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Showing LETM1 — MDM38 is a alias.

LETM1

Mitochondrial proton/calcium exchanger protein · UniProt O95202

Length
739 aa
Mass
83.4 kDa
Annotated
2026-06-10
64 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LETM1 is an integral protein of the mitochondrial inner membrane whose primary, evolutionarily conserved function is electroneutral, obligatorily coupled K+/H+ exchange that governs matrix volume and osmotic balance from yeast and trypanosomes to humans (PMID:15138253, PMID:15904662, PMID:23893410). Loss of this exchange activity drives matrix swelling, mitochondrial fragmentation, cristae disorganization, and selective mitophagy, phenotypes that are rescued by the K+/H+ ionophore nigericin, placing ion exchange upstream of mitochondrial morphology control (PMID:17541427, PMID:17925330, PMID:32139798). Purified LETM1 reconstituted into liposomes also directly mediates electroneutral 1 Ca2+/2 H+ antiport (Km ~25 µM Ca2+), with activity enhanced by the proton gradient and dependent on a defined ion-binding residue (Glu221) and on cardiolipin in the bilayer (PMID:19797662, PMID:24344246, PMID:27669901, PMID:30503650); cellular work positions LETM1 as the route for mitochondrial Ca2+ uptake under low cytosolic Ca2+ and links its Ca2+ transport to bioenergetic output, with knockdown impairing complex IV activity and ATP production while activating AMPK and autophagy (PMID:21613221, PMID:23716663, PMID:25077561). A matrix-facing EF-hand (the non-canonical 'F-EF-hand') acts as a bidirectional Ca2+/pH sensor that tunes matrix Ca2+ levels and undergoes Ca2+-dependent conformational changes (PMID:25077561, PMID:39317198, PMID:39927520). Beyond transport, LETM1 assembles into higher-order oligomeric complexes and, through a conserved 14-3-3-like ribosome-binding domain, associates with mitochondrial ribosomes to regulate translation of specific mitochondrially encoded mRNAs and respiratory chain biogenesis (PMID:16476776, PMID:20427570, PMID:21718401, PMID:30012579). Transport activity is modulated by post-translational control, including PINK1-mediated phosphorylation at Thr192 and SIRT3-mediated deacetylation at Lys597 (PMID:29123128, PMID:41819224). Bi-allelic loss-of-function LETM1 variants cause a neurological disease through defective mitochondrial K+ efflux and loss of oxidative phosphorylation, and LETM1 haploinsufficiency contributes to Wolf–Hirschhorn syndrome pathology (PMID:25077561, PMID:36055214).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 High

    Established LETM1 as a conserved inner-membrane determinant of mitochondrial K+ homeostasis and volume, answering whether the gene had a defined mitochondrial role.

    Evidence Yeast YOL027 deletion, fractionation and swelling assays, cross-species complementation with human LETM1

    PMID:15138253

    Open questions at the time
    • Did not establish whether LETM1 is the transporter itself or a regulator
    • No direct in vitro transport demonstration
  2. 2005 High

    Showed LETM1/Yol027p is essential for obligatorily coupled electroneutral K+/H+ exchange, moving from a homeostatic association to a direct transport function.

    Evidence Submitochondrial particle transport assays with ion-sensitive dyes plus genetic complementation

    PMID:15904662

    Open questions at the time
    • Did not prove LETM1 is the pore versus an essential cofactor
    • Ca2+ handling not addressed
  3. 2006 High

    Identified a translation-coupled role distinct from ion transport, showing the ortholog binds mitochondrial ribosomes and aids insertion of specific encoded proteins.

    Evidence Reciprocal Co-IP with ribosomes, Blue Native PAGE, deletion and import assays in yeast

    PMID:16476776

    Open questions at the time
    • Mechanistic link between ion transport and translation roles unresolved
    • Not validated in human cells
  4. 2007 High

    Placed K+/H+ exchange upstream of mitochondrial morphology and mitophagy, defining the downstream consequences of LETM1 loss in both yeast and human cells.

    Evidence Inducible knockdown time-course, matrix biosensor, nigericin rescue, EM, and Drp1 epistasis

    PMID:17541427 PMID:17606466 PMID:17925330

    Open questions at the time
    • Whether fragmentation is purely osmotic or signaling-mediated unresolved
    • Ca2+ contribution not yet distinguished
  5. 2008 Medium

    Linked LETM1 complex assembly to respiratory biogenesis via interaction with the AAA-ATPase BCS1L.

