhos, oxidative phosphorylation system; TCA, tricarboxylic acid; RyR, ryanodine receptor; SERCA, SR Ca²⁺ ATPase pump; L, L-type Ca²⁺ channel; ANT, adenine nucleotide translocator; NNT, nicotinamide nucleotide transhydrogenase; NCLX, mitochondrial Na⁺/Ca²⁺ exchanger; IDH2, isocitrate dehydrogenase 2; ME, malic enzyme; SOD, super oxide dismutase; GPX, glutathione peroxidase; GR, glutathione reductase.