LETM1 (leucine zipper-EF-hand-containing transmembrane protein 1) is a nuclear-encoded mitochondrial inner-membrane protein with a single transmembrane segment and a large matrix-exposed C-terminal region containing a LETM (ribosome-binding type) domain, coiled-coils and an EF-hand motif. It assembles into high-molecular-weight homo-oligomeric complexes whose assembly depends on BCS1L, and it interacts with the Ca2+/H+ exchanger TMBIM5. LETM1 is the principal mediator of electroneutral K+/H+ exchange across the inner membrane, extruding matrix K+ in exchange for protons and thereby controlling mitochondrial osmotic volume, matrix ion composition and the pH component of the proton-motive force. Loss of LETM1 causes matrix swelling, cristae disorganisation, fragmentation of the mitochondrial network and defective assembly of respiratory-chain complexes, and LETM1 can deform membranes in reconstituted proteoliposomes. A role as an electroneutral Ca2+/H+ antiporter was proposed from RNAi and liposome reconstitution studies, but subsequent work indicates that TMBIM5, not LETM1, is the physiological mitochondrial Ca2+/H+ exchanger and that LETM1 levels do not set Ca2+ extrusion rates; LETM1 nevertheless influences mitochondrial Ca2+ homeostasis. Haploinsufficiency of LETM1 has been implicated in features of Wolf-Hirschhorn syndrome, and biallelic variants cause a childhood-onset mitochondrial neurodegenerative disorder with defective mitochondrial K+ efflux and respiratory-chain deficiency.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro EF-hand domain mapping to calcium ion binding. LETM1 contains an EF-hand motif in its matrix region; direct Ca2+ binding by full-length human LETM1 has not been established in the evidence reviewed here. Reason: A reasonable domain-based inference; not the core function. The core activity of LETM1 is K+/H+ exchange. Supporting Evidence: PMID:10486213 LETM1 encodes a putative member of the EF-hand family of Ca(2+)-binding proteins. |
| GO:0005509 calcium ion binding | TAS PMID:10486213 LETM1, a novel gene encoding a putative EF-hand Ca(2+)-bindi... | KEEP AS NON CORE | Summary: TAS from the original cloning paper, which described LETM1 as a putative EF-hand Ca2+-binding protein based on sequence alone. Reason: Sequence-based and explicitly putative; retained as a non-core feature of the protein. Supporting Evidence: PMID:10486213 LETM1 encodes a putative member of the EF-hand family of Ca(2+)-binding proteins. |
| GO:0005509 calcium ion binding | TAS PMID:26975899 Identification of EFHD1 as a novel Ca(2+) sensor for mitofla... | KEEP AS NON CORE | Summary: TAS from a mitoflash study that screened mitochondrial proteins carrying Ca2+-binding motifs in silico; LETM1 was included because of its EF-hand. Reason: The paper selected candidates by predicted Ca2+-binding motifs and did not measure LETM1 Ca2+ binding. Non-core. Supporting Evidence: PMID:26975899 screening mitochondrial proteins containing the Ca(2+)-binding motifs |
| GO:0005515 protein binding | IPI PMID:18628306 Characterization of the mitochondrial protein LETM1, which m... | REMOVE | Summary: Co-precipitation of LETM1 with the AAA-ATPase BCS1L; LETM1 complex formation depends on BCS1L levels. Biologically meaningful but generic protein binding. Reason: protein binding (GO:0005515) is uninformative; the interaction is not disputed. Supporting Evidence: PMID:18628306 LETM1 was co-precipitated with BCS1L and formation of the LETM1 complex depended on BCS1L levels |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput Y2H interaction (proteasome subunit). Generic protein binding. Reason: protein binding (GO:0005515) is uninformative and not linked to LETM1 function. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput Y2H interactions from the HuRI reference interactome with non-mitochondrial partners. Generic protein binding. Reason: protein binding (GO:0005515) is uninformative; partners are not co-localised with the inner-membrane protein. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput Y2H interactions from the HuRI reference interactome with non-mitochondrial partners. Generic protein binding. Reason: protein binding (GO:0005515) is uninformative; partners are not co-localised with the inner-membrane protein. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:36321428 TMBIM5 is the Ca(2+) /H(+) antiporter of mammalian mitochond... | REMOVE | Summary: Interaction of LETM1 with TMBIM5 (GHITM), identified in the LETM1 mitochondrial interactome and validated; the two proteins appear to cooperate in cation/H+ exchange. Generic protein binding term. Reason: protein binding (GO:0005515) is uninformative; the interaction itself is not disputed. Supporting Evidence: PMID:36321428 validate the physical interaction of TMBIM5 and LETM1 |
