Ishimoto, YuInagi, ReikoYoshihara, DaisukeKugita, MasanoriNagao, ShizukoShimizu, AkiraTakeda, NorihikoWake, MasakiHonda, KenjiroZhou, JingNangaku, Masaomi2018-01-182017Ishimoto, Y., R. Inagi, D. Yoshihara, M. Kugita, S. Nagao, A. Shimizu, N. Takeda, et al. 2017. “Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease.” Molecular and Cellular Biology 37 (24): e00337-17. doi:10.1128/MCB.00337-17. http://dx.doi.org/10.1128/MCB.00337-17.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34651933ABSTRACT 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 Ca2+ 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 PKD1flox/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 Ca2+ 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.en-USSpotlightmitochondrial metabolismpolycystic kidney diseaseJournal Article2018-01-1810.1128/MCB.00337-17