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

Rachel Nechushtai, Linda Rowland, Ola Karmi, Henri Baptiste Marjault, Thi Thao Nguyen, Shubham Mittal, Raheel S. Ahmed, De Ana Grant, Camila Manrique-Acevedo, Faruck Morcos, José N. Onuchic, Ron Mittler

Research output: Contribution to journalArticlepeer-review


Mitochondria 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.

Original languageAmerican English
Pages (from-to)e2405123121
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number22
StatePublished - 28 May 2024


  • complex I
  • Duchenne muscular dystrophy
  • mitochondria
  • NDUFV2
  • NEET/CISD proteins


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