    Evidence Co-IP, siRNA knockdown, Blue Native PAGE, EM

    PMID:18628306

    Open questions at the time
    • Direct vs. indirect nature of BCS1L interaction unclear
    • Single-lab Co-IP without structural mapping
  6. 2009 High

    Reframed LETM1 as a Ca2+/H+ antiporter via genome-wide screening and liposome reconstitution, opening the still-debated dual K+/Ca2+ transport question.

    Evidence Drosophila RNAi screen, mammalian knockdown/overexpression, liposome reconstitution of purified protein; cross-species complementation and MRPL36 Co-IP in parallel studies

    PMID:19318571 PMID:19797662 PMID:20026556

    Open questions at the time
    • Reconciliation of K+/H+ versus Ca2+/H+ activities not settled
    • Physiological selectivity in vivo unresolved
  7. 2010 High

    Refined the translation role, showing overlapping regulation with Mba1 of specific mRNA translation rather than generic ribosome anchoring.

    Evidence Yeast double-mutant analysis, ribosome association, translation assays, mRNA regulatory-region swaps

    PMID:20427570

    Open questions at the time
    • Human relevance of mRNA-specific regulation not tested
    • Molecular basis of selectivity unknown
  8. 2011 High

    Structurally defined the ribosome-binding domain as a 14-3-3-like fold and showed translation and transport functions are spatially separable.

    Evidence 2.1 Å crystal structure, domain deletions, complementation and translation assays

    PMID:21718401

    Open questions at the time
    • Structure of the membrane transport domain not solved
    • How two domains coordinate in vivo unresolved
  9. 2013 High

    Quantitatively defined LETM1 as an electroneutral 1 Ca2+/2 H+ antiporter and demonstrated organismal consequences of its Ca2+/bioenergetic role.

    Evidence Purified-protein liposome reconstitution with kinetics and ion selectivity; mouse knockout/heterozygote, cellular ion and ATP measurements; T. brucei depletion showing K+/H+ as primary

    PMID:23716663 PMID:23893410 PMID:24344246

    Open questions at the time
    • Whether Ca2+ transport is physiologically dominant over K+/H+ in vivo unresolved
    • Direction (influx vs efflux) of cellular Ca2+ flux debated
  10. 2014 High

    Tied Ca2+ transport to bioenergetics and identified the EF-hand as required for transport, while raising the question of LETM1's role in Ca2+ efflux.

    Evidence EF-hand mutagenesis, mitoplast patch-clamp, WHS patient fibroblasts, Seahorse and ROS readouts; contrasting overexpression data favoring NCLX for efflux

    PMID:24898248 PMID:25077561

    Open questions at the time
    • Conflicting evidence on LETM1 as a Ca2+ exporter
    • Conditions determining influx versus efflux unclear
  11. 2016 High

    Provided structural and active-site detail, identifying Glu221 as essential and revealing a hexameric, pH-responsive assembly.

    Evidence Liposome reconstitution, E221Q mutagenesis, EM of hexamer with two pH-dependent conformations

    PMID:27669901

    Open questions at the time
    • High-resolution transport-domain structure absent
    • Conformational cycle to ion translocation not directly mapped
  12. 2017 High

    Established post-translational regulation by PINK1 phosphorylation of Thr192 controlling Ca2+ transport, and resolved part of the efflux question by linking LETM1 to NCLX-dependent Ca2+ flux via Na+ homeostasis.

    Evidence In vitro kinase assay, liposome Ca2+ release, phospho-mimetic rescue in PINK1-KO neurons; shRNA with K+/H+ and Na+/H+ exchange assays and ruthenium-red dissection

    PMID:29123128 PMID:29204122

    Open questions at the time
    • Whether T192 phosphorylation occurs under physiological mitochondrial stress in vivo not fully defined
    • Interplay of K+, Na+, and Ca2+ exchange by one protein unresolved
  13. 2018 Medium

    Defined the lipid dependence (cardiolipin) of Ca2+ transport and reinforced the ribosome/mtDNA-linked role with metabolic consequences.

    Evidence Cell-free liposome synthesis with defined lipids; ribosome Co-IP, mtDNA staining, pyruvate dehydrogenase assays in WHS fibroblasts

    PMID:30012579 PMID:30503650

    Open questions at the time
    • Mechanism by which cardiolipin enables transport unknown
    • Direct vs indirect effect on mtDNA distribution unresolved
  14. 2020 High

    Showed the LETM domain directly remodels membranes and shapes cristae, distinguishing a structural-morphogenic activity from ion transport.

