MRPS31

MRPS31 (mS31) is a structural protein of the mitochondrial small ribosomal subunit that links mitoribosome assembly to mitochondrial mRNA delivery during translation (PMID:39134711). Cryo-EM of the LRPPRC–SLIRP–mRNA–mitoribosome complex shows that the N-terminus of mS31 is directly recognized by the LRPPRC helical repeats, together with mS39, forming a corridor that hands off mitochondrial mRNA to the small subunit (PMID:39134711). Consistent with this structural role, loss of MRPS31 disrupts assembly of the whole mitoribosome and impairs mitochondrial protein homeostasis: depletion in hepatoma cells blocks mitoribosome assembly (PMID:34772924), and a missense mutation in the C. elegans ortholog activates the mitochondrial unfolded protein response and impairs development (PMID:39410965). In hepatocellular carcinoma, MRPS31 loss enhances cell invasiveness by augmenting MMP7 and COL1A1 expression, with COL1A1 driving invasiveness through ZEB1-mediated epithelial-to-mesenchymal transition (PMID:34772924). Beyond its role in mitoribosomal assembly and mRNA handoff, no additional catalytic or regulatory mechanism for MRPS31 has been characterized in the available corpus.

1. 2021 Medium

   Whether MRPS31 is functionally required for mitoribosome assembly—and whether its loss has cellular consequences in cancer—was unresolved; this established MRPS31 as essential for mitoribosome assembly and as a modulator of tumor cell invasiveness.

   Evidence Loss-of-function (KO/KD) in hepatoma cell lines with SCNA-dependent MRPS31 expression, mitoribosome assembly assays, invasion and gene-expression analysis

   PMID:34772924

   Open questions at the time

   • Mechanism linking mitoribosome disruption to upregulation of MMP7/COL1A1 not defined
   • Direct structural role of MRPS31 in the ribosome not addressed
   • Single-lab cellular system
2. 2021 Low

   The physical interaction partners of MRPS31 outside the mitoribosome were unknown; a pulldown screen catalogued putative interactions and noted overexpression in breast cancer, hinting at broader cellular associations.

   Evidence GST-pulldown of recombinant GST-MRPS31 from HEK293 lysate with nLC/MS/MS, plus cancer cell line expression screening

   PMID:34492114

   Open questions at the time

   • Single GST pulldown without functional validation of any MRPS31-specific interaction
   • Putative roles (e.g., fatty acid oxidation) inferred from network analysis, not tested
   • No reciprocal validation
3. 2024 High

   How MRPS31 connects to mitochondrial mRNA delivery at the structural level was unknown; cryo-EM established direct contact between the mS31 N-terminus and LRPPRC, defining a corridor for mRNA handoff to the mitoribosome.

   Evidence Cryo-EM of the LRPPRC-SLIRP-mRNA-mitoribosome complex with RNA-seq, metabolic labeling, and mitoribosome profiling

   PMID:39134711

   Open questions at the time

   • Functional contribution of the mS31 N-terminus to mRNA handoff not isolated by mutagenesis
   • Dynamics/kinetics of the handoff not resolved
   • Conservation of the interface across species not addressed
4. 2024 Medium

   Whether MRPS31 function and its requirement for mitochondrial proteostasis are conserved in a whole organism was untested; an ortholog mutant established that MRPS-31 is required for normal mitoribosome function and triggers UPRmt when lost.

   Evidence Forward genetic screen and complementation in C. elegans, UPRmt reporter assays, developmental phenotyping

   PMID:39410965

   Open questions at the time

   • Molecular step in mitoribosome function disrupted by the missense allele not defined
   • Link between UPRmt and developmental defects not mechanistically dissected

• How MRPS31 deficiency mechanistically couples mitoribosome/mitochondrial stress to the EMT and invasion program (MMP7, COL1A1, ZEB1) remains unresolved.
• Signaling pathway from mitoribosome disruption to ZEB1-mediated EMT undefined
• Whether the invasion phenotype is mitochondria-dependent untested