METTL17 is an Fe-S cluster checkpoint for mitochondrial translation

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. [Display omitted] •The Fe-S proteome is destabilized when the synthesis of its cofactor is impaired•METTL17, a mitoribosome assembly factor, is depleted without Fe-S cluster biosynthesis•METTL17 binds a previously unrecognized [4Fe4S]2+ cluster•Overexpression of METTL17 rescues the bioenergetic defects of frataxin null cells Ast et al. examine the cellular consequences of frataxin deficiency, modeling Friedreich’s ataxia. They discover a decrease in METTL17, an essential mitoribosome assembly factor. They show that METTL17 binds a Fe-S cluster, which is critical for its stability. Overexpression of METTL17 rectifies the bioenergetic deficits of Friedreich’s ataxia.