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

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          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 Ca 2+ levels and downstream Ca 2+-dependent signaling pathways appear to modulate gene transcription and the activities of many enzymes involved in cellular metabolism. Ca 2+ uptake into mitochondria modulates a number of Ca 2+-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 Ca 2+ 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 Ca 2+ level. Mitochondria couple cellular metabolic state by regulating not only their own Ca 2+ levels, but also influence the entire network of cellular Ca 2+ 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 Ca 2+ 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 Ca 2+ homeostasis warrant further studies to assist the development of therapeutics for prevention and medication of insulin resistance and T2D.

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          Most cited references 52

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          Mitochondria as sensors and regulators of calcium signalling.

          During the past two decades calcium (Ca(2+)) accumulation in energized mitochondria has emerged as a biological process of utmost physiological relevance. Mitochondrial Ca(2+) uptake was shown to control intracellular Ca(2+) signalling, cell metabolism, cell survival and other cell-type specific functions by buffering cytosolic Ca(2+) levels and regulating mitochondrial effectors. Recently, the identity of mitochondrial Ca(2+) transporters has been revealed, opening new perspectives for investigation and molecular intervention.
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            MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake

            Mitochondrial calcium uptake plays a central role in cell physiology by stimulating ATP production, shaping cytosolic calcium transients, and regulating cell death. The biophysical properties of mitochondrial calcium uptake have been studied in detail, but the underlying proteins remain elusive. Here, we utilize an integrative strategy to predict human genes involved in mitochondrial calcium entry based on clues from comparative physiology, evolutionary genomics, and organelle proteomics. RNA interference against 13 top candidates highlighted one gene that we now call mitochondrial calcium uptake 1 (MICU1). Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential but abolishes mitochondrial calcium entry in intact and permeabilized cells, and attenuates the metabolic coupling between cytosolic calcium transients and activation of matrix dehydrogenases. MICU1 is associated with the organelle’s inner membrane and has two canonical EF hands that are essential for its activity, suggesting a role in calcium sensing. MICU1 represents the founding member of a set of proteins required for high capacity mitochondrial calcium entry. Its discovery may lead to the complete molecular characterization of mitochondrial calcium uptake pathways, and offers genetic strategies for understanding their contribution to normal physiology and disease.
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              EMRE is an essential component of the mitochondrial calcium uniporter complex.

              The mitochondrial uniporter is a highly selective calcium channel in the organelle's inner membrane. Its molecular components include the EF-hand-containing calcium-binding proteins mitochondrial calcium uptake 1 (MICU1) and MICU2 and the pore-forming subunit mitochondrial calcium uniporter (MCU). We sought to achieve a full molecular characterization of the uniporter holocomplex (uniplex). Quantitative mass spectrometry of affinity-purified uniplex recovered MICU1 and MICU2, MCU and its paralog MCUb, and essential MCU regulator (EMRE), a previously uncharacterized protein. EMRE is a 10-kilodalton, metazoan-specific protein with a single transmembrane domain. In its absence, uniporter channel activity was lost despite intact MCU expression and oligomerization. EMRE was required for the interaction of MCU with MICU1 and MICU2. Hence, EMRE is essential for in vivo uniporter current and additionally bridges the calcium-sensing role of MICU1 and MICU2 with the calcium-conducting role of MCU.
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                Author and article information

                Contributors
                chwang0116@gmail.com
                +886-4-7225121 , 181765@cch.org.tw , joeman@mmc.edu.tw
                Journal
                J Biomed Sci
                J. Biomed. Sci
                Journal of Biomedical Science
                BioMed Central (London )
                1021-7770
                1423-0127
                7 September 2017
                7 September 2017
                2017
                : 24
                Affiliations
                [1 ]ISNI 0000 0004 0572 7372, GRID grid.413814.b, Center for Mitochondrial Medicine and Free Radical Research, , Changhua Christian Hospital, ; No. 176, 6th Floor, Zhonghua Rd, Changhua City, 500 Taiwan
                [2 ]ISNI 0000 0001 0425 5914, GRID grid.260770.4, Institute of Biochemistry and Molecular Biology, , National Yang-Ming University, ; Shih-Pai, Taipei 112 Taiwan
                [3 ]ISNI 0000 0004 1762 5613, GRID grid.452449.a, Institute of Biomedical Sciences, , Mackay Medical College, ; Sanzhi, New Taipei City, 252 Taiwan
                Article
                375
                10.1186/s12929-017-0375-3
                5588717
                28882140
                f6a686e2-ca42-4d67-b75c-37be2f1ebfff
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: MOST104-2627-M-715-002
                Award ID: MOST104-2320-B-715-006-MY2
                Award Recipient :
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                © The Author(s) 2017

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