Role of mitochondrial dysfunction and dysregulation of Ca²⁺ homeostasis in insulin insensitivity of mammalian cells

Mitochondria and endoplasmic reticulum (ER) play an important role in the maintenance of intracellular Ca²⁺ homeostasis, and their defects may be etiological factors contributing to insulin resistance and type 2 diabetes (T2D). Recent studies indicate that alterations of Ca²⁺ levels and Ca²⁺-dependent signaling pathways can impede the insulin signaling cascade, resulting in insulin resistance of β cells and insulin-responsive cells. Mitochondria-associated ER membranes (MAMs) are essential for efficient communication between the ER and mitochondria. Thus, abnormalities in the structure and function of MAMs in affected tissue cells in T2D are an important area of study. Recently, we demonstrated that a deficiency of Cisd2, an iron–sulfur protein localized on MAMs, could lead to mitochondrial dysfunction and disturbance of intracellular Ca²⁺ homeostasis. Moreover, we first elucidated that defects in the function of MAMs in Ca²⁺ uptake resulted in insulin insensitivity of adipocytes, which plays an important role in the pathogenesis of diabetes in Cisd2 knockout mice. On the basis of these observations, we suggest improving the bioenergetic function of mitochondria and the function of MAMs in maintaining Ca²⁺ homeostasis as a novel strategy for the development of new therapeutics aimed at preventing and treating insulin resistance and T2D.