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Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways
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 ce...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240072/ https://www.ncbi.nlm.nih.gov/pubmed/30480096 http://dx.doi.org/10.1038/s42003-018-0200-x |
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author | Podrini, Christine Rowe, Isaline Pagliarini, Roberto Costa, Ana S. H. Chiaravalli, Marco Di Meo, Ivano Kim, Hyunho Distefano, Gianfranco Tiranti, Valeria Qian, Feng di Bernardo, Diego Frezza, Christian Boletta, Alessandra |
author_facet | Podrini, Christine Rowe, Isaline Pagliarini, Roberto Costa, Ana S. H. Chiaravalli, Marco Di Meo, Ivano Kim, Hyunho Distefano, Gianfranco Tiranti, Valeria Qian, Feng di Bernardo, Diego Frezza, Christian Boletta, Alessandra |
author_sort | Podrini, Christine |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6240072 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62400722018-11-26 Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways Podrini, Christine Rowe, Isaline Pagliarini, Roberto Costa, Ana S. H. Chiaravalli, Marco Di Meo, Ivano Kim, Hyunho Distefano, Gianfranco Tiranti, Valeria Qian, Feng di Bernardo, Diego Frezza, Christian Boletta, Alessandra Commun Biol Article 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. Nature Publishing Group UK 2018-11-16 /pmc/articles/PMC6240072/ /pubmed/30480096 http://dx.doi.org/10.1038/s42003-018-0200-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Podrini, Christine Rowe, Isaline Pagliarini, Roberto Costa, Ana S. H. Chiaravalli, Marco Di Meo, Ivano Kim, Hyunho Distefano, Gianfranco Tiranti, Valeria Qian, Feng di Bernardo, Diego Frezza, Christian Boletta, Alessandra Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways |
title | Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways |
title_full | Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways |
title_fullStr | Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways |
title_full_unstemmed | Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways |
title_short | Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways |
title_sort | dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240072/ https://www.ncbi.nlm.nih.gov/pubmed/30480096 http://dx.doi.org/10.1038/s42003-018-0200-x |
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