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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...

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Autores principales: Bülow, Margret H., Wingen, Christian, Senyilmaz, Deniz, Gosejacob, Dominic, Sociale, Mariangela, Bauer, Reinhard, Schulze, Heike, Sandhoff, Konrad, Teleman, Aurelio A., Hoch, Michael, Sellin, Julia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2018
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.
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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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