Abstract
The mitochondrial electron transport chain (ETC) is a four complex unit that could be considered the most essential infrastructure within the mitochondria, as it primarily functions to generate the mitochondrial membrane potential (ΔΨm), which can then be utilized for ATP synthesis or heat production. Another important aspect of ETC function is the generation of mitochondrial reactive oxygen species (mtROS), which are essential physiologic signaling mediators that can be toxic to the cell if their levels become too high. Currently, it remains unresolved how a highly utilized and functioning ETC can sense excessive mtROS generation and adapt, to enhance ΔΨm. Here, we identified a redox hub consisting of cysteine (Cys) residues 64, 75, 78, and 92 within Ndufs1 of complex I of the ETC. Oxidation of these Cys residues promotes the incorporation of complex I into the respirasome super complex. Mechanistically, oxidation of the redox hub increased the distance between Fe-S clusters N5 and N6a in complex I, compromising complex I activity. This impairment was rescued by integration with complex III2 and IV into the respirasome super complex. Compared to parental cells or Ndufs1-KO cells, C92D (an oxidation mimetic) Ndufs1-knockin A549 cells had higher levels of ETC super complexes, ΔΨm and oxygen consumption rates, while isolated mitochondrial membranes generated more electrical current when integrated onto a biobattery platform. Disruption of ETC super complexes with MitoTam increased the therapeutic efficacy of mtROS inducing chemotherapeutics in both C92D Ndufs1-knockin or metastatic lung cancer cells. These findings provide new insights into how the ETC can initiate super complex transformation.
Recommended Citation
R. Chen and S. A. Tabatabaei Dakhili and R. Gerulskis and Y. Y. Zhao and S. Lockhart and L. Tonoyan and A. G. Siraki and G. Huang and A. Kinnaird and D. H. Freed and S. D. Minteer and E. D. Michelakis and J. R. Ussher, "Cysteine Oxidation of a Redox Hub within Complex I Can Facilitate Electron Transport Chain Supercomplex Formation," Journal of Biological Chemistry, vol. 301, no. 9, article no. 110555, Elsevier; American Society for Biochemistry and Molecular Biology, Sep 2025.
The definitive version is available at https://doi.org/10.1016/j.jbc.2025.110555
Department(s)
Chemistry
Publication Status
Open Access
Keywords and Phrases
cancer resistance; cysteine oxidation; electron transport chain; mitochondria; reactive oxygen species; redox; respirasome; supercomplex
International Standard Serial Number (ISSN)
1083-351X; 0021-9258
Document Type
Article - Journal
Document Version
Final Version
File Type
text
Language(s)
English
Rights
© 2025 Elsevier; American Society for Biochemistry and Molecular Biology, All rights reserved.
Creative Commons Licensing
This work is licensed under a Creative Commons Attribution 4.0 License.
Publication Date
01 Sep 2025
PubMed ID
40752580
Comments
China Scholarship Council, Grant 2154206/2406605