Unbalanced lipolysis results in lipotoxicity and mitochondrial damage in peroxisome-deficient Pex19 mutants.

Autor:	Bülow MH; Department of Molecular Developmental Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany mbuelow@uni-bonn.de m.hoch@uni-bonn.de sellin@uni-bonn.de., Wingen C; Department of Molecular Developmental Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany., Senyilmaz D; Division of Signal Transduction in Cancer and Metabolism, German Cancer Research Center, 69120 Heidelberg, Germany., Gosejacob D; Department of Molecular Developmental Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany., Sociale M; Department of Molecular Developmental Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany., Bauer R; Department of Molecular Developmental Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany., Schulze H; Department of Membrane Biology & Lipid Biochemistry, Life & Medical Sciences Institute (LIMES), Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, 53121 Bonn, Germany., Sandhoff K; Department of Membrane Biology & Lipid Biochemistry, Life & Medical Sciences Institute (LIMES), Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, 53121 Bonn, Germany., Teleman AA; Division of Signal Transduction in Cancer and Metabolism, German Cancer Research Center, 69120 Heidelberg, Germany., Hoch M; Department of Molecular Developmental Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany mbuelow@uni-bonn.de m.hoch@uni-bonn.de sellin@uni-bonn.de., Sellin J; Department of Molecular Developmental Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany mbuelow@uni-bonn.de m.hoch@uni-bonn.de sellin@uni-bonn.de.
Jazyk:	angličtina
Zdroj:	Molecular biology of the cell [Mol Biol Cell] 2018 Feb 15; Vol. 29 (4), pp. 396-407. Date of Electronic Publication: 2017 Dec 27.
DOI:	10.1091/mbc.E17-08-0535
Abstrakt:	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. (© 2018 Bülow et al. 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 (http://creativecommons.org/licenses/by-nc-sa/3.0).)
Databáze:	MEDLINE
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