Figure 2.

Schematic representation of potential ROS sources in the cardiomyocytes during myocardial IR. Superoxide (O₂•⁻) anion is largely generated in the mitochondrial ETC at complexes I and III. Particularly, succinate accumulated during ischemia leads to RET, which produces O₂•⁻ at complex I. Mitochondrial NOX also generates O₂•⁻. Impaired ROS scavenging systems such as SOD2, CAT, GPx, and Prx/Trx insufficiently eliminate O₂•⁻ or hydrogen peroxide (H₂O₂), leading to ROS accumulation. Excess H₂O₂ is converted into a highly reactive hydroxyl radical (•OH) through the Fenton reaction. Mitochondrial ROS, along with the Ca²⁺ overload and restoration of pH, induces the opening of mPTP, further promoting ROS production. Prolonged or excessive opening of the mPTP ruptures the mitochondria, accelerates cell death, and causes ROS generation via an inflammatory response in recruited leucocytes. In the external space of mitochondria, NOX and XO play a major role in ROS production during IR. Moreover, Fe²⁺ released by the ruptured mitochondria initiates the Fenton reaction, generating •OH in the cytosol. Excessive ROS causes oxidative damage to lipids, proteins, and nucleic acids, leading to cell death and exacerbating IR injury.