FIGURE 6.

Synergistic protection by combining MCU_cx inhibition with Ru265 and NCLX activation with Bay 60-7550. Box 1, Ru265 inhibits Ca²⁺, Mn²⁺, Zn²⁺, and Fe²⁺ uptake by the MCU_cx. Box 2, Bay 60-7550 inhibits PDE2. Box 3, The resultant elevation of cAMP levels activates PKA. Box 4, PKA phosphorylates serine residue (S258) of the NCLX. Box 5, This increases NCLX activity resulting in elevated mitochondrial Ca²⁺ efflux. Box 6, MCU_cx inhibition further reduces mitochondrial Ca²⁺ levels. Box 7, Ru265 and Bay 60-7550 synergistically block ROS overproduction and pro-death factor release that confers profound protection. (See section “6.4. Protection of the NVU by the inhibition of mitochondrial Ca2⁺ overloading” for abbreviations and mechanistic details).