The interplay between cardiac dyads and mitochondria regulated the calcium handling in cardiomyocytes

FIGURE 1. Cardiomyocyte excitation-contraction (EC) coupling based on the close spatial and arrangement localization of the dyads. Transverse tubule (T-tubule) depolarization is mediated by coupling L-type Ca2+ channels (LTCCs) next to ryanodine receptors (RyRs), which activates RyR2 channels by a small amount of Ca2+ entry through LTCCs and lead to a following large amount calcium release mediated by RyR2. Bridging integrator 1 (BIN1) facilitates LTCC localization to T-tubule membrane. The released Ca2+ from SR would be reuptake by SR calcium ATPase (SERCA) on every cardiac cycle to sustain a steady state with stable Ca2+ level.

FIGURE 2. The mechanisms crosstalk between calcium and mitochondrial homeostasis. RyR2 activity is regulated by the phosphorylation level of RyR2 by the protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and protein phosphatase type-1 and type-2A, associating with the Ca2+ level of SR. TOM70 regulates the constitutive of Ca2+ shuttling from ER to mitochondria. Mitochondrial RyR in the IMM could be activated as soon as Ca2+ released from the ER, and further increasing of mitochondrial Ca2+ would lead inactivation of mRyR1 to prevent mitochondrial Ca2+ overloading and permeability transition pore opening. Mitochondrial uptake calcium mainly through mtCU, which is a dedicated regulator for mitochondrial responding different stress to match cardiac workload with ROS and ATP production.