MRPS15

MRPS15 (uS15m) is a small-subunit mitoribosomal protein required for mitochondrial translation and the downstream assembly of oxidative phosphorylation complexes (PMID:42162768, PMID:41648325). Loss of MRPS15 (with MRPS21) in cardiomyocytes inhibits mitochondrial translation, depolarizes the mitochondrial membrane potential, impairs respiration, reduces import of nuclear-encoded mitochondrial proteins, and triggers mitochondrial ROS associated with loss of glutaredoxin-2; its transcription is driven by the zinc-finger factor Zhx1, and MRPS15/MRPS21 act downstream of Zhx1 to confer cardioprotection in hypertensive heart disease (PMID:42162768). In C. elegans, a point mutation in the MRPS-15 ortholog suppresses LONP-1 deficiency by slowing mitochondrial translation and restoring OXPHOS complex assembly, identifying mitoribosomal translation rate as a tunable determinant of complex biogenesis (PMID:41648325). Beyond its canonical mitoribosomal role, MRPS15 is recruited to cytosolic polysomes during ER stress, where it interacts with cytosolic ribosomal proteins and activates IRES-dependent translation of unfolded protein response mRNAs, defining a stress-induced extra-mitochondrial function (PMID:38542224).

1. 2024 High

   Whether MRPS15 functions exclusively within mitoribosomes was unknown; this work established a stress-induced cytosolic role in selective translation, expanding the protein's functional repertoire beyond mitochondria.

   Evidence Mass spectrometry of translating ribosomes, proximity ligation assay, Co-IP, knockdown/overexpression and polysome profiling with anti-MRPS15 IP in stressed human cardiomyocytes

   PMID:38542224

   Open questions at the time

   • Mechanism by which MRPS15 relocalizes to cytosolic polysomes is undefined
   • How MRPS15 selects or activates IRES-containing UPR mRNAs molecularly is not resolved
   • No structural model of an MRPS15-containing cytosolic ribosome
2. 2026 Medium

   The mitochondrial consequences of MRPS15 loss and its transcriptional control were unknown; knockdown/rescue and epistasis placed MRPS15 as a Zhx1-driven effector required for mitochondrial translation, respiration and protein import in cardiac protection.

   Evidence Knockdown/overexpression in cardiomyocytes, membrane potential and respiration assays, hypertensive heart disease mouse model, Zhx1 activator and combined Mrps15/Mrps21 silencing epistasis

   PMID:42162768

   Open questions at the time

   • Separable contributions of MRPS15 versus MRPS21 not dissected
   • No in vitro reconstitution or structural data for the mitoribosomal role
   • Direct binding of Zhx1 to the MRPS15 promoter not demonstrated within the timeline
3. 2026 Medium

   Whether mitoribosomal translation rate gates OXPHOS assembly was untested; a suppressor mutation in MRPS-15 that slows translation and restores OXPHOS in LONP-1-deficient worms identified translation speed as a modulator of complex biogenesis.

   Evidence Forward genetic suppressor screen in C. elegans lonp-1 mutants with OXPHOS restoration measurements (preprint)

   PMID:41648325

   Open questions at the time

   • Preprint, not yet peer-reviewed
   • Mechanism linking slowed translation to improved assembly is inferred, not directly shown
   • Relevance of the suppressor mechanism to human MRPS15 not established

• How a single protein partitions between mitoribosomal and cytosolic-polysome pools, and what governs that switch under stress, remains unresolved.
• Signals and trafficking controlling cytosolic relocalization are unknown
• Whether the cytosolic and mitochondrial functions share a structural basis is unknown