    Evidence Alanine-scanning yeast complementation, Blue Native PAGE, proteoliposome reconstitution with EM

    PMID:32139798

    Open questions at the time
    • Relationship between membrane-shaping and transport activities unclear
    • In vivo contribution to cristae versus osmotic effects not separated
  15. 2022 High

    Connected LETM1 to MAM/mitophagy via GRP78/GRP75 interactions and confirmed K+/H+ exchange as the primary pathogenic mechanism in human disease.

    Evidence Co-IP and CRISPR KO at MAM in lung cancer cells; patient fibroblast and yeast K+/H+ assays, EM, OXPHOS analysis, exome sequencing; circadian neuronal knockdown imaging

    PMID:35545046 PMID:35680871 PMID:36055214

    Open questions at the time
    • Direct versus scaffold nature of GRP75/GRP78 interaction unresolved
    • Mechanism linking ion transport to clock rhythms not defined
  16. 2024 High

    Resolved the EF-hand as a non-canonical 'F-EF-hand' Ca2+/pH sensor that bidirectionally tunes matrix Ca2+ and undergoes Ca2+-dependent inter-domain and GHITM interactions.

    Evidence NMR structures (holo and apo), pKa determination, mutagenesis with cellular Ca2+ readouts, interaction NMR

    PMID:39317198 PMID:39927520

    Open questions at the time
    • How sensor conformational changes mechanically gate the transporter unresolved
    • Functional significance of GHITM contact not established
  17. 2026 Medium

    Identified SIRT3-mediated deacetylation at Lys597 as a regulatory switch stabilizing LETM1 and protecting against Ca2+-overload injury.

    Evidence AAV9 overexpression, SIRT3 Co-IP/deacetylation assay, K597 analysis, Caco-2 knockdown, in vivo intestinal I/R model

    PMID:41819224

    Open questions at the time
    • Direct effect of K597 acetylation on transport kinetics not measured
    • Single-lab in vivo model

