SHMOOSE (Small Human Mitochondrial ORF Over SErine tRNA) is a 58-aa microprotein encoded by a short open reading frame in human mitochondrial DNA. The ORF lies on the heavy-strand-encoded sense at m.12234-12410, overlapping the genes for tRNA-Ser(AGY) (MT-TS2) and tRNA-Leu(CUN) (MT-TL2) and the 5' end of MT-ND5 in a different reading frame. It contains no codons whose meaning differs between the standard and vertebrate mitochondrial genetic codes, so it encodes the same peptide whether translated by mitochondrial or cytosolic ribosomes, and the site of its translation is unknown. The peptide has a predicted N-terminal amphipathic helix, a disordered proline-rich C-terminal half and no recognisable mitochondrial targeting sequence. Endogenous SHMOOSE has been detected in neuronal mitochondrial and nuclear fractions (absent from cells lacking mtDNA), by mass spectrometry of peptides from mitochondria, and in cerebrospinal fluid. Synthetic SHMOOSE binds the MICOS core subunit mitofilin (IMMT/MIC60) and, when added to neuronal cells, increases basal oxygen consumption and protects against oligomeric amyloid-beta toxicity; these effects come from added peptide, and the role of the endogenous peptide has not been tested by loss of function. The m.12372G>A (rs2853499) haplogroup U marker changes Asp47 to Asn (D47N) and was associated with Alzheimer disease risk and brain imaging traits, but this association, which cannot separate the peptide from the overlapping mtDNA sequence and linked haplogroup variants, does not by itself establish what the peptide does.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:36127429 Mitochondrial DNA variation in Alzheimer's disease reveals a... | REMOVE | Summary: Binding of SHMOOSE to mitofilin (IMMT, Q16891), shown with synthetic peptide by IP-mass spectrometry from spiked lysate, reciprocal co-IP after treating cells with peptide, and dot blot with recombinant proteins. GOA carries the row twice (UniProt and IntAct). Reason: The interaction itself is reasonably supported (three methods in one study, plus siRNA against IMMT abolishing a peptide effect), but bare protein binding says nothing about what SHMOOSE does, and there is no informative MF term to replace it with. GO has no MICOS complex binding term, and the data do not show that SHMOOSE regulates MICOS assembly or crista organisation. All binding data use exogenous synthetic or recombinant peptide; no interaction of the endogenous peptide is shown. The interaction is recorded in the description, and a more specific term is a question for future work. Supporting Evidence: PMID:36127429 The SHMOOSE-mitofilin interaction was confirmed in vitro by treating cells with SHMOOSE followed by gentle lysis, reciprocal immunoprecipitation, and western blot at least three times PMID:36127429 Mass spectrometry-based analysis suggested SHMOOSE bound 98 proteins; however, during protein quantification filtering and indexing by p value and fold change, we considered mitofilin a top SHMOOSE binding protein candidate |
| GO:0005634 nucleus | IDA PMID:36127429 Mitochondrial DNA variation in Alzheimer's disease reveals a... | KEEP AS NON CORE | Summary: Endogenous SHMOOSE detected by western blot at ~6 kDa in nuclear as well as mitochondrial fractions of differentiated SH-SY5Y neuronal cells. Reason: Direct experimental observation, so the curator call is kept. It rests on one fractionation experiment with one polyclonal antibody, without imaging, and no nuclear activity has been described; mitochondria are where the peptide was confirmed by mass spectrometry and where its reported partner resides. Kept as a non-core location. Supporting Evidence: PMID:36127429 SHMOOSE was detected in neuronal mitochondria and nuclei fractions at the predicted ~6kDa molecular weight |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location keyword mapping (SL-0191 Nucleus), derived from the same fractionation data as the IDA row. Reason: Correct mapping of the UniProt location; same basis and same non-core status as the IDA row. Supporting Evidence: PMID:36127429 SHMOOSE was detected in neuronal mitochondria and nuclei fractions at the predicted ~6kDa molecular weight |
| GO:0005739 mitochondrion | IDA PMID:36127429 Mitochondrial DNA variation in Alzheimer's disease reveals a... | ACCEPT | Summary: Endogenous SHMOOSE detected in mitochondrial fractions by western blot, absent in rho0 cells, and identified by two unique peptides in mass spectrometry of material immunoprecipitated from neuronal mitochondria. Reason: Supported by two independent methods on the endogenous peptide (western blot of fractions, mass spectrometry after IP from mitochondria). It matches the mtDNA origin and the inner-membrane partner IMMT. The submitochondrial compartment is not known, so the general term is right; the fractionation and IP from purified mitochondria resolve the organelle, not a sub-compartment (ORGANELLES check, 2026-10-24). Supporting Evidence: PMID:36127429 Notably, following precipitation of SHMOOSE from neuronal mitochondria, two unique SHMOOSE-derived peptides were confidently identified using mass spectrometry PMID:36127429 in rho zero cells (i.e., cells without mtDNA), SHMOOSE was not detected, further confirming SHMOOSE is derived from mitochondrial DNA |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location keyword mapping (SL-0173 Mitochondrion), based on the same study. Reason: Correct mapping, concordant with the IDA row. ORGANELLES check (2026-10-24), as a synthesis row - GO_REF:0000044 maps UniProt SL-0173, which the record gives with ECO:0000269 from PMID:36127429 (the same neuronal fractionation and IP-mass spectrometry as the IDA row), so the feature the mapping assumes is present and the organelle claim is right. Stays at the root - SHMOOSE has no presequence or predicted TM segment (UniProt features are only a MobiDB-lite disordered, proline-rich C-terminal region), the cached full text has no mitoplast, protease protection or sub-mitochondrial fractionation, and binding of exogenous peptide to the inner-membrane protein IMMT is a single, indirect line, so no inner-membrane row is added. Supporting Evidence: PMID:36127429 SHMOOSE was detected in neuronal mitochondria and nuclei fractions at the predicted ~6kDa molecular weight file:human/C0HM83/C0HM83-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:36127429} |
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Download this section (compressed HTML)Q: Is SHMOOSE translated by mitochondrial or cytosolic ribosomes? Its codons read the same under both genetic codes, and its start codon lies within the tRNA-Ser(AGY) sequence, so translation would seem to require an RNA that escapes normal tRNA punctuation processing of the heavy-strand transcript. Which RNA species carries the intact ORF?
Q: Does endogenous SHMOOSE associate with mitofilin/MICOS, and on which side of the inner membrane? If so, does it change MICOS assembly or crista junction structure, which would support a more specific function term than protein binding?
Q: Is the nuclear signal real (imaging, protease protection, other antibodies), and how would a mitochondrially encoded peptide reach the nucleus?
Q: Is the Alzheimer disease association of m.12372G>A caused by the D47N peptide change rather than by linked haplogroup U variants or effects of the variant on the overlapping RNA?
Experiment: Ribosome profiling of mitochondrial versus cytosolic ribosomes (or mitoribosome inhibitor sensitivity of endogenous peptide levels) to find where SHMOOSE is translated.
Experiment: Loss of function of the endogenous peptide, e.g. base editing of the start codon or an internal stop in cybrid or mtDNA-edited cells, choosing edits silent for MT-TS2/MT-TL2 and MT-ND5, followed by respirometry and cristae imaging.
Experiment: Cybrid lines that differ only at m.12372 (D47N), to separate the variant from its haplogroup background.
Experiment: Protease-protection and immuno-EM localisation of endogenous SHMOOSE, with co-IP of the endogenous peptide and MICOS subunits (MIC60, MIC19, MIC10).
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