Role of mitochondrial dysfunction and dysregulation of Ca2+ homeostasis in the pathophysiology of insulin resistance and type 2 diabetes

Abstract

Metabolic diseases such as obesity, type 2 diabetes (T2D) and insulin resistance have attracted great attention from biomedical researchers and clinicians because of the astonishing increase in its prevalence. Decrease in the capacity of oxidative metabolism and mitochondrial dysfunction are a major contributor to the development of these metabolic disorders. Recent studies indicate that alteration of intracellular Ca²⁺ levels and downstream Ca²⁺-dependent signaling pathways appear to modulate gene transcription and the activities of many enzymes involved in cellular metabolism. Ca²⁺ uptake into mitochondria modulates a number of Ca²⁺-dependent proteins and enzymes participating in fatty acids metabolism, tricarboxylic acid cycle, oxidative phosphorylation and apoptosis in response to physiological and pathophysiological conditions. Mitochondrial calcium uniporter (MCU) complex has been identified as a major channel located on the inner membrane to regulate Ca²⁺ transport into mitochondria. Recent studies of MCU complex have increased our understanding of the modulation of mitochondrial function and retrograde signaling to the nucleus via regulation of the mitochondrial Ca²⁺ level. Mitochondria couple cellular metabolic state by regulating not only their own Ca²⁺ levels, but also influence the entire network of cellular Ca²⁺ signaling. The mitochondria-associated ER membranes (MAMs), which are specialized structures between ER and mitochondria, are responsible for efficient communication between these organelles. Defects in the function or structure of MAMs have been observed in affected tissue cells in metabolic disease or neurodegenerative disorders. We demonstrated that dysregulation of intracellular Ca²⁺ homeostasis due to mitochondrial dysfunction or defects in the function of MAMs are involved in the pathogenesis of insulin insensitivity and T2D. These observations suggest that mitochondrial dysfunction and disturbance of Ca²⁺ homeostasis warrant further studies to assist the development of therapeutics for prevention and medication of insulin resistance and T2D.

Keywords: Ca2+ homeostasis; Insulin resistance; Metabolic disease; Mitochondria-associated ER membranes; Mitochondrial calcium uniporter; Type 2 diabetes.

Fig. 1

Mitochondrial calcium uniporter complex and the regulation of the entry of Ca²⁺ ions into mitochondria. The protein complex of mitochondrial calcium uniporter is composed of the pore-forming proteins (MCU, MCUb, EMRE), and the regulatory proteins (MICU1, MICU2). The regulation of the entry of Ca²⁺ ions by mitochondrial calcium uniporter complex is demonstrated here. a When the concentration of Ca²⁺ ions is low in the IMS, the heterodimer of MICU1 and MICU2 blocks the channel of MCU to inhibit the entry of Ca²⁺ ions. b When the Ca²⁺ ions level is high upon stimulation, binding of Ca²⁺ ions to the MICU protein elicits a conformational change to open the channel, resulting in the transport of Ca²⁺ ions into mitochondria to activate several dehydrogenases in the matrix of mitochondria. IMS, intermembrane space; IMM, inner mitochondrial membrane

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