Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways.
di Bernardo, Diego
MetadataShow full item record
Podrini, C., Rowe, I., Pagliarini, R., Costa, A. S., Chiaravalli, M., Di Meo, I., Kim, H., et al. (2018). Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways.. Communications biology, 1 194. https://doi.org/10.1038/s42003-018-0200-x
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 if and how it impacts on other metabolic pathways is unknown. Here, we present a comprehensive 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). In particular, 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 the glutamine is diverted to asparagine via asparagine synthetase (ASNS). Importantly, transcriptional profiling of PKD1-mutant human kidneys confirmed these alterations. Notably, we see that the silencing of Asns is lethal in Pkd1-mutant cells when combined with glucose deprivation, opening novel therapeutic perspectives for ADPKD.
MRC (MC_UU_12022/1_do not transfer?)
Medical Research Council (MC_UU_12022/6)
External DOI: https://doi.org/10.1038/s42003-018-0200-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287268
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/