Unknown

Dataset Information

0

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.

SUBMITTER: Podrini C 

PROVIDER: S-EPMC6240072 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Podrini Christine C   Rowe Isaline I   Pagliarini Roberto R   Costa Ana S H ASH   Chiaravalli Marco M   Di Meo Ivano I   Kim Hyunho H   Distefano Gianfranco G   Tiranti Valeria V   Qian Feng F   di Bernardo Diego D   Frezza Christian C   Boletta Alessandra A  

Communications biology 20181116


Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder caused by loss-of-function mutations in <i>PKD1</i> or <i>PKD2</i>. 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 <i>Pkd1</i> mutant cells and kidneys to investigate the metabolic reprogramming of this pathology. We show that loss of <i>Pkd1</i> leads to profound metabolic changes that affect glycolysis, mitochon  ...[more]

Similar Datasets

2019-06-07 | MTBLS677 | MetaboLights
2018-11-16 | GSE121563 | GEO
| PRJNA497797 | ENA
| S-EPMC7133124 | biostudies-literature
| S-EPMC7273358 | biostudies-literature
| S-EPMC11362800 | biostudies-literature
| S-EPMC6992713 | biostudies-literature
| S-EPMC9233026 | biostudies-literature
| S-EPMC5297506 | biostudies-literature
| S-EPMC6009840 | biostudies-literature