RT Journal Article
SR Electronic
T1 METTL17 is an Fe-S cluster checkpoint for mitochondrial translation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.24.517765
DO 10.1101/2022.11.24.517765
A1 Tslil Ast
A1 Yuzuru Itoh
A1 Shayan Sadre
A1 Jason G. McCoy
A1 Gil Namkoong
A1 Ivan Chicherin
A1 Pallavi R. Joshi
A1 Piotr Kamenski
A1 Daniel L. M. Suess
A1 Alexey Amunts
A1 Vamsi K. Mootha
YR 2022
UL http://biorxiv.org/content/early/2022/11/24/2022.11.24.517765.abstract
AB Friedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed quantitative proteome profiling of human cells depleted for FXN. Nearly every known Fe-S cluster-containing protein was depleted in the absence of FXN, indicating that as a rule, cluster binding confers stability to Fe-S proteins. Proteomic and genetic interaction mapping identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector. Using comparative sequence analysis, mutagenesis, biochemistry and cryogenic electron 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 on the mitoribosome. Notably, METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN null cells. Our data suggest that METTL17 serves as an Fe-S cluster checkpoint: promoting the translation and assembly of Fe-S cluster rich OXPHOS proteins only when Fe-S cluster levels are replete.Competing Interest StatementVKM is on the scientific advisory boards of Janssen Pharmaceuticals and 5AM Ventures. TA and VKM are listed as inventors on a patent application filed by The Broad Institute on the use of METTL17 as a therapy.