Figure 3.

Scheme for Ca²⁺/ROS crosstalk in cardiac mitochondrial microdomains. A: Ca²⁺ stimulation of ox-phos and ROS production. Pulses of Ca²⁺ resulting from excitation-contraction derived SR RyR Ca²⁺ release ((in red, (1)) leads to mitochondrial Ca²⁺ uptake via MCU, RaM, and mRyR (in yellow, (2)). Increased [Ca²⁺]_m stimulates TCA cycle enzymes (3) which generates NADH that feeds into the respiratory electron transport chain (in blue), in turn increasing APT synthesis and ROS production (4). B: ROS modulation of Ca²⁺ channel activity. Diffusion of ox-phos derived ROS eads to a shift in redox homeostasis resulting in a locally oxidizing environment. Redox and ROS modulation of Ca²⁺ channels increases Ca²⁺ release from SR RyR channels (5), increased mitochondrial Ca²⁺ uptake by mitochondrial Ca²⁺ channels (6), and changes in Na⁺/Ca²⁺ exchange (7). Continued Ca²⁺ uptake can lead to Ca²⁺ overload and further Ca²⁺ induced ROS generation which can ultimately lead to PTP opening (8) and mitochondrial dysfunction. IMM, inner mitochondrial membrane; IMS, intermembrane space; OMM, outer mitochondrial membrane; SR/ER, sarcoplasmic reticulum/endoplasmic reticulum; VDAC, voltage dependant anion channel; PTP, permeability transition pore.