A cleavage product of Polycystin-1 is a mitochondrial matrix protein that affects mitochondria morphology and function when heterologously expressed

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.

Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression

“…Mitochondrial mass, on the contrary, is preserved in the proximal tubules of Ksp‐Cre;Pkd1 flox/− kidneys (KO, cortex) as expected (Figure 1C and S1B). In the cystic epithelia, we observed swollen mitochondria as previously reported either in situ 10 or on isolated cells derived from Pkd1 mutant mice, 11 with few cristae and decreased electron density within the matrix, both in the cortex and in the medulla. Of interest, we also detected healthy, and normally appearing mitochondria scattered among damaged ones in the cysts suggesting that the absence of PC‐1 does not per se result in this structural damage.…”

“…In this study, we show that in cystic kidneys due to Pkd1 inactivation, epithelial cells of the distal tubules and collecting ducts have reduced mitochondrial mass and decreased activity of mitochondria RCCs in vivo. Mitochondria also appear swollen and damaged as previously reported in human tissues 10,11 . Of interest, we also found healthy mitochondria scattered among aberrant ones, suggesting that the lack of Pkd1 is not per se sufficient to cause mitochondrial damage and that perhaps a progressive degeneration of mitochondria occurs in these tissues.…”

“…The remodeling of glucose utilization for energy production and a wide rewiring of metabolic reprograming of energetic pathways have been reported in mouse Pkd1 mutant cells and kidneys 3,5,8 . Reduction in mitochondrial oxygen consumption rate and alterations in mitochondrial structure have also been described 5,8‐11 . These alterations correlate in human and mouse ADPKD cells with increased expression of miR‐17, which negatively modulates mitochondrial function, through repression of the master regulator of mitochondrial biogenesis, PPARalpha 12 .…”

“…Moreover, PC1 and PC2 proteins localize also in the mitochondria‐associated membranes (MAMs), where they can mediate calcium signaling from the ER lumen to the mitochondria matrix thus modulating mitochondrial metabolism 7,9,13 . Of note, a cleaved carboxyl‐terminal fragment of PC1 has been proposed to accumulate in mitochondria, indicating that PC1 may directly modulate mitochondrial function 11 …”

Physiological and pathophysiological role of reactive oxygen species and reactive nitrogen species in the kidney

“…This in turn enhances proliferation via extracellular signal‐related kinase 1 and 2 activation . In addition, a recent study suggested a direct role of polycystin‐1 in regulating mitochondrial function in renal epithelial cells . These various findings indicate that mitochondria and O 2 ˙− play important roles in the pathogenesis of ADPKD.…”