Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder caused by loss-of-function mutations in PKD1 or PKD2. Increased glycolysis is a prominent feature of the disease, but how it impacts on other metabolic pathways is unknown. Here, we present an analysis of mouse Pkd1 mutant cells and kidneys to investigate the metabolic reprogramming of this pathology. We show that loss of Pkd1 leads to profound metabolic changes that affect glycolysis, mitochondrial metabolism, and fatty acid synthesis (FAS). We find that Pkd1-mutant cells preferentially use glutamine to fuel the TCA cycle and to sustain FAS. Interfering with either glutamine uptake or FAS retards cell growth and survival. We also find that glutamine is diverted to asparagine via asparagine synthetase (ASNS). Transcriptional profiling of PKD1-mutant human kidneys confirmed these alterations. We find that silencing of Asns is lethal in Pkd1-mutant cells when combined with glucose deprivation, suggesting therapeutic approaches for ADPKD.

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

“…Metabolic reprogramming has been described as an important feature of ADPKD 1‐7 . In particular, we previously found increased glycolysis and TCA cycle metabolic reprogramming in an orthologous mouse model of PKD 3,8 . In the attempt to establish whether mitochondrial dysfunction could account for such an alteration, we analyzed mitochondrial structure and activity in situ in the same animal model ( Ksp‐Cre;Pkd1 flox/− mice), 3,8 bearing inactivation of Pkd1 in the distal tubules and collecting ducts of the kidney 15,19 .…”

“…In particular, we previously found increased glycolysis and TCA cycle metabolic reprogramming in an orthologous mouse model of PKD 3,8 . In the attempt to establish whether mitochondrial dysfunction could account for such an alteration, we analyzed mitochondrial structure and activity in situ in the same animal model ( Ksp‐Cre;Pkd1 flox/− mice), 3,8 bearing inactivation of Pkd1 in the distal tubules and collecting ducts of the kidney 15,19 . Ksp‐Cre;Pkd1 flox/− mice display an early onset, severe cystic phenotype with already enlarged kidneys at postnatal day (P) P4 with the presence of numerous large cysts (Figure 1A) as compared to controls ( Ksp‐Cre;Pkd1 flox/+ ).…”

“…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 .…”

“…Loss‐of‐function of PC1 or PC2 induces deregulation of several signaling pathways and recent findings indicate that the alteration in cellular metabolism is a hallmark of the disease 1‐7 . 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 .…”

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

“…Several signaling molecules, including cAMP, mTOR, AMPK, and growth factors have been implicated in the pathogenesis of ADPKD, and many of these pathways have been shown to be modulated by the energy state of the organism (6)(7)(8)(9). Recent findings have revealed that metabolic alterations (10) including defective glucose metabolism (7,(11)(12)(13), impaired beta-oxidation (14), and abnormal mitochondrial activity (15-17) play a role in ADPKD pathogenesis. In fact, recent studies demonstrated that dietary intervention Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of end-stage renal disease (ESRD).…”