METTL17 is an Fe-S cluster checkpoint for mitochondrial translation
Open accessPublished version of a preprint
Abstract
A bstract 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 [Fe 4 S 4 ] 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.
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- Authors
- Ast, T., Itoh, Y., Sadre, S., McCoy, J. G., Namkoong, G., Wengrod, J. C., Chicherin, I., Joshi, P. R., Kamenski, P., Suess, D. L. M., Amunts, A., & Mootha, V. K.
- Affiliations
- Broad Institute (US)
- Stockholm University (SE)
- Massachusetts Institute of Technology (US)
- Lomonosov Moscow State University (RU)
- Corresponding author
- Mootha, Vamsi K.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2024-01
- Volume
- 84
- Issue
- 2
- Pages
- 359-374.e8
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC11046306
- OpenAlex
- W4390736168
- Cited by
- 58
- References
- 7
- Citations by year
- 2026: 14 · 2025: 24 · 2024: 17 · 2023: 3
- FWCI
- 7.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (GM141203, H2020-MSCA-IF-2017, 799399-Itohribo, P30-ES002109)
- Russian Science Foundation
- European Research Council (ERC-2018-StG-805230)
- European Commission Marie Sklodowska-Curie Actions (H2020-MSCA-IF-2017)
- Russell Sage Foundation (P30-ES002109, 21-14-00008)
- Knut and Alice Wallenberg Foundation (2018.0080)
- National Institute of Environmental Health Sciences
- Friedreichs Ataxia Research Alliance
- Kempe Foundation
- National Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- Friedreich's ataxia, frataxin, iron-sulfur cluster assembly, mitochondrial translation, mitochondrial ribosome, protein stability, oxidative phosphorylation
- MeSH terms
- Frataxin, Friedreich Ataxia, Humans, Iron-Sulfur Proteins, Methyltransferases, Mitochondria, Protein Biosynthesis, Cryoelectron Microscopy
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