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      Melatonin prevents Drp1‐mediated mitochondrial fission in diabetic hearts through SIRT1‐PGC1α pathway

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          Abstract

          Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly promotes diabetes‐induced cardiac dysfunction is still unknown. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. This study investigated whether melatonin protects against diabetes‐induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Here, we show that melatonin prevented diabetes‐induced cardiac dysfunction by inhibiting dynamin‐related protein 1 (Drp1)‐mediated mitochondrial fission. Melatonin treatment decreased Drp1 expression, inhibited mitochondrial fragmentation, suppressed oxidative stress, reduced cardiomyocyte apoptosis, improved mitochondrial function and cardiac function in streptozotocin ( STZ)‐induced diabetic mice, but not in SIRT1 −/− diabetic mice. In high glucose‐exposed H9c2 cells, melatonin treatment increased the expression of SIRT1 and PGC‐1α and inhibited Drp1‐mediated mitochondrial fission and mitochondria‐derived superoxide production. In contrast, SIRT1 or PGC‐1α si RNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1‐mediated mitochondrial fission in a SIRT1/ PGC‐1α‐dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC‐1α directly regulated the expression of Drp1 by binding to its promoter. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi‐1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. These findings show that melatonin attenuates the development of diabetes‐induced cardiac dysfunction by preventing mitochondrial fission through SIRT1‐ PGC1α pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes.

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          Most cited references 42

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          Mitochondrial dynamics--mitochondrial fission and fusion in human diseases.

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            Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species.

            One of the main causes of cardiovascular complications in diabetes is the hyperglycaemia-induced cell injury, and mitochondrial fission has been implicated in the apoptotic process. We investigated the role of mitochondrial fission in high glucose-induced cardiovascular cell injury. We used several types of cultured mouse, rat, and bovine cells from the cardiovascular system, and evaluated mitochondrial morphology, reactive oxygen species (ROS) levels, and apoptotic parameters in sustained high glucose incubation. Adenoviral infection was used for the inhibition of the fission protein DLP1. We found that mitochondria were short and fragmented in cells incubated in sustained high glucose conditions. Under the same conditions, cellular ROS levels were high and cell death was increased. We demonstrated that the increased level of ROS causes mitochondrial permeability transition (MPT), phosphatidylserine exposure, cytochrome c release, and caspase activation in prolonged high glucose conditions. Importantly, maintaining tubular mitochondria by inhibiting mitochondrial fission in sustained high glucose conditions normalized cellular ROS levels and prevented the MPT and subsequent cell death. These results demonstrate that mitochondrial fragmentation is an upstream factor for ROS overproduction and cell death in prolonged high glucose conditions. These findings indicate that the fission-mediated fragmentation of mitochondrial tubules is causally associated with enhanced production of mitochondrial ROS and cardiovascular cell injury in hyperglycaemic conditions.
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              Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes.

              The clinical correlations linking diabetes mellitus with accelerated atherosclerosis, cardiomyopathy, and increased post-myocardial infarction fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in reactive oxygen species (ROS) production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP-ribose) polymerase, which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and poly(ADP-ribose) polymerase also reduce sirtuin, PGC-1α, and AMP-activated protein kinase activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of proatherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, peptidylarginine deiminase 4, and activates the NOD-like receptor family, pyrin domain-containing 3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of forkhead box O 1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after myocardial infarction by increasing post-translational protein modifications, which cause increased ryanodine receptor phosphorylation and downregulation of sarco-endoplasmic reticulum Ca(++)-ATPase transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor α3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy.
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                Author and article information

                Contributors
                fufeng048@126.com
                jmpei8@fmmu.edu.cn
                Journal
                J Pineal Res
                J. Pineal Res
                10.1111/(ISSN)1600-079X
                JPI
                Journal of Pineal Research
                John Wiley and Sons Inc. (Hoboken )
                0742-3098
                1600-079X
                14 April 2018
                September 2018
                : 65
                : 2 ( doiID: 10.1111/jpi.2018.65.issue-2 )
                Affiliations
                [ 1 ] Department of Cardiology and Department of Geriatrics Xi'an Central Hospital Xi'an Jiaotong University Xi'an China
                [ 2 ] Department of Physiology National Key Discipline of Cell Biology School of Basic Medicine Fourth Military Medical University Xi'an China
                [ 3 ] Department of Endocrinology Affiliated Zhongshan Hospital of Dalian University Dalian China
                Author notes
                [* ] Correspondence

                Feng Fu and Jianming Pei, Department of Physiology, National Key Discipline of Cell Biology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.

                Emails: fufeng048@ 123456126.com ; jmpei8@ 123456fmmu.edu.cn

                Article
                JPI12491
                10.1111/jpi.12491
                6099285
                29575122
                © 2018 The Authors. Journal of Pineal Research Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 11, Tables: 0, Pages: 16, Words: 7574
                Product
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81670354
                Award ID: 81600235
                Award ID: 81770243
                Funded by: Key Project of Natural Science Foundation of Shaanxi, China
                Award ID: 2016KTCL03‐11
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jpi12491
                September 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:20.08.2018

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