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      Mitochondrial destiny in type 2 diabetes: the effects of oxidative stress on the dynamics and biogenesis of mitochondria

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          Abstract

          Background

          One reason for the development of insulin resistance is the chronic inflammation in obesity.

          Materials & Methods

          Scientific articles in the field of knowledge on the involvement of mitochondria and mitochondrial DNA (mtDNA) in obesity and type 2 diabetes were analyzed.

          Results

          Oxidative stress developed during obesity contributes to the formation of peroxynitrite, which causes cytochrome C-related damage in the mitochondrial electron transfer chain and increases the production of reactive oxygen species (ROS), which is associated with the development of type 2 diabetes. Oxidative stress contributes to the nuclease activity of the mitochondrial matrix, which leads to the accumulation of cleaved fragments and an increase in heteroplasmy. Mitochondrial dysfunction and mtDNA variations during insulin resistance may be connected with a change in ATP levels, generation of ROS, mitochondrial division/fusion and mitophagy. This review discusses the main role of mitochondria in the development of insulin resistance, which leads to pathological processes in insulin-dependent tissues, and considers potential therapeutic directions based on the modulation of mitochondrial biogenesis. In this regard, the development of drugs aimed at the regulation of these processes is gaining attention.

          Conclusion

          Changes in the mtDNA copy number can help to protect mitochondria from severe damage during conditions of increased oxidative stress. Mitochondrial proteome studies are conducted to search for potential therapeutic targets. The use of mitochondrial peptides encoded by mtDNA also represents a promising new approach to therapy.

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          Most cited references71

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          Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network.

          The PGC-1 family of regulated coactivators, consisting of PGC-1α, PGC-1β and PRC, plays a central role in a regulatory network governing the transcriptional control of mitochondrial biogenesis and respiratory function. These coactivators target multiple transcription factors including NRF-1, NRF-2 and the orphan nuclear hormone receptor, ERRα, among others. In addition, they themselves are the targets of coactivator and co-repressor complexes that regulate gene expression through chromatin remodeling. The expression of PGC-1 family members is modulated by extracellular signals controlling metabolism, differentiation or cell growth and in some cases their activities are known to be regulated by post-translational modification by the energy sensors, AMPK and SIRT1. Recent gene knockout and silencing studies of many members of the PGC-1 network have revealed phenotypes of wide ranging severity suggestive of complex compensatory interactions or broadly integrative functions that are not exclusive to mitochondrial biogenesis. The results point to a central role for the PGC-1 family in integrating mitochondrial biogenesis and energy production with many diverse cellular functions. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. Copyright © 2010 Elsevier B.V. All rights reserved.
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            Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization.

            Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.
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              Translocation of proteins into mitochondria.

              About 10% to 15% of the nuclear genes of eukaryotic organisms encode mitochondrial proteins. These proteins are synthesized in the cytosol and recognized by receptors on the surface of mitochondria. Translocases in the outer and inner membrane of mitochondria mediate the import and intramitochondrial sorting of these proteins; ATP and the membrane potential are used as energy sources. Chaperones and auxiliary factors assist in the folding and assembly of mitochondrial proteins into their native, three-dimensional structures. This review summarizes the present knowledge on the import and sorting of mitochondrial precursor proteins, with a special emphasis on unresolved questions and topics of current research.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                peerj
                peerj
                PeerJ
                PeerJ Inc. (San Diego, USA )
                2167-8359
                25 August 2020
                2020
                : 8
                : e9741
                Affiliations
                [-1] Immanuel Kant Baltic Federal University , Kaliningrad, Russian Federation
                Article
                9741
                10.7717/peerj.9741
                7453922
                4abe5d1b-ce71-4309-99a1-3a5a2296fc81
                ©2020 Skuratovskaia et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 13 April 2020
                : 26 July 2020
                Funding
                Funded by: Russian Foundation for Basic Research
                Award ID: 18-015-00084-a
                Funded by: Russian Foundation for Basic Research and Kaliningrad Region
                Award ID: 19-415-393004 - r_mol_a
                Award ID: 9-44-390005 - r_a
                Funded by: The State Assignment
                Award ID: 075-03-2020-080
                Funded by: Scientific Schools of the Russian Federation
                Award ID: 2495.2020.7
                The research was supported by Russian Foundation for Basic Research (No. 18-015-00084-a to Larisa Litvinova), by the Russian Foundation for Basic Research and Kaliningrad Region (No.19-415-393004r_mol_a and No.19-44-390005r_a to Daria Skuratovskaia), by State Assignment (No. 075-03-2020-080 to Larisa Litvinova), and by state support of leading scientific schools of the Russian Federation (No. 2495.2020.7 to Larisa Litvinova). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Biochemistry
                Genetics
                Diabetes and Endocrinology
                Medical Genetics
                Metabolic Sciences

                obesity, insulin resistance, mitochondrial fission and fusion, inflammation, mots-c

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