| GO:0005515 protein binding | IPI PMID:40355756 The solute carrier superfamily interactome. | REMOVE | Summary: Solute-carrier interactome affinity-purification identifying BCS1L as a LETM1 partner. Generic protein binding. Reason: protein binding (GO:0005515) is uninformative. Supporting Evidence: PMID:40355756 The solute carrier superfamily interactome. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-confidence human mitochondrial proteome. Reason: Consistent with targeted evidence placing LETM1 in the inner membrane. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA is_active_in mitochondrion for the LETM1/Mdm38 family. Reason: Correct; the family acts in the mitochondrial inner membrane. Supporting Evidence: PMID:18628306 LETM1 is a mitochondrial inner-membrane protein with a large domain extruding to the matrix. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localisation to mitochondria. Reason: Consistent with established localisation. Supporting Evidence: PMID:18628306 LETM1 is a mitochondrial inner-membrane protein with a large domain extruding to the matrix. |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of mitochondrion from mouse Letm1. Reason: Consistent with established localisation. Supporting Evidence: PMID:18628306 LETM1 is a mitochondrial inner-membrane protein with a large domain extruding to the matrix. |
| GO:0005739 mitochondrion | TAS PMID:26975899 Identification of EFHD1 as a novel Ca(2+) sensor for mitofla... | ACCEPT | Summary: TAS mitochondrion from the mitoflash screen of mitochondrial EF-hand proteins. Reason: Consistent with established localisation. Supporting Evidence: PMID:26975899 identified four mitoflash activators (MICU1, EFHD1, SLC25A23, SLC25A25) and one mitoflash inhibitor (LETM1) |
| GO:0005743 mitochondrial inner membrane | IDA PMID:18628306 Characterization of the mitochondrial protein LETM1, which m... | ACCEPT | Summary: IDA: LETM1 is an inner-membrane protein with a large matrix-exposed domain. Reason: Direct evidence; core location. Supporting Evidence: PMID:18628306 LETM1 is a mitochondrial inner-membrane protein with a large domain extruding to the matrix. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:19797662 Genome-wide RNAi screen identifies Letm1 as a mitochondrial ... | ACCEPT | Summary: IDA from the Drosophila RNAi screen paper that characterised mammalian Letm1 as an inner-membrane cation/H+ antiporter. Reason: Correct core location. Supporting Evidence: PMID:19797662 the molecules that govern Ca2+ movement across the inner mitochondrial membrane are unknown |
| GO:0005743 mitochondrial inner membrane | IDA PMID:32139798 The mitochondrial inner membrane protein LETM1 modulates cri... | ACCEPT | Summary: IDA inner membrane from the LETM1 cristae-organisation study. Reason: Correct core location. Supporting Evidence: PMID:32139798 LETM1 is a mitochondrial inner membrane protein that is required for maintaining the mitochondrial morphology and cristae structures |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation to mitochondrial inner membrane. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:18628306 LETM1 is a mitochondrial inner-membrane protein with a large domain extruding to the matrix. |
| GO:0006816 calcium ion transport | IMP PMID:36321428 TMBIM5 is the Ca(2+) /H(+) antiporter of mammalian mitochond... | KEEP AS NON CORE | Summary: IMP calcium ion transport from the study that identified TMBIM5 as the mitochondrial Ca2+/H+ exchanger. The paper concludes that TMBIM5, not LETM1, is the exchanger; LETM1 perturbation influences mitochondrial Ca2+ handling, likely through its K+/H+ exchange and partnership with TMBIM5. Reason: LETM1 loss perturbs mitochondrial Ca2+ handling, so an effect on Ca2+ transport is supported, but LETM1 is not the Ca2+ carrier according to this same study. Non-core. Supporting Evidence: PMID:36321428 we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE |
| GO:0006851 mitochondrial calcium ion transmembrane transport | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: PAINT IBA to mitochondrial calcium ion transmembrane transport, seeded largely by the Ca2+/H+ antiporter claim for human LETM1 and Drosophila Letm1. Reason: The Ca2+/H+ antiporter role of LETM1 is contested: NCLX rather than LETM1 sets Ca2+ extrusion rates in intact cells, and TMBIM5 has been identified as the mitochondrial Ca2+/H+ exchanger. LETM1's established transport activity is K+/H+ exchange; propagating a Ca2+ transport process across the family over-states the evidence. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: PANTHER:PTN000360990 SOURCE WEAK OR INFERRED Node seeded by Ca2+-transport claims for human LETM1 and fly Letm1 that later cell-based work (NCLX, TMBIM5 studies) disputes. Supporting Evidence: PMID:24898248 We conclude that NCLX, but not LETM1, mediates Ca(2+) extrusion from mitochondria. PMID:36321428 we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE |
| GO:0006851 mitochondrial calcium ion transmembrane transport | IDA PMID:19797662 Genome-wide RNAi screen identifies Letm1 as a mitochondrial ... | MARK AS OVER ANNOTATED | Summary: IDA from Jiang et al. (2009), who reported Ca2+/H+ exchange mediated by Letm1 from RNAi, overexpression and liposome reconstitution. Later reconstitution (Tsai et al. 2014) and PINK1-phosphorylation studies support Ca2+ transport in vitro, while cell-based studies dispute a physiological Ca2+ extrusion role. Reason: Direct experimental data that LETM1 can move Ca2+ across membranes in vitro exist, but cell-based studies dispute that this is a physiological function, so the process is over-annotated for LETM1. Not removed, deferring to the curator's reading of the full text. Supporting Evidence: PMID:19797662 RNAi knockdown, overexpression, and liposome reconstitution of the purified Letm1 protein demonstrate that Letm1 is a mitochondrial Ca2+/H+ antiporter. PMID:24898248 NCLX overexpression enhanced the rates of Ca(2+) efflux, whereas increasing LETM1 levels had no impact on Ca(2+) extrusion. |
| GO:0006851 mitochondrial calcium ion transmembrane transport | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of mitochondrial calcium ion transmembrane transport. Reason: Propagates the contested Ca2+/H+ antiporter role; LETM1's established activity is K+/H+ exchange. Supporting Evidence: PMID:36321428 we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE |
| GO:0006851 mitochondrial calcium ion transmembrane transport | IMP PMID:32139798 The mitochondrial inner membrane protein LETM1 modulates cri... | MARK AS OVER ANNOTATED | Summary: IMP from the cristae-organisation study; LETM1 mutants were assessed for effects on mitochondrial ion homeostasis. The paper's focus is membrane organisation. Reason: LETM1 perturbation affects mitochondrial ion (including Ca2+) homeostasis, but whether LETM1 transports Ca2+ itself is disputed; the specific transport process is over-annotated, while the homeostasis annotation is retained as non-core. Supporting Evidence: PMID:32139798 regulates mitochondrial ion homeostasis |
| GO:0007005 mitochondrion organization | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA to mitochondrion organization for the LETM1/Mdm38 family, whose loss in yeast, flies and human cells causes swelling and loss of tubular morphology. Reason: LETM1 maintains mitochondrial tubular shape and cristae, both via volume control and by direct membrane deformation. Supporting Evidence: PMID:18628306 LETM1 downregulation caused mitochondrial swelling and cristae disorganization PMID:32139798 suggesting that LETM1 plays a fundamental role in the organization of mitochondrial membrane morphology |
| GO:0007007 inner mitochondrial membrane organization | IMP PMID:32139798 The mitochondrial inner membrane protein LETM1 modulates cri... | ACCEPT | Summary: IMP: LETM1 point mutants that fail to assemble the LETM1 complex fail to remodel mitochondrial morphology, and LETM1 itself deforms proteoliposome membranes into invaginations, indicating direct participation in inner-membrane shaping. Reason: Supported by genetic complementation and an in vitro membrane-deformation activity of the purified protein. Supporting Evidence: PMID:32139798 the LETM1 protein changes the shapes of the membranes of in vitro-reconstituted proteoliposomes, leading to the formation of invaginated membrane structures on artificial liposomes |
