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EMBO Mol Med February 1, 2010; 2 (2): 51-62.

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

Rauschenberger K , Schöler K , Sass JO , Sauer S , Djuric Z , Rumig C , Wolf NI , Okun JG , Kölker S , Schwarz H , Fischer C , Grziwa B , Runz H , Nümann A , Shafqat N , Kavanagh KL , Hämmerling G , Wanders RJ , Shield JP , Wendel U , Stern D , Nawroth P , Hoffmann GF , Bartram CR , Arnold B , Bierhaus A , Oppermann U , Steinbeisser H , Zschocke J .

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.

PubMed ID: 20077426
PMC ID: PMC3377269
Article link: EMBO Mol Med
Grant support: [+]

Species referenced: Xenopus
Genes referenced: dbh fadd fas foxg1 hsd17b10 kit myc odc1 otx2 tek
GO keywords: isoleucine metabolic process [+]
Morpholinos: hsd17b10 MO1 hsd17b10 MO2

Disease Ontology terms: organic acidemia [+]

Article Images: [+] show captions
References [+] :
Chen, Amyloid-beta-induced mitochondrial dysfunction. 2007, Pubmed