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LETM1, deleted in Wolf–Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability

Human molecular genetics, 2008-01, Vol.17 (2), p.201-214 [Peer Reviewed Journal]

The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org 2008 ;2008 INIST-CNRS ;ISSN: 0964-6906 ;EISSN: 1460-2083 ;DOI: 10.1093/hmg/ddm297 ;PMID: 17925330 ;CODEN: HNGEE5

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Title:
LETM1, deleted in Wolf–Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability
Author: Dimmer, Kai Stefan ; Navoni, Francesca ; Casarin, Alberto ; Trevisson, Eva ; Endele, Sabine ; Winterpacht, Andreas ; Salviati, Leonardo ; Scorrano, Luca
Subjects: Biological and medical sciences ; Calcium-Binding Proteins - analysis ; Calcium-Binding Proteins - genetics ; Calcium-Binding Proteins - metabolism ; Cell Survival ; Complex syndromes ; Fibroblasts - cytology ; Fundamental and applied biological sciences. Psychology ; Gene Deletion ; Genetics of eukaryotes. Biological and molecular evolution ; Humans ; Medical genetics ; Medical sciences ; Membrane Proteins - analysis ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mitochondria - metabolism ; Mitochondrial Membranes - chemistry ; Molecular and cellular biology ; Necrosis ; Organelle Shape ; Wolf-Hirschhorn Syndrome - genetics ; Wolf-Hirschhorn Syndrome - metabolism
Is Part Of: Human molecular genetics, 2008-01, Vol.17 (2), p.201-214
Description: Wolf–Hirschhorn syndrome (WHS) is a complex congenital syndrome caused by a monoallelic deletion of the short arm of chromosome 4. Seizures in WHS have been associated with deletion of LETM1 gene. LETM1 encodes for the human homologue of yeast Mdm38p, a mitochondria-shaping protein of unclear function. Here we show that human LETM1 is located in the inner membrane, exposed to the matrix and oligomerized in higher molecular weight complexes of unknown composition. Down-regulation of LETM1 did not disrupt these complexes, but led to DRP1-independent fragmentation of the mitochondrial network. Fragmentation was not associated with changes in the levels of respiratory chain complexes, or with obvious or latent mitochondrial dysfunction, but was recovered by nigericin, which catalyzes the electroneutral exchange of K+ against H+. Down-regulation of LETM1 caused ‘necrosis-like’ death, without activation of caspases and not inhibited by overexpression of Bcl-2. Primary fibroblasts from a WHS patient displayed reduced LETM1 mRNA and protein, but mitochondrial morphology was surprisingly unaffected, raising the question of whether and how WHS patients counteract the consequences of monoallelic deletion of LETM1. LETM1 highlights the relationship between mitochondrial ion homeostasis, integrity of the mitochondrial network and cell viability.
Publisher: Oxford: Oxford University Press
Language: English
Identifier: ISSN: 0964-6906
EISSN: 1460-2083
DOI: 10.1093/hmg/ddm297
PMID: 17925330
CODEN: HNGEE5
Source: Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
Alma/SFX Local Collection

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LETM1, deleted in Wolf–Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability

The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org 2008 ;2008 INIST-CNRS ;ISSN: 0964-6906 ;EISSN: 1460-2083 ;DOI: 10.1093/hmg/ddm297 ;PMID: 17925330 ;CODEN: HNGEE5

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