Human Molecular Genetics Advance Access originally published online on October 9, 2007
Human Molecular Genetics 2008 17(2):201-214; doi:10.1093/hmg/ddm297
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LETM1, deleted in Wolf–Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability
1 Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy 2 Section of Human Genetics, Department of Paediatrics, University of Padova, 35121 Padova, Italy 3 Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University, 91054 Erlangen, Germany
* To whom correspondence should be addressed at: Istituto Veneto di Medicina Molecolare, Via Orus 2, 35129 Padova, Italy. Tel: +39 0497923221; Fax: +39 0497923271; Email: lscorrano{at}dti.telethon.it
Received August 22, 2007; Accepted October 7, 2007
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.