2. Academic Validation
  3. A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival

A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival

  • EMBO Mol Med. 2010 Feb;2(2):51-62. doi: 10.1002/emmm.200900055.
Katharina Rauschenberger 1,  Katja Schöler,  Jörn Oliver Sass,  Sven Sauer,  Zdenka Djuric,  Cordula Rumig,  Nicole I Wolf,  Jürgen G Okun,  Stefan Kölker,  Heinz Schwarz,  Christine Fischer,  Beate Grziwa,  Heiko Runz,  Astrid Nümann,  Naeem Shafqat,  Kathryn L Kavanagh,  Günter Hämmerling,  Ronald J A Wanders,  Julian P H Shield,  Udo Wendel,  David Stern,  Peter Nawroth,  Georg F Hoffmann,  Claus R Bartram,  Bernd Arnold,  Angelika Bierhaus,  Udo Oppermann,  Herbert Steinbeisser,  Johannes Zschocke
Affiliations

Affiliation

  • 1 Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
PMID: 20077426 DOI: 10.1002/emmm.200900055
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.

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