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

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dc.citation.articleNumbere2405123121en_US
dc.citation.issueNumber22en_US
dc.citation.journalTitleProceedings of the National Academy of Sciencesen_US
dc.citation.volumeNumber121en_US
dc.contributor.authorNechushtai, Rachelen_US
dc.contributor.authorRowland, Lindaen_US
dc.contributor.authorKarmi, Olaen_US
dc.contributor.authorMarjault, Henri-Baptisteen_US
dc.contributor.authorNguyen, Thi Thaoen_US
dc.contributor.authorMittal, Shubhamen_US
dc.contributor.authorAhmed, Raheel S.en_US
dc.contributor.authorGrant, DeAnaen_US
dc.contributor.authorManrique-Acevedo, Camilaen_US
dc.contributor.authorMorcos, Farucken_US
dc.contributor.authorOnuchic, José N.en_US
dc.contributor.authorMittler, Ronen_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2024-08-02T13:32:10Zen_US
dc.date.available2024-08-02T13:32:10Zen_US
dc.date.issued2024en_US
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.en_US
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.2405123121en_US
dc.identifier.digitalnechushtai-et-al-2024en_US
dc.identifier.doihttps://doi.org/10.1073/pnas.2405123121en_US
dc.identifier.urihttps://hdl.handle.net/1911/117577en_US
dc.language.isoengen_US
dc.publisherNational Academy of Sciencesen_US
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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.titleCISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenanceen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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