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      PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity to protect against kidney injury

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          Abstract

          Cisplatin is a widely used chemotherapeutic drug with notorious toxicity in the kidneys, which involves mitochondrial dysfunction and damage in renal tubular cells. Mitophagy is a form of selective autophagy that removes damaged or dysfunctional mitochondria to maintain cellular homeostasis. In this study, we have used mouse and cell models to examine the role and regulation of mitophagy in cisplatin nephrotoxicity. Cisplatin treatment was associated with the activation of autophagy and mitophagy. Rapamycin, a pharmacological inhibitor of mTOR, stimulated autophagy and mitophagy, and alleviated the development of cisplatin nephrotoxicity. PINK1 and Parkin were increased in kidney tissues during cisplatin treatment of mice. In PINK1 or Parkin gene knockout mouse models, both basal and cisplatin-induced mitophagy in kidneys were defective. Compared with wild-type littermates, PINK1 and Parkin knockout mice showed more severe renal functional loss, tissue damage, and apoptosis during cisplatin treatment. The results suggest that PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity and has a protective role against kidney injury.

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          Mechanisms of Cisplatin Nephrotoxicity

          Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention.
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            Mitochondrial energetics in the kidney

            Mitochondria provide the kidney with energy to remove waste from the blood and regulate fluid and electrolyte balance. This Review discusses how mitochondrial homeostasis is maintained, the changes in mitochondrial energetics that occur in acute kidney injury and diabetic nephropathy, and how targeting mitochondrial energetics might aid the treatment of renal disease.
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              Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models.

              The mechanism of mitochondrial damage, a key contributor to renal tubular cell death during acute kidney injury, remains largely unknown. Here, we have demonstrated a striking morphological change of mitochondria in experimental models of renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. This change contributed to mitochondrial outer membrane permeabilization, release of apoptogenic factors, and consequent apoptosis. Following either ATP depletion or cisplatin treatment of rat renal tubular cells, mitochondrial fragmentation was observed prior to cytochrome c release and apoptosis. This mitochondrial fragmentation was inhibited by Bcl2 but not by caspase inhibitors. Dynamin-related protein 1 (Drp1), a critical mitochondrial fission protein, translocated to mitochondria early during tubular cell injury, and both siRNA knockdown of Drp1 and expression of a dominant-negative Drp1 attenuated mitochondrial fragmentation, cytochrome c release, caspase activation, and apoptosis. Further in vivo analysis revealed that mitochondrial fragmentation also occurred in proximal tubular cells in mice during renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. Notably, both tubular cell apoptosis and acute kidney injury were attenuated by mdivi-1, a newly identified pharmacological inhibitor of Drp1. This study demonstrates a rapid regulation of mitochondrial dynamics during acute kidney injury and identifies mitochondrial fragmentation as what we believe to be a novel mechanism contributing to mitochondrial damage and apoptosis in vivo in mouse models of disease.
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                Author and article information

                Contributors
                zdong@csu.edu.cn , zdong@augusta.edu
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                1 November 2018
                1 November 2018
                November 2018
                : 9
                : 11
                : 1113
                Affiliations
                [1 ]ISNI 0000 0004 1803 0208, GRID grid.452708.c, Department of Nephrology, , The Second Xiangya Hospital at Central South University, ; Changsha, Hunan China
                [2 ]ISNI 0000 0004 1803 0208, GRID grid.452708.c, Department of Emergency Medicine, , The Second Xiangya Hospital at Central South University, ; Changsha, Hunan China
                [3 ]ISNI 0000 0004 1757 7615, GRID grid.452223.0, Institute of Precision Medicine, , Xiangya Hospital at Central South University, ; Changsha, Hunan China
                [4 ]ISNI 0000 0004 0419 3970, GRID grid.413830.d, Department of Cellular Biology and Anatomy, , Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, ; Augusta, GA USA
                Article
                1152
                10.1038/s41419-018-1152-2
                6212494
                30385753
                1a671180-22a3-4068-81f6-adfc2f010e3f
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 11 June 2018
                : 12 October 2018
                : 16 October 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81430017
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: 087843
                Award Recipient :
                Categories
                Article
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                © The Author(s) 2018

                Cell biology
                Cell biology

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