Abstract
Recent studies have reported intrinsic metabolic reprogramming in Pkd1 knock-out cells, implicating dysregulated cellular metabolism in the pathogenesis of polycystic kidney disease. However, the exact nature of the metabolic changes and their underlying cause remains controversial. We show herein that Pkd1ko/ko renal epithelial cells have impaired fatty acid utilization, abnormal mitochondrial morphology and function, and that mitochondria in kidneys of ADPKD patients have morphological alterations. We further show that a C-terminal cleavage product of polycystin-1 (CTT) translocates to the mitochondria matrix and that expression of CTT in Pkd1ko/ko cells rescues some of the mitochondrial phenotypes. Using Drosophila to model in vivo effects, we find that transgenic expression of mouse CTT results in decreased viability and exercise endurance but increased CO2 production, consistent with altered mitochondrial function. Our results suggest that PC1 may play a direct role in regulating mitochondrial function and cellular metabolism and provide a framework to understand how impaired mitochondrial function could be linked to the regulation of tubular diameter in both physiological and pathological conditions.
Highlights
Recent studies have reported intrinsic metabolic reprogramming in Pkd[1] knock-out cells, implicating dysregulated cellular metabolism in the pathogenesis of polycystic kidney disease
To further investigate a metabolic phenotype in Pkd[1] mutant cells, we analyzed the rate of metabolite turnover – or metabolic flux – by mass spectrometry of cells treated with 13C-labeled glucose
We examined whether abnormal fatty acid utilization was accompanied by changes in phospholipid levels
Summary
Recent studies have reported intrinsic metabolic reprogramming in Pkd[1] knock-out cells, implicating dysregulated cellular metabolism in the pathogenesis of polycystic kidney disease. We show that Pkd1ko/ko renal epithelial cells have impaired fatty acid utilization, abnormal mitochondrial morphology and function, and that mitochondria in kidneys of ADPKD patients have morphological alterations. In addition to its initially described role as a regulator of apoptosis and proliferation[17], emerging evidence of intrinsic metabolic reprogramming in Pkd[1] knockout cells suggests that the PC1-PC2 complex regulates cellular metabolism[18,19,20,21]. The exact nature of the metabolic alterations remains controversial, with some groups reporting enhanced glycolysis reminiscent of the Warburg phenomenon[19,21] and others observing no evidence for a glycolytic switch[20,22] and/or proposing fatty acid oxidation impairment[20,23]. We report that a proteolytic product of PC1 localizes to mitochondria matrix and show that its over-expression in heterologous systems can alter mitochondrial structure and function
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