Figure 5. Proposed mechanism for I_NaL-mediated Na⁺ overload-induced disruption of myocyte Ca²⁺ handling.

An increase of I_NaL leads to an increase of [Na⁺]_i Cytosolic Na⁺ overload attenuates mitochondrial Ca²⁺ uptake via the mitochondrial Na⁺/Ca²⁺ exchanger, thereby reducing NADPH regeneration and increasing mitochondrial ROS, ROS oxidize and activate CaMKII, resulting in phosphorylation of the CaMKII substrate RyR2 and increasing Ca²⁺ leak from sarcoplasmic reticulum (SR).