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single protein integrates K+/H+ and Ca2+/H+ antiport, membrane remodeling, and ribosome-coupled translation, and how the F-EF-hand sensor mechanically gates ion flux.
  • No high-resolution structure of the full transport domain in a transporting state
  • Relative physiological weighting of K+ versus Ca2+ transport in mammals unsettled
  • Coordination between transport and translation functions in human cells undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140104 molecular carrier activity 3 GO:0140299 molecular sensor activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-1430728 Metabolism 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9612973 Autophagy 2
Partners
BCS1LGHITMGRP75GRP78MRPL36PINK1SIRT3USP30
Complex memberships
LETM1 oligomeric (hexameric) complexLETM1/GRP75/GRP78 MAM complexmitochondrial ribosome-associated complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 LETM1 and its yeast ortholog YOL027 encode integral proteins of the inner mitochondrial membrane involved in mitochondrial K+ homeostasis and volume control; deletion of YOL027 causes mitochondrial K+/H+ exchange deficiency and osmotic swelling, and this phenotype is complemented by human LETM1, demonstrating functional conservation. Yeast deletion mutant analysis, mitochondrial fractionation, swelling assays, complementation with human LETM1 The Journal of biological chemistry High 15138253
2005 Yol027p/Letm1 is essential for electroneutral, obligatorily coupled K+/H+ exchange across the yeast inner mitochondrial membrane, as demonstrated directly in submitochondrial particles; human LETM1 restores K+/H+ exchange in yol027Δ mutants. Submitochondrial particle transport assays with K+- and H+-sensitive fluorescent dyes, yeast deletion mutant, complementation with human LETM1 Biochimica et biophysica acta High 15904662
2006 Yeast Mdm38 (LETM1 ortholog) forms stable complexes with mitochondrial ribosomes and functions as a component of an Oxa1-independent insertion machinery in the inner membrane, coupling ribosome function to transport of specific mitochondrially encoded proteins (Atp6, cytochrome b) across the inner membrane. Co-immunoprecipitation with ribosomes, Blue Native PAGE, genetic deletion analysis, import assays The Journal of cell biology High 16476776
2007 Loss of Mdm38 in yeast causes early loss of mitochondrial K+/H+ exchange activity and osmotic swelling, which triggers mitochondrial fragmentation and selective mitophagy (uptake by vacuoles); nigericin (a K+/H+ ionophore) fully rescues these effects, placing K+/H+ exchange upstream of morphological changes and mitophagy. Doxycycline-regulated gene shut-off, fluorescent matrix biosensor, nigericin rescue, electron microscopy Cell death and differentiation High 17541427
2007 Human LETM1 localizes to the mitochondrial inner membrane, exposed to the matrix, and oligomerizes into higher molecular weight complexes; LETM1 knockdown causes DRP1-independent fragmentation of the mitochondrial network that is rescued by nigericin, linking LETM1-mediated K+/H+ exchange to mitochondrial morphology maintenance. Immunofluorescence, fractionation, Blue Native PAGE, siRNA knockdown, nigericin rescue, Drp1 double-knockdown epistasis Human molecular genetics High 17925330
2007 LETM1 localizes to the mitochondrial inner membrane as part of a ~550 kDa complex and can bind to itself in vitro; reduced LETM1 levels cause swellings along mitochondria consistent with osmotic dysregulation, and overexpression increases matrix electron density — consistent with a role in matrix volume regulation. GFP fusion localization, Blue Native PAGE, in vitro self-binding assay, siRNA knockdown, electron microscopy, C. elegans mutant analysis Human molecular genetics Medium 17606466
2008 LETM1 is a mitochondrial inner-membrane protein with a large matrix-facing domain; LETM1 knockdown causes mitochondrial swelling and cristae disorganization and impairs respiratory chain complex formation; LETM1 physically interacts with the AAA-ATPase BCS1L, and BCS1L levels regulate LETM1 complex assembly. Co-immunoprecipitation, siRNA knockdown, Blue Native PAGE, electron microscopy, mitochondria fractionation Journal of cell science Medium 18628306
2009 Genome-wide Drosophila RNAi screen identified Letm1 as a regulator of mitochondrial Ca2+ and H+; RNAi knockdown, overexpression, and liposome reconstitution of purified human Letm1 protein collectively demonstrate that Letm1 is a mitochondrial Ca2+/H+ antiporter. Genome-wide Drosophila RNAi screen, mammalian knockdown and overexpression, liposome reconstitution of purified protein Science High 19797662
2009 LETM1 associates with mitochondrial ribosome protein L36 (MRPL36) and acts as an anchor protein for this interaction; LETM1 overexpression reduces mitochondrial biogenesis and ATP production and induces necrotic cell death. Co-immunoprecipitation, adenovirus-mediated overexpression, ATP measurement, cell death assays Cancer research Medium 19318571
2009 Drosophila DmLETM1 functions as a mitochondrial K+/H+ exchanger (osmoregulator) and complements K+/H+ exchange in yeast lacking LETM1; neuronal-specific knockdown impairs locomotor behavior and reduces synaptic neurotransmitter release. Yeast complementation assay for K+/H+ exchange, tissue-specific Drosophila RNAi, behavioral analysis, electrophysiology Human molecular genetics High 20026556
