Genome-Wide RNAi Screen Identifies Letm1 as a Mitochondrial Ca
            <sup>2+</sup>
            /H
            <sup>+</sup>
            Antiporter

Jiang, Dawei; Zhao, Linlin; Clapham, David E.

doi:10.1126/science.1175145

Cited by 485 publications

(468 citation statements)

References 23 publications

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“…3B). The abundant upper band migrated at the expected ϳ90 kDa size with a less intense one just below, a pattern also observed when the protein was expressed in Escherichia coli (14).…”

Section: Rnai Silencing Of Letm1 In Procyclic Stage Results In Mitochsupporting

confidence: 59%

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Trypanosome Letm1 Protein Is Essential for Mitochondrial Potassium Homeostasis

Hashimi

McDonald

Stříbrná

et al. 2013

Journal of Biological Chemistry

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Background: Letm1 is a mitochondrial protein attributed disparate roles, including cation/proton antiport and translation. Results: Letm1 RNAi silencing in Trypanosoma brucei triggers swelling mitochondria and translation arrest that is ameliorated by chemical potassium/proton exchangers. Conclusion:The ancestral function of Letm1, to maintain mitochondrial potassium homeostasis, shows remarkable conservation. Significance: Results from diverged T. brucei provide a better understanding of Letm1 function throughout eukaryotes.

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“…3B). The abundant upper band migrated at the expected ϳ90 kDa size with a less intense one just below, a pattern also observed when the protein was expressed in Escherichia coli (14).…”

Section: Rnai Silencing Of Letm1 In Procyclic Stage Results In Mitochsupporting

confidence: 59%

“…In all of these model systems, treatment with the chemical K ϩ /H ϩ exchanger nigericin compensates for the loss of Letm1-mediated KHE. However, Letm1 was also identified as a calcium (Ca 2ϩ )/H ϩ antiporter in the genome-wide RNAi screen in Drosophila S2 cells (14), a finding corroborated in a later report (15).…”

supporting

confidence: 60%

Trypanosome Letm1 Protein Is Essential for Mitochondrial Potassium Homeostasis

Hashimi

McDonald

Stříbrná

et al. 2013

Journal of Biological Chemistry

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“…38 Its cellular function as an ion exchanger [37][38][39][40][41] suggests potential roles in cell signaling and energy production. In flies and worms, LETM1 loss-of-function causes severe growth restriction and decreased viability.…”

Section: Discussionmentioning

confidence: 99%

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

et al. 2013

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Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (o400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-offunction for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.

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“…25,26,57 A recent report based on genome wide siRNA screen identified a 1:1 Ca 2þ /H þ exchanger protein named Letm1, which does not have all of the biophysical properties of MCU but may be involved in the slow Ca 2þ uptake pathway. 59 In addition, the uncoupling proteins 2 and 3 have been implicated in mitochondrial Ca 2þ uptake, but their roles remain controversial. 60 Our data indicate that hydroxyl CoQs are generated under physiological conditions and that they are able to bind and transport Ca 2þ across artificial biomembranes.…”

Section: ' Discussionmentioning

confidence: 99%

Calcium Binding and Transport by Coenzyme Q

et al. 2011

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Coenzyme Q10 (CoQ10) is one of the essential components of the mitochondrial electron-transport chain (ETC) with the primary function to transfer electrons along and protons across the inner mitochondrial membrane (IMM). The concomitant proton gradient across the IMM is essential for the process of oxidative phosphorylation and consequently ATP production. Cytochrome P450 (CYP450) monoxygenase enzymes are known to induce structural changes in a variety of compounds and are expressed in the IMM. However, it is unknown if CYP450 interacts with CoQ10 and how such an interaction would affect mitochondrial function. Using voltammetry, UV–vis spectrometry, electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), fluorescence microscopy and high performance liquid chromatography–mass spectrometry (HPLC–MS), we show that both CoQ10 and its analogue CoQ1, when exposed to CYP450 or alkaline media, undergo structural changes through a complex reaction pathway and form quinone structures with distinct properties. Hereby, one or both methoxy groups at positions 2 and 3 on the quinone ring are replaced by hydroxyl groups in a time-dependent manner. In comparison with the native forms, the electrochemically reduced forms of the new hydroxylated CoQs have higher antioxidative potential and are also now able to bind and transport Ca2+ across artificial biomimetic membranes. Our results open new perspectives on the physiological importance of CoQ10 and its analogues, not only as electron and proton transporters, but also as potential regulators of mitochondrial Ca2+ and redox homeostasis.

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Genome-Wide RNAi Screen Identifies Letm1 as a Mitochondrial Ca ²⁺ /H ⁺ Antiporter

Cited by 485 publications

References 23 publications

Trypanosome Letm1 Protein Is Essential for Mitochondrial Potassium Homeostasis

Trypanosome Letm1 Protein Is Essential for Mitochondrial Potassium Homeostasis

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

Calcium Binding and Transport by Coenzyme Q

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Genome-Wide RNAi Screen Identifies Letm1 as a Mitochondrial Ca 2+ /H + Antiporter

Cited by 485 publications

References 23 publications

Trypanosome Letm1 Protein Is Essential for Mitochondrial Potassium Homeostasis

Trypanosome Letm1 Protein Is Essential for Mitochondrial Potassium Homeostasis

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

Calcium Binding and Transport by Coenzyme Q

Contact Info

Product

Resources

About

Genome-Wide RNAi Screen Identifies Letm1 as a Mitochondrial Ca ²⁺ /H ⁺ Antiporter