Open AccessA non‐enzymatic function of 17β‐hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival
Author(s) -
Rauschenberger Katharina,
Schöler Katja,
Sass Jörn Oliver,
Sauer Sven,
Djuric Zdenka,
Rumig Cordula,
Wolf Nicole I.,
Okun Jürgen G.,
Kölker Stefan,
Schwarz Heinz,
Fischer Christine,
Grziwa Beate,
Runz Heiko,
Nümann Astrid,
Shafqat Naeem,
Kavanagh Kathryn L.,
Hämmerling Günter,
Wanders Ronald J. A.,
Shield Julian P. H.,
Wendel Udo,
Stern David,
Nawroth Peter,
Hoffmann Georg F.,
Bartram Claus R.,
Arnold Bernd,
Bierhaus Angelika,
Oppermann Udo,
Steinbeisser Herbert,
Zschocke Johannes
Publication year - 2010
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.200900055
Subject(s) - enzyme , dehydrogenase , biology , function (biology) , mitochondrion , hydroxysteroid dehydrogenase , microbiology and biotechnology , biochemistry
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 17β‐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.