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

Published version
Peer-reviewed

Type

Article

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Authors

Rowe, Isaline 
Pagliarini, Roberto 
Chiaravalli, Marco 

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.

Description

Keywords

Renal and Urogenital

Journal Title

Commun Biol

Conference Name

Journal ISSN

2399-3642
2399-3642

Volume Title

1

Publisher

Springer Science and Business Media LLC
Sponsorship
MRC (unknown)
Medical Research Council (MC_UU_12022/6)