Figure 2.

Interaction between mitochondria and SR Ca²⁺-release channels. This structural arrangement allows mitochondria and SR to be connected by tether proteins (not shown), which allows regulation of matrix Ca²⁺ that may modulate mitochondrial activity. Mitochondria take up Ca²⁺ ions entering the cytosol from internal stores (SR) of the local “microdomain” via signaling molecules that include Ca²⁺ and ROS. After cell stimulation, inositol 1,4,5-trisphosphate (IP₃) and cADP ribose (cADPr) release calcium from SR through their respective receptors [IP₃R and ryanodine receptors (RyR)]. Local increases in cytosolic Ca²⁺ concentrations are buffered by mitochondrial uptake through the calcium uniporter (CaU) and possible alternative routes, such as the putative Ca²⁺/H⁺ exchanger [the so-called Na⁺ independent Ca²⁺ exchanger (NICE, or CHE); not shown]. Intra-mitochondrial Ca²⁺ may activate synthesis of reduced substrates (NADH) by metabolic pathways and accelerate the electron transport chain (ETC); a resulting increase in ROS production may in turn facilitate Ca²⁺ release by sensitization of IP₃R and RyR. The increase in respiration is associated with enhanced proton pumping and subsequently increase state 3 respiration with perhaps increase CHE activity so that more Ca²⁺ is taken up from the localized “microdomain.” Other putative mechanisms that increase ROS generation are modifications of ETC complexes by mCa²⁺ and inhibition of the ETC by nitric oxide (${\text{NO}}^{·}$). The ${\text{NO}}^{·}$ can be increased by Ca²⁺-induced ${\text{NO}}^{·}$ synthase. Mitochondrial can also support Ca²⁺ release by efflux via Na⁺/Ca²⁺ exchange (NCE). The delicate balance in the regulation of Ca²⁺ in the “microdomain” is crucial in the pathology of mitochondria-related cardiovascular complications. Reproduced and modified by permission from Camello-Almaraz et al. (2006).