Figure 2.

Holistic overview of sarcolemmal and intracellular ion balances in cardiomyocytes and their alterations under mitochondrial dysfunction. Sarcoplasmic reticulum (SR) oversees Ca²⁺ storage and releasing into the cytosol. The main Ca²⁺ release channel in cardiomyocytes is RyR2 while SERCA recycles Ca²⁺ during diastole. ROS increase RyR opening and reduce SERCA recycling via decreased ATP production, thereby causing Ca²⁺ overload. Increased inward Na⁺ from HCN channel can reverse the Na⁺/Ca²⁺ exchanger activity and subsequently lead to intracellular Ca²⁺ overload and arrhythmias. Moreover, under excessive ROS generation, a net decrease in K⁺ exit along with increased inward late Na⁺ current can cause delayed repolarization and prolonged action potential duration (APD). Sarcoplasmic reticulum mitochondrial contacts (SRMCs) are another important location of calcium transport regulation. The IP3R/GRP75/VDAC complex interacts with MCU to relocate Ca²⁺ into the mitochondria matrix. Brown dashed arrows represent directions of ion currents; black solid arrows represent increased or suppressed channel activities.