Dietary rescue of lipotoxicity-induced mitochondrial damage in Peroxin19 mutants.

Autor: Sellin J; University of Bonn, Life & Medical Sciences Institute (LIMES), Molecular Developmental Biology, Bonn, Germany., Wingen C; University of Bonn, Life & Medical Sciences Institute (LIMES), Molecular Developmental Biology, Bonn, Germany., Gosejacob D; University of Bonn, Life & Medical Sciences Institute (LIMES), Molecular Developmental Biology, Bonn, Germany., Senyilmaz D; German Cancer Research Center, Signal Transduction in Cancer and Metabolism, Heidelberg, Germany., Hänschke L; University of Bonn, Life & Medical Sciences Institute (LIMES), Molecular Developmental Biology, Bonn, Germany., Büttner S; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany., Meyer K; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany., Bano D; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany., Nicotera P; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany., Teleman AA; German Cancer Research Center, Signal Transduction in Cancer and Metabolism, Heidelberg, Germany., Bülow MH; University of Bonn, Life & Medical Sciences Institute (LIMES), Molecular Developmental Biology, Bonn, Germany.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2018 Jun 19; Vol. 16 (6), pp. e2004893. Date of Electronic Publication: 2018 Jun 19 (Print Publication: 2018).
DOI: 10.1371/journal.pbio.2004893
Abstrakt: Mutations in peroxin (PEX) genes lead to loss of peroxisomes, resulting in the formation of peroxisomal biogenesis disorders (PBDs) and early lethality. Studying PBDs and their animal models has greatly contributed to our current knowledge about peroxisomal functions. Very-long-chain fatty acid (VLCFA) accumulation has long been suggested as a major disease-mediating factor, although the exact pathological consequences are unclear. Here, we show that a Drosophila Pex19 mutant is lethal due to a deficit in medium-chain fatty acids (MCFAs). Increased lipolysis mediated by Lipase 3 (Lip3) leads to accumulation of free fatty acids and lipotoxicity. Administration of MCFAs prevents lipolysis and decreases the free fatty acid load. This drastically increases the survival rate of Pex19 mutants without reducing VLCFA accumulation. We identified a mediator of MCFA-induced lipolysis repression, the ceramide synthase Schlank, which reacts to MCFA supplementation by increasing its repressive action on lip3. This shifts our understanding of the key defects in peroxisome-deficient cells away from elevated VLCFA levels toward elevated lipolysis and shows that loss of this important organelle can be compensated by a dietary adjustment.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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