Abstract
Multiple studies of tissue and cell samples from patients and preclinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities, and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease. Using control and Pkd1-/- kidney epithelial cells, we investigated peroxisome abundance, biogenesis, and morphology by immunoblotting, immunofluorescence, and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific β-oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl;Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C terminus or full-length polycystin-1 colocalize with peroxisome markers by imaging studies. Peroxisome abundance, morphology, and peroxisome-related protein expression in Pkd1-/- cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal β-oxidation was not impaired in Pkd1-/- cells, and there was no obvious accumulation of very-long-chain fatty acids in kidneys of mutant mice. Reanalysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, and provide further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full-length polycystin-1 or its C terminus, a fragment previously shown to go to the mitochondria, showed minimal colocalization with peroxisome markers restricted to putative mitochondrion-peroxisome contact sites. Our studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid metabolism.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases, affecting approximately one in 1000 individuals
Our studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisomedependent fatty acid metabolism
Peroxisomal disorders can be broadly divided into two groups: those that are the result of biogenesis defects, a genetically and phenotypically heterogeneous group mostly characterized by peroxisomal protein import deficiency; and those resulting from single enzyme defects and mostly affecting specific metabolic pathways [14]
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases, affecting approximately one in 1000 individuals. It is primarily caused by mutations in the PKD1 or PKD2 genes, and is characterized by the appearance and growth of cystic lesions in multiple organs, kidney and liver. Multiple groups have investigated and reported mitochondrial functional or morphologic abnormalities in experimental ADPKD models and human patient samples, including impaired glucose metabolism [2], fatty acid oxidation [4], and disorganized mitochondrial cristae with altered mitochondrial network [5,6]. Multiple studies of tissue and cell samples from patients and preclinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
