MRPS18C

MRPS18C encodes bS18m, a protein of the mitochondrial small ribosomal subunit that is required for mitoribosome assembly, mitochondrial translation, and the energy supply that sustains cellular and developmental programs (PMID:32376682, PMID:39675708). Mechanistically, bS18m coordinates one of three [2Fe-2S] clusters of the human mitoribosomal small subunit through bridging cysteine residues shared with a second mitoribosomal protein; cysteine-exchange mutations that ablate this cluster, like depletion of bS18m itself, destabilize the mitoribosome, impair mitochondrial translation, reduce respiratory chain complex activity, and disrupt mitochondrial morphology with loss of cristae (PMID:39675708). Consistent with this role in oxidative energy production, loss of Mrps18c in mouse embryos lowers ATP production, distorts organelle morphology, and stalls cells at the G2/M checkpoint, blocking gastrulation despite successful implantation (PMID:32376682). Overexpression of MRPS18C suppresses the complex I defect and excess ROS caused by the m.3946G>A mutation in MT-ND1 in patient fibroblasts, identifying it as a positive modifier of this mtDNA mutation (PMID:28526948).

1. 2017 Medium

   Whether mitoribosomal protein dosage could compensate for primary mtDNA-encoded respiratory chain defects was unknown; this work showed MRPS18C overexpression rescues a complex I mutation, establishing it as a functional modifier of mitochondrial energy metabolism.

   Evidence Functional complementation by episomal cDNA library transfection with metabolic selection in respiratory-deficient patient fibroblasts, scored by complex I activity and ROS

   PMID:28526948

   Open questions at the time

   • Mechanism by which increased bS18m suppresses the MT-ND1 defect not defined
   • Single mutation context; generality to other mtDNA mutations untested
   • No structural or biochemical link to mitoribosome established here
2. 2020 High

   The in vivo physiological requirement for MRPS18C was unknown; embryonic knockout demonstrated it is essential for mitochondrial energy supply at the pre-gastrulation stage, linking mitoribosome function to early developmental checkpoint control.

   Evidence Null knockout mouse embryo analysis with ATP assay, organelle morphology, and G2/M checkpoint markers

   PMID:32376682

   Open questions at the time

   • Molecular mechanism linking reduced ATP to G2/M arrest not resolved
   • Does not define bS18m's biochemical role within the mitoribosome
   • Tissue-specific or postnatal roles not addressed
3. 2024 High

   The molecular basis of bS18m function within the mitoribosome was unknown; structure-guided mutagenesis showed it coordinates a [2Fe-2S] cluster via shared cysteines required for mitoribosome assembly, stability, and translation.

   Evidence siRNA depletion with wild-type versus cysteine-exchange mutant complementation, assessing mitoribosome assembly/stability, mitochondrial translation, respiratory complex activity, and morphology

   PMID:39675708

   Open questions at the time

   • Identity and source of the Fe-S cluster delivery machinery not defined
   • How cluster loss propagates to cristae morphology not mechanistically resolved
   • The partner mitoribosomal protein sharing bridging cysteines not characterized in detail

• How bS18m's [2Fe-2S] cluster integrates iron-sulfur biogenesis with mitoribosome assembly, and whether this links to its suppressor activity on mtDNA mutations, remains open.
• No mechanistic bridge between the 2017 suppressor phenotype and the 2024 Fe-S cluster role
• Assembly intermediates and cluster insertion timing unknown
• Human disease association from loss-of-function variants not established in the corpus