Affinage

TMEM223

Transmembrane protein 223 · UniProt A0PJW6

Length
202 aa
Mass
22.0 kDa
Annotated
2026-06-10
10 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM223 is a mitochondrial inner-membrane protein that couples mitochondrial translation to oxidative phosphorylation complex biogenesis (PMID:34969438). It associates with the mitochondrial ribosome and stimulates translation of COX1 mRNA, and is found within early COX1 assembly intermediates, placing it at the interface of mitoribosome activity and complex IV assembly (PMID:34969438). Its yeast ortholog Mrx15 contacts nascent mitochondrial translation products through a soluble C-terminal domain that engages the large ribosomal subunit, acting with the ribosome receptor Mba1 in cotranslational membrane protein insertion (PMID:30091672), and genetically couples this insertion activity to i-AAA protease quality control, since loss of Mrx15 together with the protease regulators Mgr1/Mgr3 causes respiratory deficiency (PMID:30336542). TMEM223 belongs to the TMEM70/TMEM186/TMEM223 family that co-occurs only in species possessing OXPHOS complexes, consistent with a conserved assembly role (PMID:32275929). Separately, TMEM223 has been identified as an interaction partner of the neuronal CaV2.2 voltage-gated Ca2+ channel, where it lowers current density and alters inactivation kinetics, indicating a negative modulatory role on Ca2+ entry (PMID:30612149).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2018 High

    Established the molecular basis for how this protein engages the translation machinery: the yeast ortholog Mrx15 was shown to bind the large mitoribosomal subunit via a soluble C-terminal domain and contact nascent chains during synthesis, defining a role in cotranslational membrane insertion overlapping with Mba1.

    Evidence Mass spectrometry interaction screen, ribosome co-purification, and genetic epistasis in yeast

    PMID:30091672

    Open questions at the time
    • Direct demonstration in human TMEM223 not shown at this stage
    • Specific membrane substrates inserted via this pathway not defined
    • Structural detail of the ribosome contact unresolved
  2. 2018 Medium

    Connected membrane-insertion activity to quality control by showing Mrx15 functionally couples to the i-AAA protease, indicating that insertion and proteolytic surveillance act in a shared pathway.

    Evidence Double/triple deletion epistasis with Mgr1/Mgr3, respiratory growth and proteotoxic stress assays in yeast

    PMID:30336542

    Open questions at the time
    • Mechanism of coupling between insertion and protease not biochemically defined
    • Direct protein-protein contacts with the protease not shown
    • Not validated in human cells
  3. 2019 Medium

    Identified an unexpected non-mitochondrial activity: TMEM223 binds the CaV2.2 Ca2+ channel and negatively modulates its gating, raising the possibility of a role in neuronal Ca2+ signaling.

    Evidence Yeast split-ubiquitin screen, colocalization, and patch-clamp electrophysiology

    PMID:30612149

    Open questions at the time
    • Interaction not reconstituted with reciprocal biochemical validation in native neurons
    • Reconciliation with mitochondrial localization unclear
    • Physiological significance in vivo not established
  4. 2020 Medium

    Placed TMEM223 in a defined evolutionary context, showing it is a mitochondrial protein in the TMEM70/TMEM186/TMEM223 family that co-occurs only with OXPHOS complexes, supporting a conserved assembly function.

    Evidence Subcellular localization experiments plus evolutionary coevolution analysis

    PMID:32275929

    Open questions at the time
    • Family membership inferred from coevolution, not direct functional equivalence
    • Specific molecular activity not assigned by this analysis
  5. 2021 High

    Directly established the human function: TMEM223 is a mitoribosome-associated protein that stimulates COX1 mRNA translation and is part of early COX1 assembly intermediates, linking mitochondrial translation to complex IV biogenesis.