2010 Mdm38 and Mba1 have overlapping regulatory functions in the translation of selected mitochondrial mRNAs (Cox1 and cytochrome b); simultaneous loss of both causes severe synthetic defects in respiratory chain biogenesis, not due to impaired ribosome membrane binding but due to mis-regulation of specific mRNA translation. Yeast double-mutant analysis, ribosome association assays, mitochondrial translation assays, mRNA regulatory region replacement Molecular biology of the cell High 20427570
2011 The conserved ribosome-binding domain (RBD) of Mdm38 adopts a 14-3-3-like fold (crystal structure at 2.1 Å) and is critical for respiratory chain assembly through regulation of Cox1 and Cytb translation; this function can be spatially separated from the ion transport activity of the membrane-integrated portion. Crystal structure determination at 2.1 Å, domain deletion mutants, genetic complementation, translation assays Traffic High 21718401
2011 Letm1 knockdown specifically diminishes mitochondrial uptake of Ca2+ entering via store-operated Ca2+ entry at low cytosolic Ca2+ concentrations, operating independently from UCP2/3-mediated mitochondrial Ca2+ uptake; Letm1 contributes exclusively to mitochondrial Ca2+ uptake under low Ca2+ conditions in permeabilized cells. siRNA knockdown of Letm1 and UCP2/3, digitonin-permeabilized cell Ca2+ assays, live-cell Ca2+ imaging, SOCE measurement The Journal of biological chemistry Medium 21613221
2013 Purified, reconstituted human Letm1 in liposomes directly mediates electroneutral 1 Ca2+/2 H+ antiport with a Km of ~25 µM Ca2+ and turnover of 2 Ca2+/s; Letm1 is insensitive to ruthenium red and CGP-37157 but shows selectivity sequence Ca2+ ≈ Mn2+ > Gd3+ ≈ La3+ > Sr2+ >> Ba2+, Mg2+, K+, Na+. Protein purification, liposome reconstitution, Ca2+ fluorophore assays, 45Ca2+-based assays, kinetic analysis The Journal of general physiology High 24344246
2013 Cellular Letm1 knockdown reduces mitochondrial Ca2+ uptake, H+ extrusion, and mitochondrial ATP generation; homozygous Letm1 deletion in mice is embryonic lethal, and heterozygous mice exhibit altered glucose metabolism, impaired brain ATP regulation, and increased seizure activity. siRNA knockdown, mitochondrial ion measurements, mouse knockout/heterozygous model, metabolomics, seizure recording Proceedings of the National Academy of Sciences High 23716663
2013 Letm1 depletion in Trypanosoma brucei causes K+ accumulation in the mitochondrial matrix and loss of mitochondrial volume control via K+/H+ exchange; mitochondrial translation defects upon Letm1 ablation are an indirect consequence of K+ accumulation rather than a primary function; human LETM1 complements procyclic T. brucei Letm1 depletion. RNAi knockdown in T. brucei, ion measurement, volume assays, complementation with human LETM1, translation assays The Journal of biological chemistry High 23893410
2014 NCLX (not LETM1) overexpression enhances mitochondrial Ca2+ efflux; increasing LETM1 levels had no detectable impact on Ca2+ extrusion rates in HeLa cells under agonist stimulation conditions. Genetically encoded mitochondrial Ca2+ indicator, NCLX and LETM1 overexpression, agonist stimulation, roGFP redox assay The Journal of biological chemistry Medium 24898248
2014 LETM1-mediated mitochondrial Ca2+ transport (both influx and efflux) is required for normal mitochondrial bioenergetics; the EF-hand domain (D676A D688K mutation) is necessary for Ca2+ transport function; LETM1 knockdown impairs complex IV activity, ATP production, increases ROS, activates AMPK, and promotes autophagy and cell cycle arrest. siRNA knockdown, EF-hand mutant overexpression, WHS patient fibroblasts, mitoplast patch-clamp (IMCU), mitochondrial Ca2+ measurement, Seahorse bioenergetics, ROS measurement FASEB journal High 25077561
2016 Purified LETM1 mediates Ca2+/H+ antiport activity in vitro, with activity enhanced by increased proton gradient; the residue Glu221 is required for Ca2+ transport, as E221Q mutation abolishes Ca2+-transport activity in cells; electron microscopy reveals a hexameric LETM1 assembly with a central cavity and two conformational states at different pH. Liposome reconstitution with purified protein, Ca2+ flux assays, site-directed mutagenesis (E221Q), electron microscopy, intracellular Ca2+ measurement Scientific reports High 27669901
2017 PINK1 directly phosphorylates LETM1 at Thr192 in vitro; phosphorylated (or phospho-mimetic T192E) LETM1 increases Ca2+ release in artificial liposomes and facilitates Ca2+ transport in intact mitochondria; LETM1-T192E but not WT rescues mitochondrial Ca2+ mishandling in PINK1-deficient neurons. In vitro kinase assay (PINK1 + LETM1), liposome Ca2+ release assay, phospho-mimetic/phospho-null mutant overexpression, mitochondrial Ca2+ measurement in neurons, PINK1 KO neurons Nature communications High 29123128
2017 LETM1 depletion by shRNA reduces both mitochondrial K+/H+ and Na+/H+ exchange, causing matrix K+ accumulation; LETM1 depletion selectively decreases Na+/Ca2+ exchange mediated by NCLX (in the presence of ruthenium red), indicating LETM1 affects Ca2+ efflux indirectly through its regulation of Na+ homeostasis. shRNA knockdown, K+/H+ and Na+/H+ exchange assays, ruthenium red-treated mitochondrial Ca2+ measurement Frontiers in physiology Medium 29204122
