Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most common inherited kidney disease. Mutations in the PKD1 and PKD2 genes, encoding respective polycystin-1 and polycystin-2 Ca2+ ion channels, results in tubular epithelial cell-derived renal cysts. Recent clinical studies demonstrate oxidative stress as 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, 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 mitochondria-specific antioxidant MitoQ reduced intracellular superoxide and inhibited cyst epithelial-cell proliferation through extracellular signal-related kinase/MAPK inactivation. Collectively, these results indicated mitochondrial abnormalities facilitate cyst formation in ADPKD.