Disruption of polycystin-1 cleavage impairs mitochondrial bioenergetics and calcium uptake in a substrate-dependent manner.

Metabolic and mitochondrial alterations are central in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) since therapies targeting these alterations slow kidney disease progression in orthologous animal models. To investigate metabolic and mitochondrial defects in an animal model orthologous to ADPKD, we used male mice homozygous for a point variant in the GPS cleavage site of the polycystin-1 (Pkd1V/V) and evaluated oxygen consumption, Ca2+ uptake, and redox state in the mitochondrial fraction of Pkd1V/V kidneys and wild-type controls (WT). Our findings revealed mitochondrial heterogeneity in Pkd1V/V kidneys, with regions of preserved morphology alongside areas displaying swollen and disorganized mitochondria. Notably, preserved mitochondria were smaller, with either unchanged mitochondrial mass markers (TFAM, CYTC, mDNA/nDNA) or increased TOM20 levels compared with WT. Mitochondria isolated from Pkd1V/V kidneys showed a reduction in oxygen consumption rates and calcium retention capacity in the presence of NADH-generating substrates, but not in the presence of succinate. Consistently, levels of specific proteins of complex I, III, and V were decreased, but not of complex II. Proteins involved in calcium homeostasis (VDAC1, MCU, MICU1, MICU2, and dimeric NCLX) were decreased in Pkd1V/V kidneys. No change in horseradish peroxidase (HRP)-H2O2-mediated Amplex Red oxidation was observed in diseased mitochondria, and mitochondrial 4-hydroxynonenal (4-HNE) levels were unchanged, although increased in whole kidney extracts. Together, our results showed that cleaved PC1 plays a critical role in maintaining mitochondrial mass, integrity, and function. Given the orthologous nature of our animal model, the observed alterations may be applicable to human ADPKD.NEW & NOTEWORTHY Cleavage-deficient polycystin-1 disrupts mitochondrial function in an ADPKD mouse model (Pkd1V/V). Pkd1V/V kidneys exhibit heterogeneous mitochondrial morphology, reduced oxygen consumption, and calcium retention when relying on NADH-linked substrates, but preserved function with succinate. Consistent decreases in complexes I, III, V, and calcium-handling proteins accompany these defects. Although oxidative stress is unchanged in Pkd1V/V mitochondria, 4-HNE is increased in cystic kidney. Given the orthologous nature of Pkd1V/V, the observed alterations might be relevant to human ADPKD.