Figure 9.

Schema of the potential mechanism by which CsA mediates delay in Ca²⁺-induced mPTP opening. Pathological conditions, like cardiac ischemia-reperfusion injury, leads to an increase in cytosolic Ca²⁺ ([Ca²⁺]_c). This in turn increases [Ca²⁺]_m and generation of reactive oxygen species (ROS), impairs respiration and substrate utilization, and leads to uncoupling of oxidative phosphorylation. Lower ΔΨ_m, oxidized redox state, and dissipation of the pH_m gradient, together induces mPTP opening which triggers apoptosis. These detrimental consequences that underlie IR injury could be mollified by CsA, which allows the mitochondria to maintain their basal [Ca²⁺]_m via enhanced P_i-dependent matrix Ca²⁺ buffering, in addition to, or through, Cyp D inhibition. Sustained low [Ca²⁺]_m maintains mitochondrial integrity and function and delays mPTP opening.