Molecular identity of cardiac mitochondrial chloride intracellular channel proteins

• CLIC1, CLIC4 and CLIC5 are cardiac proteins.
• CLIC4 localizes to the OMM whereas CLIC5 localizes to the IMM.
• DmCLIC localizes to cardiac mitochondria.
• CLIC5 plays a role in modulating mitochondrial ROS generation.

Emerging evidences demonstrate significance of chloride channels in cardiac function and cardioprotection from ischemia–reperfusion (IR) injury. Unlike mitochondrial potassium channels sensitive to calcium (BKCa) and ATP (KATP), molecular identity of majority of cardiac mitochondrial chloride channels located at the inner membrane is not known. In this study, we report the presence of unique dimorphic chloride intracellular channel (CLIC) proteins namely CLIC1, CLIC4 and CLIC5 as abundant CLICs in the rodent heart. Further, CLIC4, CLIC5, and an ortholog present in Drosophila (DmCLIC) localize to adult cardiac mitochondria. We found that CLIC4 is enriched in the outer mitochondrial membrane, whereas CLIC5 is present in the inner mitochondrial membrane. Also, CLIC5 plays a direct role in regulating mitochondrial reactive oxygen species (ROS) generation. Our study highlights that CLIC5 is localized to the cardiac mitochondria and directly modulates mitochondrial function.