| GO:0015369 calcium:proton antiporter activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: PAINT IBA calcium:proton antiporter activity, seeded by human LETM1 (O95202) and mouse Letm1 experimental annotations. Reason: The physiological mitochondrial Ca2+/H+ exchanger is TMBIM5; LETM1's established activity is K+/H+ exchange. Propagating Ca2+/H+ antiport across the family over-states contested evidence. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: PANTHER:PTN002678824 SOURCE WEAK OR INFERRED Node seeded by the contested Ca2+/H+ antiporter annotation of human LETM1 (O95202) and mouse Letm1; TMBIM5 was later shown to be the mitochondrial Ca2+/H+ exchanger. Supporting Evidence: PMID:36321428 Originally identified as the mitochondrial K+ /H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. PMID:36321428 we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE |
| GO:0015369 calcium:proton antiporter activity | IDA PMID:19797662 Genome-wide RNAi screen identifies Letm1 as a mitochondrial ... | MARK AS OVER ANNOTATED | Summary: IDA from Jiang et al. (2009): purified Letm1 reconstituted in liposomes mediated Ca2+/H+ exchange. A later reconstitution of human LETM1 reported electroneutral 1 Ca2+/2 H+ antiport, but cell-based work found LETM1 does not set Ca2+ extrusion and identified TMBIM5 as the mitochondrial Ca2+/H+ exchanger. Reason: Reconstitution data show the purified protein can mediate Ca2+/H+ antiport in vitro, so the annotation is not removed, but its physiological relevance is disputed by cell-based work identifying TMBIM5 as the exchanger; it is over-annotated as an activity of LETM1. Supporting Evidence: PMID:19797662 RNAi knockdown, overexpression, and liposome reconstitution of the purified Letm1 protein demonstrate that Letm1 is a mitochondrial Ca2+/H+ antiporter. PMID:24344246 Further experiments show that Letm1 mediates electroneutral 1 Ca(2+)/2 H(+) antiport. PMID:24898248 We conclude that NCLX, but not LETM1, mediates Ca(2+) extrusion from mitochondria. |
| GO:0015369 calcium:proton antiporter activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Combined automated annotation of calcium:proton antiporter activity. Reason: Propagates a contested activity; the established LETM1 activity is K+/H+ exchange. Supporting Evidence: PMID:36321428 we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE |
| GO:0015386 potassium:proton antiporter activity | EXP PMID:24898248 NCLX protein, but not LETM1, mediates mitochondrial Ca2+ ext... | ACCEPT | Summary: EXP potassium:proton antiporter activity from De Marchi et al. (2014). The paper itself measured Ca2+ extrusion and found LETM1 does not set it; it cites earlier work for LETM1-mediated K+/H+ exchange rather than measuring it. The activity is nonetheless well established by other studies. Reason: K+/H+ exchange is the best-supported LETM1 activity (patient fibroblasts and yeast complementation showing defective K+ efflux, and the conclusion of the TMBIM5 study). Supporting Evidence: PMID:24898248 Previous studies, however, indicated that LETM1 mediates mitochondrial K + /H + exchange PMID:36055214 bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures |
| GO:0015386 potassium:proton antiporter activity | EXP PMID:36055214 Bi-allelic LETM1 variants perturb mitochondrial ion homeosta... | ACCEPT | Summary: EXP from the bi-allelic LETM1 disease study: patient fibroblasts show loss of quinine-sensitive K+/H+ exchange (light-scattering swelling assays) and valinomycin sensitivity normalised by nigericin; yeast complementation was used to test variant pathogenicity. Reason: Core molecular function with direct functional evidence. Supporting Evidence: PMID:36055214 bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures |
| GO:0015386 potassium:proton antiporter activity | EXP PMID:36321428 TMBIM5 is the Ca(2+) /H(+) antiporter of mammalian mitochond... | ACCEPT | Summary: EXP from the TMBIM5 study, which concluded that LETM1 is the mitochondrial K+/H+ exchanger, interacting with TMBIM5 in K+/H+ exchange, while TMBIM5 is the Ca2+/H+ exchanger. Reason: Core molecular function. Supporting Evidence: PMID:36321428 Originally identified as the mitochondrial K+ /H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. |
