A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival.
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.
Rauschenberger
Katharina
K
Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Schöler
Katja
K
Sass
Jörn Oliver
JO
Sauer
Sven
S
Djuric
Zdenka
Z
Rumig
Cordula
C
Wolf
Nicole I
NI
Okun
Jürgen G
JG
Kölker
Stefan
S
Schwarz
Heinz
H
Fischer
Christine
C
Grziwa
Beate
B
Runz
Heiko
H
Nümann
Astrid
A
Shafqat
Naeem
N
Kavanagh
Kathryn L
KL
Hämmerling
Günter
G
Wanders
Ronald J A
RJ
Shield
Julian P H
JP
Wendel
Udo
U
Stern
David
D
Nawroth
Peter
P
Hoffmann
Georg F
GF
Bartram
Claus R
CR
Arnold
Bernd
B
Bierhaus
Angelika
A
Oppermann
Udo
U
Steinbeisser
Herbert
H
Zschocke
Johannes
J
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
D006913:Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases