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Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants
Inherited peroxisomal biogenesis disorders (PBDs) are characterized by the absence of functional peroxisomes. They are caused by mutations of peroxisomal biogenesis factors encoded by Pex genes, and result in childhood lethality. Owing to the many metabolic functions fulfilled by peroxisomes, PBD pa...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014165/ https://www.ncbi.nlm.nih.gov/pubmed/29282281 http://dx.doi.org/10.1091/mbc.E17-08-0535 |
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author | Bülow, Margret H. Wingen, Christian Senyilmaz, Deniz Gosejacob, Dominic Sociale, Mariangela Bauer, Reinhard Schulze, Heike Sandhoff, Konrad Teleman, Aurelio A. Hoch, Michael Sellin, Julia |
author_facet | Bülow, Margret H. Wingen, Christian Senyilmaz, Deniz Gosejacob, Dominic Sociale, Mariangela Bauer, Reinhard Schulze, Heike Sandhoff, Konrad Teleman, Aurelio A. Hoch, Michael Sellin, Julia |
author_sort | Bülow, Margret H. |
collection | PubMed |
description | Inherited peroxisomal biogenesis disorders (PBDs) are characterized by the absence of functional peroxisomes. They are caused by mutations of peroxisomal biogenesis factors encoded by Pex genes, and result in childhood lethality. Owing to the many metabolic functions fulfilled by peroxisomes, PBD pathology is complex and incompletely understood. Besides accumulation of peroxisomal educts (like very-long-chain fatty acids [VLCFAs] or branched-chain fatty acids) and lack of products (like bile acids or plasmalogens), many peroxisomal defects lead to detrimental mitochondrial abnormalities for unknown reasons. We generated Pex19 Drosophila mutants, which recapitulate the hallmarks of PBDs, like absence of peroxisomes, reduced viability, neurodegeneration, mitochondrial abnormalities, and accumulation of VLCFAs. We present a model of hepatocyte nuclear factor 4 (Hnf4)-induced lipotoxicity and accumulation of free fatty acids as the cause for mitochondrial damage in consequence of peroxisome loss in Pex19 mutants. Hyperactive Hnf4 signaling leads to up-regulation of lipase 3 and enzymes for mitochondrial β-oxidation. This results in enhanced lipolysis, elevated concentrations of free fatty acids, maximal β-oxidation, and mitochondrial abnormalities. Increased acid lipase expression and accumulation of free fatty acids are also present in a Pex19-deficient patient skin fibroblast line, suggesting the conservation of key aspects of our findings. |
format | Online Article Text |
id | pubmed-6014165 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-60141652018-06-22 Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants Bülow, Margret H. Wingen, Christian Senyilmaz, Deniz Gosejacob, Dominic Sociale, Mariangela Bauer, Reinhard Schulze, Heike Sandhoff, Konrad Teleman, Aurelio A. Hoch, Michael Sellin, Julia Mol Biol Cell Articles Inherited peroxisomal biogenesis disorders (PBDs) are characterized by the absence of functional peroxisomes. They are caused by mutations of peroxisomal biogenesis factors encoded by Pex genes, and result in childhood lethality. Owing to the many metabolic functions fulfilled by peroxisomes, PBD pathology is complex and incompletely understood. Besides accumulation of peroxisomal educts (like very-long-chain fatty acids [VLCFAs] or branched-chain fatty acids) and lack of products (like bile acids or plasmalogens), many peroxisomal defects lead to detrimental mitochondrial abnormalities for unknown reasons. We generated Pex19 Drosophila mutants, which recapitulate the hallmarks of PBDs, like absence of peroxisomes, reduced viability, neurodegeneration, mitochondrial abnormalities, and accumulation of VLCFAs. We present a model of hepatocyte nuclear factor 4 (Hnf4)-induced lipotoxicity and accumulation of free fatty acids as the cause for mitochondrial damage in consequence of peroxisome loss in Pex19 mutants. Hyperactive Hnf4 signaling leads to up-regulation of lipase 3 and enzymes for mitochondrial β-oxidation. This results in enhanced lipolysis, elevated concentrations of free fatty acids, maximal β-oxidation, and mitochondrial abnormalities. Increased acid lipase expression and accumulation of free fatty acids are also present in a Pex19-deficient patient skin fibroblast line, suggesting the conservation of key aspects of our findings. The American Society for Cell Biology 2018-02-15 /pmc/articles/PMC6014165/ /pubmed/29282281 http://dx.doi.org/10.1091/mbc.E17-08-0535 Text en © 2018 Bülow et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0/ This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License. |
spellingShingle | Articles Bülow, Margret H. Wingen, Christian Senyilmaz, Deniz Gosejacob, Dominic Sociale, Mariangela Bauer, Reinhard Schulze, Heike Sandhoff, Konrad Teleman, Aurelio A. Hoch, Michael Sellin, Julia Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants |
title | Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants |
title_full | Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants |
title_fullStr | Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants |
title_full_unstemmed | Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants |
title_short | Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants |
title_sort | unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient pex19 mutants |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014165/ https://www.ncbi.nlm.nih.gov/pubmed/29282281 http://dx.doi.org/10.1091/mbc.E17-08-0535 |
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