2018 LETM1 associates with mitochondrial ribosomes, is required for mitochondrial DNA distribution and expression, and regulates pyruvate dehydrogenase activity; LETM1 deficiency in WHS alters mitochondrial DNA organization and morphology. Co-immunoprecipitation with ribosomes, mitochondrial DNA staining, pyruvate dehydrogenase activity assay, WHS patient fibroblasts EMBO molecular medicine Medium 30012579
2018 LETM1 Ca2+ transport activity in liposomes depends on phospholipid composition; cardiolipin, present in the mitochondrial membrane, is specifically required for LETM1 transport activity. Cell-free in vitro transcription-translation synthesis in liposomes of defined lipid composition, flow cytometry-based pH-dependent Ca2+ transport assay Journal of bioscience and bioengineering Medium 30503650
2020 The LETM domain of LETM1 is required for cristae organization; four critical amino acid residues are necessary for yeast complementation and for correct LETM1 complex assembly; purified LETM1 directly reshapes lipid bilayers, generating invaginated membrane structures on liposomes, and alanine substitution mutants abolish this activity. Yeast complementation with alanine-scanning mutants, Blue Native PAGE, proteoliposome reconstitution with EM, mitochondrial morphology imaging Communications biology High 32139798
2022 LETM1 acts as an anchor protein for mitochondria-associated ER membranes (MAM); LETM1 physically interacts with GRP78 and GRP75; this interaction is enhanced by mitophagy induction; the LETM1/GRP75/GRP78 complex promotes mitophagy in lung cancer cells. Co-immunoprecipitation (LETM1 with GRP78/GRP75), CRISPR/Cas9 GRP75 knockout, honokiol (GRP78 inhibitor) treatment, mitophagy assay, immunofluorescence colocalization at MAM Cell death & disease Medium 35680871
2022 Bi-allelic loss-of-function LETM1 variants in humans cause defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of oxidative phosphorylation components in patient fibroblasts and yeast models, demonstrating that K+/H+ exchange is the primary pathogenic mechanism underlying the neurological disease. Patient-derived fibroblast and yeast studies: K+/H+ exchange activity assay, mitochondrial morphology (EM), OXPHOS complex analysis, exome sequencing American journal of human genetics High 36055214
2022 LETM1 knockdown in Drosophila pacemaker neurons reduces circadian cytosolic H+ rhythms and prolongs PERIOD/TIMELESS expression rhythms; in rat SCN neurons, LETM1 knockdown dampens circadian Ca2+ and Bmal1 transcription rhythms, coupling mitochondrial ion transport to molecular clock function. Tissue-specific Drosophila RNAi, live-cell H+ and Ca2+ imaging in neurons, luciferase reporter for Bmal1, locomotor activity recording Cell reports Medium 35545046
2024 The LETM1 EF-hand domain adopts an unprecedented 'F-EF-hand' structure (NMR structure solved using AI-guided NOE assignment) with non-canonical Ca2+ coordination; mutations that augment or weaken Ca2+ binding increase or decrease mitochondrial matrix Ca2+ respectively, establishing the F-EF-hand as a bidirectional regulator of mitochondrial Ca2+; the domain also senses pH. NMR structure determination (AI-guided NOE assignment), site-directed mutagenesis of Ca2+-coordinating residues, mitochondrial Ca2+ measurement in cells Structure High 39317198
2025 The apo LETM1 F-EF-hand adopts a closed conformation with a distinct F1-helix pivot mechanism; H662 has a pKa in the physiological range enabling pH sensing; Ca2+-dependent transient interactions occur between the EF-hand and other LETM1 domains as well as GHITM protein domains. Solution NMR structure of apo EF-hand, NMR titration/dynamics, pKa determination, protein–protein interaction NMR experiments FEBS letters High 39927520
2024 LETM1 is a substrate of the deubiquitinase USP30; USP30 inhibition increases ubiquitination at LETM1, identifying LETM1 as being deubiquitinated in a USP30-dependent manner. Proximity-labeling (APEX2) combined with ubiquitination enrichment (K-ε-GG motif) and mass spectrometry upon USP30 inhibition bioRxivpreprint Low bio_10.1101_2024.10.07.616967
2024 Mdm38 (yeast LETM1 ortholog) is required for mitochondrial iron homeostasis and for signaling iron bioavailability from mitochondria to vacuoles; these processes are linked to the m-AAA quality control protease, whose unrestrained activity disrupts respiratory chain complex assembly and stability in Mdm38-deficient cells. Yeast genetic deletion, iron homeostasis assays, m-AAA protease epistasis, respiratory complex analysis bioRxivpreprint Low 39975406
2026 LETM1 is acetylated at Lys597, and this acetylation is removed by the mitochondrial deacetylase SIRT3; deacetylation stabilizes LETM1 and protects against calcium overload-mediated mitochondrial dysfunction; LETM1 knockdown impairs SIRT3-mediated protection in intestinal ischemia/reperfusion injury. AAV9 overexpression, SIRT3 co-immunoprecipitation/deacetylation assay, K597 acetylation analysis, Caco-2 siRNA knockdown, in vivo intestinal I/R model Life sciences Medium 41819224

