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Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease
Yu Ishimoto1,2, Reiko Inagi3,2, Daisuke Yoshihara4
1Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Insights
Mitochondrial dysfunction and oxidative stress are early drivers of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Targeting mitochondria with antioxidants like MitoQuinone may reduce cyst growth in ADPKD.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder.
- Mutations in PKD1/PKD2 genes cause renal cysts, and oxidative stress is an early feature.
- The role of mitochondria in ADPKD pathogenesis is not well understood.
Purpose of the Study:
- To investigate the pathophysiological role of mitochondria in ADPKD.
- To explore the relationship between mitochondrial dysfunction, oxidative stress, and cyst formation.
Main Methods:
- Examined mitochondria in cyst-lining cells of ADPKD mouse and rat models.
- Analyzed mitochondrial DNA copy number, PGC-1α expression, and oxidative stress markers.
- Investigated human ADPKD cyst-derived cells and the effect of MitoQuinone.
Main Results:
- ADPKD models showed decreased mitochondrial DNA copy number and PGC-1α expression, correlating with increased oxidative stress.
- Human ADPKD cells exhibited mitochondrial abnormalities and increased superoxide production.
- Reduced intracellular calcium suppressed PGC-1α via calcineurin, p38 MAPK, and NOS pathways.
- MitoQuinone reduced superoxide and inhibited cyst cell proliferation by inactivating ERK/MAPK.
Conclusions:
- Mitochondrial abnormalities, including reduced PGC-1α and increased oxidative stress, are integral to ADPKD.
- Decreased intracellular calcium contributes to mitochondrial dysfunction in ADPKD.
- MitoQuinone shows potential as a therapeutic agent by mitigating oxidative stress and inhibiting cyst cell proliferation.
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 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.