    Evidence Ribosome purification, interactome analysis, and knockdown with COX1 translation and assembly-intermediate readouts in human cells

    PMID:34969438

    Open questions at the time
    • Whether stimulation is direct on the ribosome or via insertion not resolved
    • Other OXPHOS substrates beyond COX1 not mapped
    • Structure of TMEM223 within assembly intermediates unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TMEM223 reconciles its mitochondrial translation/assembly role with the reported CaV2.2 channel modulation, and whether the two activities reflect distinct pools or a single mechanism, remains unresolved.
  • No structural model of TMEM223
  • No defined catalytic activity
  • Dual localization/function not reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 1 R-HSA-8953854 Metabolism of RNA 1
Partners
CACNA1BMBA1
Complex memberships
mitochondrial ribosome (large subunit)

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 TMEM223 was identified as a ribosome-associated protein in human mitochondria that stimulates the translation of COX1 mRNA and is a constituent of early COX1 assembly intermediates, linking mitochondrial translation to complex IV biogenesis. Ribosome purification from mitochondria, interactome analysis, functional knockdown with phenotypic readout (COX1 translation and complex IV assembly intermediates) eLife High 34969438
2020 TMEM223 (and TMEM186) are mitochondrially localized proteins in human cells, belonging to the TMEM70/TMEM186/TMEM223 protein family that co-occurs only in species with OXPHOS complexes, suggesting a conserved role in OXPHOS assembly. Subcellular localization experiments (mitochondrial localization confirmed), evolutionary coevolution analysis Biochimica et biophysica acta. Bioenergetics Medium 32275929
2018 Yeast Mrx15 (ortholog of TMEM223) interacts with the large mitochondrial ribosomal subunit via a soluble C-terminal domain, contacts mitochondrial translation products during their synthesis, and plays an overlapping role with ribosome receptor Mba1 in cotranslational membrane protein insertion. Mass spectrometry-based interaction screen, ribosome co-purification, genetic epistasis (double mutant analysis) Molecular biology of the cell High 30091672
2018 Yeast Mrx15 (ortholog of TMEM223) genetically interacts with regulators of the i-AAA protease (Mgr1 and Mgr3); simultaneous absence of Mrx15 and Mgr1/Mgr3 provokes respiratory deficiency, suggesting functional coupling between mitochondrial membrane protein insertion and AAA-protease quality control. Genetic epistasis (double/triple deletion mutants), respiratory growth assay, proteotoxic stress assays Cells Medium 30336542
2021 Mrx15 (yeast ortholog of TMEM223) is broadly conserved in eukaryotes and is a mitochondrial ribosome-interacting protein implicated in membrane protein targeting, functionally nonredundant with the mitochondrial SRP system. Phylogenetic/comparative genomics with experimental confirmation of mitochondrial localization in model organisms Molecular biology and evolution Low 33837778
2019 TMEM223 interacts with the CaV2.2 voltage-gated Ca2+ channel (domain IV), lowers average current density, accelerates cumulative current inactivation kinetics, and slows recovery from inactivation, suggesting a negative modulatory role on Ca2+ entry. Yeast split-ubiquitin interaction screen, colocalization with fluorescent constructs, patch-clamp electrophysiology Pflugers Archiv : European journal of physiology Medium 30612149

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 TMEM70 functions in the assembly of complexes I and V. Biochimica et biophysica acta. Bioenergetics 38 32275929
2018 The ribosome receptors Mrx15 and Mba1 jointly organize cotranslational insertion and protein biogenesis in mitochondria. Molecular biology of the cell 28 30091672
2021 Defining the interactome of the human mitochondrial ribosome identifies SMIM4 and TMEM223 as respiratory chain assembly factors. eLife 25 34969438
1996 X-linked mental retardation with neonatal hypotonia in a French family (MRX15): gene assignment to Xp11.22-Xp21.1. American journal of medical genetics 18 8826458
2021 Vestiges of the Bacterial Signal Recognition Particle-Based Protein Targeting in Mitochondria. Molecular biology and evolution 11 33837778
2020 Paclitaxel Promotes Tumor-Infiltrating Macrophages in Breast Cancer. Technology in cancer research & treatment 5 32783527
2020 Modulation of voltage-gated CaV2.2 Ca2+ channels by newly identified interaction partners. Channels (Austin, Tex.) 4 33006503
2019 Four novel interaction partners demonstrate diverse modulatory effects on voltage-gated CaV2.2 Ca2+ channels. Pflugers Archiv : European journal of physiology 4 30612149
2018 Insertion Defects of Mitochondrially Encoded Proteins Burden the Mitochondrial Quality Control System. Cells 3 30336542
2025 Genetic variation in the Nr1d1 transcription factor binding site shapes metabolism-related protein networks associated with cognitive resilience in an Alzheimer's disease mouse reference panel. Alzheimer's & dementia : the journal of the Alzheimer's Association 0 41225772

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