Source papers

Stage 0 corpus · 64 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science (New York, N.Y.) 435 19797662
2007 Mdm38 protein depletion causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and mitophagy. Cell death and differentiation 191 17541427
2004 The LETM1/YOL027 gene family encodes a factor of the mitochondrial K+ homeostasis with a potential role in the Wolf-Hirschhorn syndrome. The Journal of biological chemistry 161 15138253
2007 LETM1, deleted in Wolf-Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability. Human molecular genetics 153 17925330
1999 LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients. Genomics 128 10486213
2013 Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1. The Journal of general physiology 115 24344246
2006 Mdm38 interacts with ribosomes and is a component of the mitochondrial protein export machinery. The Journal of cell biology 112 16476776
2013 Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome. Proceedings of the National Academy of Sciences of the United States of America 108 23716663
2008 Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L. Journal of cell science 108 18628306
2014 NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, thereby limiting Ca2+-induced NAD(P)H production and modulating matrix redox state. The Journal of biological chemistry 103 24898248
2014 LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 92 25077561
2017 PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress. Nature communications 91 29123128
2011 Leucine zipper EF hand-containing transmembrane protein 1 (Letm1) and uncoupling proteins 2 and 3 (UCP2/3) contribute to two distinct mitochondrial Ca2+ uptake pathways. The Journal of biological chemistry 86 21613221
2020 Long non-coding RNA RHPN1-AS1 promotes tumorigenesis and metastasis of ovarian cancer by acting as a ceRNA against miR-596 and upregulating LETM1. Aging 85 32163372
2004 LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein. Genomics 78 14706454
2005 Electroneutral K+/H+ exchange in mitochondrial membrane vesicles involves Yol027/Letm1 proteins. Biochimica et biophysica acta 70 15904662
2009 Association of LETM1 and MRPL36 contributes to the regulation of mitochondrial ATP production and necrotic cell death. Cancer research 66 19318571
2009 A Drosophila mutant of LETM1, a candidate gene for seizures in Wolf-Hirschhorn syndrome. Human molecular genetics 66 20026556
2017 LETM1-Mediated K+ and Na+ Homeostasis Regulates Mitochondrial Ca2+ Efflux. Frontiers in physiology 61 29204122
2007 Inverse correlation between expression of the Wolfs Hirschhorn candidate gene Letm1 and mitochondrial volume in C. elegans and in mammalian cells. Human molecular genetics 60 17606466
2016 Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) forms a Ca2+/H+ antiporter. Scientific reports 57 27669901
2010 Ribosome-binding proteins Mdm38 and Mba1 display overlapping functions for regulation of mitochondrial translation. Molecular biology of the cell 53 20427570
2019 LETM1: Essential for Mitochondrial Biology and Cation Homeostasis? Trends in biochemical sciences 51 31101453
2013 Trypanosome Letm1 protein is essential for mitochondrial potassium homeostasis. The Journal of biological chemistry 51 23893410
2020 The mitochondrial inner membrane protein LETM1 modulates cristae organization through its LETM domain. Communications biology 45 32139798
2013 Association of mitochondrial letm1 with epileptic seizures. Cerebral cortex (New York, N.Y. : 1991) 44 23645710
2014 Reliance of ER-mitochondrial calcium signaling on mitochondrial EF-hand Ca2+ binding proteins: Miros, MICUs, LETM1 and solute carriers. Current opinion in cell biology 43 24999559
2011 Mdm38 is a 14-3-3-like receptor and associates with the protein synthesis machinery at the inner mitochondrial membrane. Traffic (Copenhagen, Denmark) 35 21718401
2019 LETM1 is required for mitochondrial homeostasis and cellular viability (Review). Molecular medicine reports 34 30896806
2018 LETM1 couples mitochondrial DNA metabolism and nutrient preference. EMBO molecular medicine 34 30012579
2013 Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf-Hirschhorn Syndrome. European journal of human genetics : EJHG 32 23963300
2017 Suppression of LETM1 by siRNA inhibits cell proliferation and invasion of bladder cancer cells. Oncology reports 29 29048663
2014 LETM1 haploinsufficiency causes mitochondrial defects in cells from humans with Wolf-Hirschhorn syndrome: implications for dissecting the underlying pathomechanisms in this condition. Disease models & mechanisms 25 24626991
