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Endogenous sterol biosynthesis is important for mitochondrial function and cell morphology in procyclic forms of Trypanosoma brucei.
MedLine Citation:
PMID:  22964455     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Sterol biosynthesis inhibitors are promising entities for the treatment of trypanosomal diseases. Insect forms of Trypanosoma brucei, the causative agent of sleeping sickness, synthesize ergosterol and other 24-alkylated sterols, yet also incorporate cholesterol from the medium. While sterol function has been investigated by pharmacological manipulation of sterol biosynthesis, molecular mechanisms by which endogenous sterols influence cellular processes remain largely unknown in trypanosomes. Here we analyse by RNA interference, the effects of a perturbation of three specific steps of endogenous sterol biosynthesis in order to dissect the role of specific intermediates in proliferation, mitochondrial function and cellular morphology in procyclic cells. A decrease in the levels of squalene synthase and squalene epoxidase resulted in a depletion of cellular sterol intermediates and end products, impaired cell growth and led to aberrant morphologies, DNA fragmentation and a profound modification of mitochondrial structure and function. In contrast, cells deficient in sterol methyl transferase, the enzyme involved in 24-alkylation, exhibited a normal growth phenotype in spite of a complete abolition of the synthesis and content of 24-alkyl sterols. Thus, the data provided indicates that while the depletion of squalene and post-squalene endogenous sterol metabolites results in profound cellular defects, bulk 24-alkyl sterols are not strictly required to support growth in insect forms of T. brucei.
Authors:
Guiomar Pérez-Moreno; Marco Sealey-Cardona; Carlos Rodrigues-Poveda; Michael H Gelb; Luis Miguel Ruiz-Pérez; Víctor Castillo-Acosta; Julio A Urbina; Dolores González-Pacanowska
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-29
Journal Detail:
Title:  International journal for parasitology     Volume:  -     ISSN:  1879-0135     ISO Abbreviation:  Int. J. Parasitol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-9-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0314024     Medline TA:  Int J Parasitol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Ltd.
Affiliation:
Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain.
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