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      Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

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          Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most inherited kidney disease. Mutations in the PKD1 and PKD2 genes, encoding the polycystin 1 and polycystin 2 Ca 2+ ion channels, respectively, result in tubular epithelial cell-derived renal cysts. Recent clinical studies demonstrate oxidative stress to be present early in ADPKD. Mitochondria comprise the primary reactive oxygen species source and also their main effector target; however, the pathophysiological role of mitochondria in ADPKD remains uncharacterized. To clarify this function, we examined the mitochondria of cyst-lining cells in ADPKD model mice (Ksp-Cre PKD1 flox/flox) and rats (Han:SPRD Cy/+), demonstrating obvious tubular cell morphological abnormalities. Notably, the mitochondrial DNA copy number and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) expression were decreased in ADPKD model animal kidneys, with PGC-1α expression inversely correlated with oxidative stress levels. Consistent with these findings, human ADPKD cyst-derived cells with heterozygous and homozygous PKD1 mutation exhibited morphological and functional abnormalities, including increased mitochondrial superoxide. Furthermore, PGC-1α expression was suppressed by decreased intracellular Ca 2+ levels via calcineurin, p38 mitogen-activated protein kinase (MAPK), and nitric oxide synthase deactivation. Moreover, the mitochondrion-specific antioxidant MitoQuinone (MitoQ) reduced intracellular superoxide and inhibited cyst epithelial cell proliferation through extracellular signal-related kinase/MAPK inactivation. Collectively, these results indicate that mitochondrial abnormalities facilitate cyst formation in ADPKD.

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          Most cited references 47

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          Normal oxidative damage to mitochondrial and nuclear DNA is extensive.

          Oxidative damage to DNA can be caused by excited oxygen species, which are produced by radiation or are by-products of aerobic metabolism. The oxidized base, 8-hydroxydeoxyguanosine (oh8dG), 1 of approximately 20 known radiation damage products, has been assayed in the DNA of rat liver. oh8dG is present at a level of 1 per 130,000 bases in nuclear DNA and 1 per 8000 bases in mtDNA. Mitochondria treated with various prooxidants have an increased level of oh8dG. The high level of oh8dG in mtDNA may be caused by the immense oxygen metabolism, relatively inefficient DNA repair, and the absence of histones in mitochondria. It may be responsible for the observed high mutation rate of mtDNA.
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            Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide.

            Nitric oxide was found to trigger mitochondrial biogenesis in cells as diverse as brown adipocytes and 3T3-L1, U937, and HeLa cells. This effect of nitric oxide was dependent on guanosine 3',5'-monophosphate (cGMP) and was mediated by the induction of peroxisome proliferator-activated receptor gamma coactivator 1alpha, a master regulator of mitochondrial biogenesis. Moreover, the mitochondrial biogenesis induced by exposure to cold was markedly reduced in brown adipose tissue of endothelial nitric oxide synthase null-mutant (eNOS-/-) mice, which had a reduced metabolic rate and accelerated weight gain as compared to wild-type mice. Thus, a nitric oxide-cGMP-dependent pathway controls mitochondrial biogenesis and body energy balance.
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              An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle.

               C Handschin,  J. Rhee,  J. Lin (2003)
              Skeletal muscle adapts to chronic physical activity by inducing mitochondrial biogenesis and switching proportions of muscle fibers from type II to type I. Several major factors involved in this process have been identified, such as the calcium/calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A (CnA), and the transcriptional component peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha). Transgenic expression of PGC-1alpha recently has been shown to dramatically increase the content of type I muscle fibers in skeletal muscle, but the relationship between PGC-1alpha expression and the key components in calcium signaling is not clear. In this report, we show that the PGC-1alpha promoter is regulated by both CaMKIV and CnA activity. CaMKIV activates PGC-1alpha largely through the binding of cAMP response element-binding protein to the PGC-1alpha promoter. Moreover, we show that a positive feedback loop exists between PGC-1alpha and members of the myocyte enhancer factor 2 (MEF2) family of transcription factors. MEF2s bind to the PGC-1alpha promoter and activate it, predominantly when coactivated by PGC-1alpha. MEF2 activity is stimulated further by CnA signaling. These findings imply a unified pathway, integrating key regulators of calcium signaling with the transcriptional switch PGC-1alpha. Furthermore, these data suggest an autofeedback loop whereby the calcium-signaling pathway may result in a stable induction of PGC-1alpha, contributing to the relatively stable nature of muscle fiber-type determination.

                Author and article information

                Mol Cell Biol
                Mol. Cell. Biol
                Molecular and Cellular Biology
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                9 October 2017
                28 November 2017
                15 December 2017
                28 November 2017
                : 37
                : 24
                [a ]Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
                [b ]Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
                [c ]Education and Research Center of Animal Models for Human Diseases, Fujita Health University, Aichi, Japan
                [d ]Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
                [e ]Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan
                [f ]Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
                Author notes
                Address correspondence to Reiko Inagi, inagi-npr@ , or Masaomi Nangaku, mnangaku-tky@ .

                Citation Ishimoto Y, Inagi R, Yoshihara D, Kugita M, Nagao S, Shimizu A, Takeda N, Wake M, Honda K, Zhou J, Nangaku M. 2017. Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease. Mol Cell Biol 37:e00337-17.

                Copyright © 2017 Ishimoto et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                Page count
                Figures: 13, Tables: 4, Equations: 0, References: 62, Pages: 23, Words: 10811
                Funded by: HHS | National Institutes of Health (NIH)
                Award ID: RO1DK099532
                Award ID: R37DK51050
                Award Recipient : Jing Zhou
                Funded by: U.S. Department of Defense (DOD)
                Award ID: PR152162
                Award Recipient : Jing Zhou
                Funded by: MEXT | Japan Society for the Promotion of Science (JSPS)
                Award ID: 25461207
                Award ID: 15KT0088
                Award ID: 16KI15465
                Award Recipient : Reiko Inagi
                Funded by: MEXT | Japan Society for the Promotion of Science (JSPS)
                Award ID: 24390213
                Award ID: 16K15464
                Award Recipient : Masaomi Nangaku
                Funded by: Japanese Association of Dialysis Physicians (JAPD)
                Award ID: 2012-05
                Award Recipient : Reiko Inagi
                Research Article
                Custom metadata
                December 2017

                Molecular biology

                polycystic kidney disease, mitochondrial metabolism


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