Fig. 2

Illustration of the role of defects in mitochondria-mediated regulation of Ca²⁺ homeostasis in the pathogenesis of insulin resistance and type 2 diabetes. The intracellular level of Ca²⁺ ions in a normal human cell is regulated and maintained within a small range of concentration. The fluctuation of the level of Ca²⁺ ions from extracellular influx or release of intra-organelle leads to activation of Ca²⁺-dependent signaling to alter the gene expression or protein trafficking in response to the stimulation (i.e., adiponectin or norepinephrine). Increase of cytosolic level of Ca²⁺ ions initiates the activation of insulin signaling and transcriptional regulation in insulin-responsive tissues such as adipocytes and muscle. On the other hand, Ca²⁺ ions can facilitate insulin secretion in beta cells. All of these effects are beneficial to glucose utilization and insulin sensitivity in the human body. For instance, the Ca²⁺-dependent activation of FAM3A improves phosphorylation of AKT and the activation of CaMKII or synaptotagmin VII (Syt VII) allow efficient translocation/docking/fusion of glucose transporter 4 (Glut4) to the plasma membrane in insulin- responsive cells upon insulin stimulation. Moreover, Ca²⁺ homeostasis also regulates gene transcription to affect adipogenesis, muscle trophism, and mitochondrial biogenesis through Ca²⁺-dependent activation of a number of proteins. Mitochondria modulate intracellular Ca²⁺ homeostasis by its high capacity of Ca²⁺ uptake through the MCU complex and interaction with ER via the MAMs structure. Mitochondrial Ca²⁺ uptake plays as a role in the buffering of cytosolic Ca²⁺ ions and in the boost of the ATP production. Three enzymes (PDH, IDH, αKGDH) involved in oxidative metabolism are regulated by Ca²⁺ ions directly or indirectly, providing more NADH to the electron transport chain (ETC). Mitochondrial dysfunction disrupts intracellular Ca²⁺ homeostasis and leads to dysregulation of the above-mentioned Ca²⁺-dependent signaling events and impairment of glucose utilization and insulin response in the affected cells. Ultimately, these abnormalities will culminate in insulin insensitivity of target tissue cells and thereby develop T2D