| GO:0034214 protein hexamerization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of protein hexamerization from mouse Letm1. LETM1 forms high-molecular-weight homo-oligomeric complexes. Reason: Oligomeric assembly is a structural property consistent with the observed LETM1 complexes, but it is not a core biological role. Supporting Evidence: PMID:18628306 formation of the LETM1 complex depended on BCS1L levels |
| GO:0034214 protein hexamerization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS protein hexamerization transferred from mouse Letm1 (homohexamer by similarity). Reason: Structural property of the protein; non-core. Supporting Evidence: file:human/LETM1/LETM1-uniprot.txt Homohexamer (By similarity). |
| GO:0042407 cristae formation | IMP PMID:18628306 Characterization of the mitochondrial protein LETM1, which m... | KEEP AS NON CORE | Summary: IMP cristae formation: LETM1 knockdown causes mitochondrial swelling and cristae disorganisation. Much of this phenotype can be explained by osmotic swelling from lost K+/H+ exchange, although LETM1 also shapes membranes directly. Reason: LETM1 is required for normal cristae, but a role in cristae formation per se (as opposed to maintenance via volume control) is less direct; the broader inner-membrane organization annotation captures the supported role. Supporting Evidence: PMID:18628306 LETM1 downregulation caused mitochondrial swelling and cristae disorganization |
| GO:0043022 ribosome binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro mapping of the LETM1 (ribosome-binding) domain to ribosome binding. The domain name reflects reports on yeast Mdm38; ribosome binding by human LETM1 is not established in the evidence reviewed. Reason: Domain-name-driven inference without human experimental support; LETM1's characterised activities are cation/H+ exchange and membrane organisation. Supporting Evidence: file:human/LETM1/LETM1-uniprot.txt FUNCTION: Plays an important role in maintenance of mitochondrial |
| GO:0051260 protein homooligomerization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of protein homooligomerization. Reason: Structural property; non-core. Supporting Evidence: PMID:18628306 formation of the LETM1 complex depended on BCS1L levels |
| GO:0051260 protein homooligomerization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS protein homooligomerization from mouse Letm1. Reason: Structural property; non-core. Supporting Evidence: file:human/LETM1/LETM1-uniprot.txt Homohexamer (By similarity). |
| GO:0051560 mitochondrial calcium ion homeostasis | IDA PMID:19797662 Genome-wide RNAi screen identifies Letm1 as a mitochondrial ... | KEEP AS NON CORE | Summary: IDA mitochondrial calcium ion homeostasis: LETM1 knockdown and overexpression alter mitochondrial Ca2+ handling. Reason: LETM1 perturbation clearly affects mitochondrial Ca2+ homeostasis, whether directly or through K+/H+ exchange and the pH gradient; non-core relative to K+/H+ exchange. Supporting Evidence: PMID:24344246 whose depletion severely perturbs mitochondrial Ca(2+) and K(+) homeostasis |
| GO:0051560 mitochondrial calcium ion homeostasis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined automated annotation to mitochondrial calcium ion homeostasis. Reason: Supported indirectly; non-core. Supporting Evidence: PMID:24344246 whose depletion severely perturbs mitochondrial Ca(2+) and K(+) homeostasis |
| GO:0051562 negative regulation of mitochondrial calcium ion concentration | IMP PMID:26975899 Identification of EFHD1 as a novel Ca(2+) sensor for mitofla... | MARK AS OVER ANNOTATED | Summary: IMP from the mitoflash siRNA screen, in which LETM1 behaved as a mitoflash inhibitor under hyperosmotic stress. The annotation reads this as lowering mitochondrial Ca2+, which the abstract does not show directly. Reason: The study measured mitoflash frequency, not mitochondrial Ca2+ concentration as an output regulated by LETM1; the term over-interprets an indirect screen phenotype. Supporting Evidence: PMID:26975899 identified four mitoflash activators (MICU1, EFHD1, SLC25A23, SLC25A25) and one mitoflash inhibitor (LETM1) |
