CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance

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dc.citation.articleNumbere2405123121
dc.citation.issueNumber22
dc.citation.journalTitleProceedings of the National Academy of Sciences
dc.citation.volumeNumber121
dc.contributor.authorNechushtai, Rachel
dc.contributor.authorRowland, Linda
dc.contributor.authorKarmi, Ola
dc.contributor.authorMarjault, Henri-Baptiste
dc.contributor.authorNguyen, Thi Thao
dc.contributor.authorMittal, Shubham
dc.contributor.authorAhmed, Raheel S.
dc.contributor.authorGrant, DeAna
dc.contributor.authorManrique-Acevedo, Camila
dc.contributor.authorMorcos, Faruck
dc.contributor.authorOnuchic, José N.
dc.contributor.authorMittler, Ron
dc.contributor.orgCenter for Theoretical Biological Physics
dc.date.accessioned2024-08-02T13:32:10Z
dc.date.available2024-08-02T13:32:10Z
dc.date.issued2024
dc.description.abstractMitochondria play a central role in muscle metabolism and function. A unique family of iron–sulfur proteins, termed CDGSH Iron Sulfur Domain-containing (CISD/NEET) proteins, support mitochondrial function in skeletal muscles. The abundance of these proteins declines during aging leading to muscle degeneration. Although the function of the outer mitochondrial CISD/NEET proteins, CISD1/mitoNEET and CISD2/NAF-1, has been defined in skeletal muscle cells, the role of the inner mitochondrial CISD protein, CISD3/MiNT, is currently unknown. Here, we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne muscular dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscles, as well as their mitochondria, and that CISD3 interacts with, and donates its [2Fe-2S] clusters to, complex I respiratory chain subunit NADH Ubiquinone Oxidoreductase Core Subunit V2 (NDUFV2). Using coevolutionary and structural computational tools, we model a CISD3–NDUFV2 complex with proximal coevolving residue interactions conducive of [2Fe-2S] cluster transfer reactions, placing the clusters of the two proteins 10 to 16 Å apart. Taken together, our findings reveal that CISD3/MiNT is important for supporting the biogenesis and function of complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact different muscle degeneration syndromes, aging, and related conditions.
dc.identifier.citationNechushtai, R., Rowland, L., Karmi, O., Marjault, H.-B., Nguyen, T. T., Mittal, S., Ahmed, R. S., Grant, D., Manrique-Acevedo, C., Morcos, F., Onuchic, J. N., & Mittler, R. (2024). CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance. Proceedings of the National Academy of Sciences, 121(22), e2405123121. https://doi.org/10.1073/pnas.2405123121
dc.identifier.digitalnechushtai-et-al-2024
dc.identifier.doihttps://doi.org/10.1073/pnas.2405123121
dc.identifier.urihttps://hdl.handle.net/1911/117577
dc.language.isoeng
dc.publisherNational Academy of Sciences
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) license.  Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleCISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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