Friedreich's ataxia (FA) is a debilitating, multisystemic disease caused by the depletion of frataxin (FXN), a mitochondrial iron-sulfur (Fe-S) cluster biogenesis factor. To understand the cellular pathogenesis of FA, we performed quantitative proteomics in FXN-deficient human cells. Nearly every annotated Fe-S cluster-containing protein was depleted, indicating that as a rule, cluster binding confers stability to Fe-S proteins. We also observed depletion of a small mitoribosomal assembly factor METTL17 and evidence of impaired mitochondrial translation. Using comparative sequence analysis, mutagenesis, biochemistry, and cryoelectron microscopy, we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe4S4]2+ cluster required for its stability. METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN-depleted cells. These findings suggest that METTL17 acts as an Fe-S cluster checkpoint, promoting translation of Fe-S cluster-rich oxidative phosphorylation (OXPHOS) proteins only when Fe-S cofactors are replete.
Pubmed ID: 38199006 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This monoclonal targets OXPHOS
View all literature mentionsThis polyclonal targets METT11D1
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis polyclonal secondary targets IgG
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis monoclonal targets beta-Tubulin
View all literature mentionsThis monoclonal targets beta Tubulin Loading Control
View all literature mentionsThis polyclonal targets POLD1
View all literature mentionsThis monoclonal targets NFS1 (B-7)
View all literature mentionsThis polyclonal targets Lyrm4 (LYR motif containing 4) (against the middle region of Lyrm4)(50ug)
View all literature mentionsThis monoclonal targets IscU1/2 (D-6)
View all literature mentionsThis monoclonal targets Hsp60
View all literature mentionsThis monoclonal targets FLAG
View all literature mentionsThis polyclonal targets DYKDDDK
View all literature mentionsThis polyclonal targets CDK5RAP1
View all literature mentionsThis monoclonal targets Actin antibody produced in mouse
View all literature mentions