| GO:0099093 calcium export from the mitochondrion | IDA PMID:19797662 Genome-wide RNAi screen identifies Letm1 as a mitochondrial ... | MARK AS OVER ANNOTATED | Summary: IDA calcium export from the mitochondrion based on the proposed Ca2+/H+ antiporter activity. In intact HeLa cells LETM1 levels had no effect on Ca2+ extrusion, which is set by NCLX, and Na+-independent Ca2+ release depends on TMBIM5. Reason: Directly tested in intact cells and not supported: LETM1 overexpression does not change mitochondrial Ca2+ efflux, and Na+-independent Ca2+ release is lost in TMBIM5 knockouts. Not removed because the original reconstitution data show a Ca2+ transport capacity in vitro. Supporting Evidence: PMID:24898248 NCLX overexpression enhanced the rates of Ca(2+) efflux, whereas increasing LETM1 levels had no impact on Ca(2+) extrusion. PMID:36321428 demonstrate the absence or greatly reduced Na+ -independent mitochondrial Ca2+ release in TMBIM5 knockout |
| GO:0099093 calcium export from the mitochondrion | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Combined automated annotation of calcium export from the mitochondrion. Reason: Propagates a role contradicted by cell-based measurements; see the IDA annotation. Supporting Evidence: PMID:24898248 We conclude that NCLX, but not LETM1, mediates Ca(2+) extrusion from mitochondria. |
| GO:0099093 calcium export from the mitochondrion | IMP PMID:32139798 The mitochondrial inner membrane protein LETM1 modulates cri... | MARK AS OVER ANNOTATED | Summary: IMP from the cristae-organisation study. The cached abstract reports effects on morphology and membrane shaping, not Ca2+ export. Reason: Calcium export from mitochondria is not an established LETM1 function in intact cells; NCLX mediates extrusion. Supporting Evidence: PMID:24898248 We conclude that NCLX, but not LETM1, mediates Ca(2+) extrusion from mitochondria. |
| GO:0140141 mitochondrial potassium ion transmembrane transport | IMP PMID:36055214 Bi-allelic LETM1 variants perturb mitochondrial ion homeosta... | ACCEPT | Summary: IMP: biallelic LETM1 variants cause defective mitochondrial K+ efflux, matrix swelling and loss of OXPHOS components in patient fibroblasts and muscle. Reason: Core biological process executed by LETM1's K+/H+ exchange activity. Supporting Evidence: PMID:36055214 bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures |
| GO:1900069 regulation of cellular hyperosmotic salinity response | IMP PMID:26975899 Identification of EFHD1 as a novel Ca(2+) sensor for mitofla... | MARK AS OVER ANNOTATED | Summary: IMP regulation of cellular hyperosmotic salinity response, derived from LETM1 acting as an inhibitor of mitoflash responses to hyperosmotic stress in an siRNA screen. Reason: The readout was mitoflash frequency in response to hyperosmotic stress; this does not establish that LETM1 regulates a cellular salinity-response process. LETM1's osmoregulatory role is at the level of mitochondrial matrix volume via K+/H+ exchange. Supporting Evidence: PMID:26975899 in terms of their ability to modulate mitoflash response to hyperosmotic stress |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000120 | ACCEPT | Summary: Proton transmembrane transport inferred from the antiporter MF annotations. LETM1 moves H+ into the matrix in exchange for K+. Reason: Follows from the established K+/H+ exchange activity. Supporting Evidence: PMID:36055214 we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity |
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Download this section (compressed HTML)Q: Does LETM1 itself carry K+ and H+, or does it act as a regulatory subunit of a K+/H+ exchange complex that includes TMBIM5 or other partners?
Q: Is the Ca2+/H+ antiport measured with reconstituted LETM1 physiologically relevant in any cell type, or is it a property of the purified protein that is superseded in vivo by TMBIM5?
Q: Does the matrix EF-hand of LETM1 bind Ca2+ at physiological matrix concentrations, and does Ca2+ binding regulate K+/H+ exchange?
Experiment: Reconstitute purified human LETM1, alone and with TMBIM5, in proteoliposomes and measure K+/H+ and Ca2+/H+ exchange side by side with ion-selective fluorophores, to define its intrinsic substrate selectivity.
Experiment: Measure Ca2+ binding by the isolated LETM1 matrix domain (isothermal titration calorimetry) and test whether EF-hand mutants alter K+/H+ exchange in LETM1-null cells.
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