title: Role of mitochondrial dysfunction and dysregulation of Ca(2+) homeostasis in insulin insensitivity of mammalian cells.
abstract: Mitochondria and endoplasmic reticulum (ER) play an important role in the maintenance of intracellular Ca(2+) homeostasis, and their defects may be etiological factors contributing to insulin resistance and type 2 diabetes (T2D). Recent studies indicate that alterations of Ca(2+) levels and Ca(2+) -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 Ca(2+) homeostasis. Moreover, we first elucidated that defects in the function of MAMs in Ca(2+) 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 Ca(2+) homeostasis as a novel strategy for the development of new therapeutics aimed at preventing and treating insulin resistance and T2D.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.|Brain Research Center, National Yang-Ming University, Taipei, Taiwan.|Aging and Health Research Center, National Yang-Ming University, Taipei, Taiwan.|Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Ting-Fen
authors.initials: TF
authors.lastname: Tsai
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.|Department of Medicine, Mackay Medical College, Sanzhi, New Taipei City, Taiwan.
authors.forename: Yau-Huei
authors.initials: YH
authors.lastname: Wei
mesh_terms: D017667:Adipocytes / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D000071183:Autophagy-Related Proteins; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007333:Insulin Resistance; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D028361:Mitochondrial Diseases / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D000071183:Autophagy-Related Proteins; C523851:CISD2 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C515811:Noxp70 protein, mouse
keywords: Ca2+ homeostasis; insulin insensitivity; mitochondria-associated ER membranes; mitochondrial dysfunction; type 2 diabetes