title: A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival.
abstract: Deficiency of the mitochondrial enzyme 2-methyl-3-hydroxybutyryl-CoA dehydrogenase involved in isoleucine metabolism causes an organic aciduria with atypical neurodegenerative course. The disease-causing gene is HSD17B10 and encodes 17beta-hydroxysteroid dehydrogenase type 10 (HSD10), a protein also implicated in the pathogenesis of Alzheimer's disease. Here we show that clinical symptoms in patients are not correlated with residual enzymatic activity of mutated HSD10. Loss-of-function and rescue experiments in Xenopus embryos and cells derived from conditional Hsd17b10(-/-) mice demonstrate that a property of HSD10 independent of its enzymatic activity is essential for structural and functional integrity of mitochondria. Impairment of this function in neural cells causes apoptotic cell death whilst the enzymatic activity of HSD10 is not required for cell survival. This finding indicates that the symptoms in patients with mutations in the HSD17B10 gene are unrelated to accumulation of toxic metabolites in the isoleucine pathway and, rather, related to defects in general mitochondrial function. Therefore alternative therapeutic approaches to an isoleucine-restricted diet are required.
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rauschenberger
authors.forename: Katja
authors.initials: K
authors.lastname: Schöler
authors.forename: Jörn Oliver
authors.initials: JO
authors.lastname: Sass
authors.forename: Sven
authors.initials: S
authors.lastname: Sauer
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Djuric
authors.forename: Cordula
authors.initials: C
authors.lastname: Rumig
authors.forename: Nicole I
authors.initials: NI
authors.lastname: Wolf
authors.forename: Jürgen G
authors.initials: JG
authors.lastname: Okun
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
authors.forename: Heinz
authors.initials: H
authors.lastname: Schwarz
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.forename: Beate
authors.initials: B
authors.lastname: Grziwa
authors.forename: Heiko
authors.initials: H
authors.lastname: Runz
authors.forename: Astrid
authors.initials: A
authors.lastname: Nümann
authors.forename: Naeem
authors.initials: N
authors.lastname: Shafqat
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Kavanagh
authors.forename: Günter
authors.initials: G
authors.lastname: Hämmerling
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Julian P H
authors.initials: JP
authors.lastname: Shield
authors.forename: Udo
authors.initials: U
authors.lastname: Wendel
authors.forename: David
authors.initials: D
authors.lastname: Stern
authors.forename: Peter
authors.initials: P
authors.lastname: Nawroth
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
authors.forename: Herbert
authors.initials: H
authors.lastname: Steinbeisser
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D017353:Gene Deletion; D005816:Genetic Complementation Test; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000172:deficiency* / Q000378:metabolism*; D007223:Infant; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D008958:Models, Molecular; D009474:Neurons / Q000502:physiology; D017434:Protein Structure, Tertiary; D014981:Xenopus
chemical_list: D006913:Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases