Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease
Yu Ishimoto, Reiko Inagi, Daisuke Yoshihara, Masanori Kugita, Shizuko Nagao, Akira Shimizu, Norihiko Takeda, Masaki Wake, Kenjiro Honda, Jing Zhou, Masaomi Nangaku
Education and Research Center of Animal Models for Human Diseases
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.
e00337-17
https://doi.org/10.1128/MCB.00337-17
Superoxides
Ishimoto, Y., Inagi, R., Yoshihara, D., Kugita, M., Nagao, S., Shimizu, A., ... Nangaku, M. (2017). Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease. Molecular and Cellular Biology, 37(24), [e00337-17]. https://doi.org/10.1128/MCB.00337-17
Ishimoto, Yu ; Inagi, Reiko ; Yoshihara, Daisuke ; Kugita, Masanori ; Nagao, Shizuko ; Shimizu, Akira ; Takeda, Norihiko ; Wake, Masaki ; Honda, Kenjiro ; Zhou, Jing ; Nangaku, Masaomi. / Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease. In: Molecular and Cellular Biology. 2017 ; Vol. 37, No. 24.
@article{f3d1ea926a6c4c4fbc96c9c00c8816f5,
title = "Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease",
abstract = "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.",
author = "Yu Ishimoto and Reiko Inagi and Daisuke Yoshihara and Masanori Kugita and Shizuko Nagao and Akira Shimizu and Norihiko Takeda and Masaki Wake and Kenjiro Honda and Jing Zhou and Masaomi Nangaku",
doi = "10.1128/MCB.00337-17",
journal = "Molecular and Cellular Biology",
publisher = "American Society for Microbiology",
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', Molecular and Cellular Biology, vol. 37, no. 24, e00337-17. https://doi.org/10.1128/MCB.00337-17
Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease. / Ishimoto, Yu; Inagi, Reiko; Yoshihara, Daisuke; Kugita, Masanori; Nagao, Shizuko; Shimizu, Akira; Takeda, Norihiko; Wake, Masaki; Honda, Kenjiro; Zhou, Jing; Nangaku, Masaomi.
In: Molecular and Cellular Biology, Vol. 37, No. 24, e00337-17, 01.12.2017.
T1 - Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease
AU - Ishimoto, Yu
AU - Inagi, Reiko
AU - Yoshihara, Daisuke
AU - Kugita, Masanori
AU - Nagao, Shizuko
AU - Shimizu, Akira
AU - Takeda, Norihiko
AU - Wake, Masaki
AU - Honda, Kenjiro
AU - Zhou, Jing
AU - Nangaku, Masaomi
N2 - 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.
AB - 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.
U2 - 10.1128/MCB.00337-17
DO - 10.1128/MCB.00337-17
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
M1 - e00337-17
Ishimoto Y, Inagi R, Yoshihara D, Kugita M, Nagao S, Shimizu A et al. Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease. Molecular and Cellular Biology. 2017 Dec 1;37(24). e00337-17. https://doi.org/10.1128/MCB.00337-17
10.1128/MCB.00337-17