2020 Suppression of LETM1 inhibits the proliferation and stemness of colorectal cancer cells through reactive oxygen species-induced autophagy. Journal of cellular and molecular medicine 23 33314691
2021 LETM1: A Single Entity With Diverse Impact on Mitochondrial Metabolism and Cellular Signaling. Frontiers in physiology 22 33815143
2013 New players in high fat diet-induced obesity: LETM1 and CTMP. Metabolism: clinical and experimental 20 24333006
2022 Emerging role of LETM1/GRP78 axis in lung cancer. Cell death & disease 18 35680871
2015 LETM1 overexpression is correlated with the clinical features and survival outcome of breast cancer. International journal of clinical and experimental pathology 16 26722481
2013 Co-delivery of LETM1 and CTMP synergistically inhibits tumor growth in H-ras12V liver cancer model mice. Cancer gene therapy 16 23392203
2021 LETM1 Knockdown Promotes Autophagy and Apoptosis Through AMP-Activated Protein Kinase Phosphorylation-Mediated Beclin-1/Bcl-2 Complex Dissociation in Hepatocellular Carcinoma. Frontiers in oncology 15 33552978
2021 LETM1 (leucine zipper-EF-hand-containing transmembrane protein 1) silence reduces the proliferation, invasion, migration and angiogenesis in esophageal squamous cell carcinoma via KIF14 (kinesin family member 14). Bioengineered 14 34605738
2018 Knockdown of LETM1 inhibits proliferation and metastasis of human renal cell carcinoma cells. Oncology letters 13 30405774
2020 LETM1 Promotes Gastric Cancer Cell Proliferation, Migration, and Invasion via the PI3K/Akt Signaling Pathway. Journal of gastric cancer 11 32595998
2022 Mitochondrial LETM1 drives ionic and molecular clock rhythms in circadian pacemaker neurons. Cell reports 10 35545046
2022 Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement. American journal of human genetics 10 36055214
2021 Trypanosoma cruzi Letm1 is involved in mitochondrial Ca2+ transport, and is essential for replication, differentiation, and host cell invasion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 34085343
2020 MiR-613 blocked the progression of cervical cancer by targeting LETM1. European review for medical and pharmacological sciences 10 32633345
2013 Dravet phenotype in a subject with a der(4)t(4;8)(p16.3;p23.3) without the involvement of the LETM1 gene. European journal of medical genetics 10 23999105
2022 Circ_0061140 Contributes to Ovarian Cancer Progression by Targeting miR-761/LETM1 Signaling. Biochemical genetics 9 36056285
2016 Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation. Oncotarget 9 27556512
2019 Melatonin reverses the oxidative stress and mitochondrial dysfunction caused by LETM1 silencing. Cell biology international 8 31777134
2022 The cation exchanger Letm1, circadian rhythms, and NAD(H) levels interconnect in diurnal zebrafish. Life science alliance 7 35697381
2024 Avian pathogenic Escherichia coli T6SS effector protein Hcp2a causes mitochondrial dysfunction through interaction with LETM1 protein in DF-1 cells. Poultry science 6 38367471
2018 In vitro synthesis of the human calcium transporter Letm1 within cell-sized liposomes and investigation of its lipid dependency. Journal of bioscience and bioengineering 6 30503650
2022 Mitochondrial protein LETM1 and its-mediated CTMP are potential therapeutic targets for endometrial cancer. Anti-cancer drugs 5 35324530
2019 Identification and characterization of Letm1 gene in Toxoplasma gondii. Acta biochimica et biophysica Sinica 5 30423025
2024 The mysteries of LETM1 pleiotropy. Pharmacological research 4 39481506
2023 Aberrant LETM1 elevation dysregulates mitochondrial functions and energy metabolism and promotes lung metastasis in osteosarcoma. Genes & diseases 4 38292199
2025 Elevated levels of Letm1 drives mitochondrial dysfunction and cardiomyocyte stress-mediated apoptosis in cultured cardiomyocytes. Cell communication and signaling : CCS 3 40849623
2024 Dissecting structure and function of the monovalent cation/H+ antiporters Mdm38 and Ylh47 in Saccharomyces cerevisiae. Journal of bacteriology 2 39082862
2024 An AI-informed NMR structure reveals an extraordinary LETM1 F-EF-hand domain that functions as a two-way regulator of mitochondrial calcium. Structure (London, England : 1993) 2 39317198
2025 The apo LETM1 F-EF-hand adopts a closed conformation that underlies a multi-modal sensory role in mitochondria. FEBS letters 1 39927520
2026 LETM1 deacetylation attenuates calcium overload-mediated mitochondrial injury and protects the intestine from ischemia/reperfusion damage. Life sciences 0 41819224
2025 Mdm38/LETM1 couples ion homeostasis and proteostatic mechanisms in the inner mitochondrial membrane. bioRxiv : the preprint server for biology 0 39975406

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