Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L

Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Journal of Cell Science (Impact Factor: 5.43). 08/2008; 121(Pt 15):2588-600. DOI: 10.1242/jcs.026625
Source: PubMed


LETM1 is located in the chromosomal region that is deleted in patients suffering Wolf-Hirschhorn syndrome; it encodes a homolog of the yeast protein Mdm38 that is involved in mitochondrial morphology. Here, we describe the LETM1-mediated regulation of the mitochondrial volume and its interaction with the mitochondrial AAA-ATPase BCS1L that is responsible for three different human disorders. LETM1 is a mitochondrial inner-membrane protein with a large domain extruding to the matrix. The LETM1 homolog LETM2 is a mitochondrial protein that is expressed preferentially in testis and sperm. LETM1 downregulation caused mitochondrial swelling and cristae disorganization, but seemed to have little effect on membrane fusion and fission. Formation of the respiratory-chain complex was impaired by LETM1 knockdown. Cells lacking mitochondrial DNA lost active respiratory chains but maintained mitochondrial tubular networks, indicating that mitochondrial swelling caused by LETM1 knockdown is not caused by the disassembly of the respiratory chains. LETM1 was co-precipitated with BCS1L and formation of the LETM1 complex depended on BCS1L levels, suggesting that BCS1L stimulates the assembly of the LETM1 complex. BCS1L knockdown caused disassembly of the respiratory chains as well as LETM1 downregulation and induced distinct changes in mitochondrial morphology.

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Available from: Hiroshi Iida, Dec 25, 2015
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    • "MPV17L2 may be assisted in this by LETM1 (mdm38), with which it shares a number of features. Both are inner membrane proteins that are associated with mitochondrial ribosomes (43,46,51) and the morphological abnormalities observed in MPV17L2 downregulation are similar to LETM1 deficient mitochondria (52,53). These similarities strengthen the view that MPV17L2 plays a role in the interlinked processes of translation and assembly of OXPHOS complexes (40,41). "
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    ABSTRACT: MPV17 is a mitochondrial protein of unknown function, and mutations in MPV17 are associated with mitochondrial deoxyribonucleic acid (DNA) maintenance disorders. Here we investigated its most similar relative, MPV17L2, which is also annotated as a mitochondrial protein. Mitochondrial fractionation analyses demonstrate MPV17L2 is an integral inner membrane protein, like MPV17. However, unlike MPV17, MPV17L2 is dependent on mitochondrial DNA, as it is absent from ρ0 cells, and co-sediments on sucrose gradients with the large subunit of the mitochondrial ribosome and the monosome. Gene silencing of MPV17L2 results in marked decreases in the monosome and both subunits of the mitochondrial ribosome, leading to impaired protein synthesis in the mitochondria. Depletion of MPV17L2 also induces mitochondrial DNA aggregation. The DNA and ribosome phenotypes are linked, as in the absence of MPV17L2 proteins of the small subunit of the mitochondrial ribosome are trapped in the enlarged nucleoids, in contrast to a component of the large subunit. These findings suggest MPV17L2 contributes to the biogenesis of the mitochondrial ribosome, uniting the two subunits to create the translationally competent monosome, and provide evidence that assembly of the small subunit of the mitochondrial ribosome occurs at the nucleoid.
    Full-text · Article · Jun 2014 · Nucleic Acids Research
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    • "Attributing reduced LETM1 expression as the cause of or contributing factor to seizures in WHS has evolved from a combination of (i) cataloguing patients with different sized deletions and variable seizure expression, (ii) realising LETM1's mitochondrial localisation and its role in ion transport, and (iii) the overt mitochondrial morphological changes observed in Saccharomyces cerevisiae, Drosophila, Caenorhabditis elegans and even HeLa cells, when LETM1 levels were reduced (Dimmer et al., 2008; Endele et al., 1999; Hasegawa and van der Bliek, 2007; McQuibban et al., 2010; Nowikovsky et al., 2004; Tamai et al., 2008). Furthermore, (iv) downregulation of CG4589, the LETM1 orthologue in Drosophila, also leads to reduced synaptic neurotransmitter release (McQuibban et al., 2010). "
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    ABSTRACT: Wolf-Hirschhorn syndrome (WHS) represents an archetypical example of a contiguous gene deletion disorder; a condition comprising a complex set of developmental phenotypes with a multigenic origin. Epileptic seizures, intellectual disability, growth restriction, motor delay and hypotonia are significant co-morbidities in WHS. Haploinsufficiency of LETM1, which encodes an mitochondrial inner membrane protein functioning in ion transport, has been proposed as an underlying pathomechanism; principally for seizures but also for other core features of WHS including growth and motor delay. Growing evidence derived from several model organisms suggests that reduced LETM1 expression is associated with some element of mitochondrial dysfunction. Surprisingly, LETM1-dependent mitochondrial functional deficits have not previously been described in cells from WHS patients. Here, using a unique panel of WHS patient-derived cell lines with differing sized deletions incorporating LETM1 or not, we show for the first time, that LETM1 expression is reduced in mitochondria isolated from WHS patient cells. Further, we show that this is associated with distinct mitochondrial phenotypes including altered intracellular [Ca(2+)] levels, dysfunctional mitochondrial transition pore opening along with hyperpolarization and superoxide leakage from resting mitochondria. Interestingly, we find that these phenotypes segregate with seizures in our WHS cohort. Our findings identify novel cellular phenotypes in WHS attributable to a 50% reduction in LETM1 expression levels; phenotypes which may underlie and/or contribute to some of the core clinical features of this condition.
    Full-text · Article · Mar 2014 · Disease Models and Mechanisms
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    • "The LETM1 gene was first identified as one of the genes deleted in Wolf-Hirschhorn syndrome [7], which is characterized by a contiguous gene disorder resulting from a hemizygous deletion on chromosome 4 [8], and encodes the human homolog of yeast protein Mdm38p. Recent studies have attributed several roles to LETM1, including maintaining mitochondrial morphology, mediating either calcium or potassium/proton antiports, and facilitating mitochondrial translation [9–11]. It is now recognized that most cancer cells predominantly produce energy by glycolysis in the cytoplasm, rather than by oxidative phosphorylation in mitochondria like most normal cells. "
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    ABSTRACT: Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial inner membrane protein and plays an important role in mitochondrial ATP production and biogenesis. High expression levels of LETM1 have been correlated with numerous human malignancies. This study explored the clinicopathological significance of LETM1 expression as a prognostic determinant in head and neck squamous cell carcinoma (HNSCC). HNSCC samples from 176 patients were selected for immunohistochemical staining of LETM1 protein. Correlations between LETM1 overexpression and clinicopathological features of HNSCC were evaluated by Chi-squared tests and Fisher's exact tests, and relationships between prognostic factors and patient survival were analyzed using Cox proportional hazards models. Our results demonstrated that the strongly positive rate of LETM1 protein was 65.3% in HNSCC, which was significantly higher than in either adjacent nontumor tissue (25.0%) or normal squamous epithelia (6.7%). LETM1 overexpression correlated with poor differentiation, presence of lymph node metastasis, advanced stage, absence of chemoradiotherapy, and 5-year disease-free survival and overall survival rates in HNSCC. Further analysis showed that high LETM1 expression, advanced stage, and nonchemoradiotherapy were significant independent risk factors for mortality in HNSCC. In conclusion, LETM1 plays an important role in the progression of HNSCC and is an independent poor prognostic factor for HNSCC.
    Full-text · Article · Feb 2014
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