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Diverse functions of cytochrome c in cell death and disease

Cell Death & Differentiation volume 31, pages 387–404 (2024)Cite this article

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Abstract

The redox-active protein cytochrome c is a highly positively charged hemoglobin that regulates cell fate decisions of life and death. Under normal physiological conditions, cytochrome c is localized in the mitochondrial intermembrane space, and its distribution can extend to the cytosol, nucleus, and extracellular space under specific pathological or stress-induced conditions. In the mitochondria, cytochrome c acts as an electron carrier in the electron transport chain, facilitating adenosine triphosphate synthesis, regulating cardiolipin peroxidation, and influencing reactive oxygen species dynamics. Upon cellular stress, it can be released into the cytosol, where it interacts with apoptotic peptidase activator 1 (APAF1) to form the apoptosome, initiating caspase-dependent apoptotic cell death. Additionally, following exposure to pro-apoptotic compounds, cytochrome c contributes to the survival of drug-tolerant persister cells. When translocated to the nucleus, it can induce chromatin condensation and disrupt nucleosome assembly. Upon its release into the extracellular space, cytochrome c may act as an immune mediator during cell death processes, highlighting its multifaceted role in cellular biology. In this review, we explore the diverse structural and functional aspects of cytochrome c in physiological and pathological responses. We summarize how posttranslational modifications of cytochrome c (e.g., phosphorylation, acetylation, tyrosine nitration, and oxidation), binding proteins (e.g., HIGD1A, CHCHD2, ITPR1, and nucleophosmin), and mutations (e.g., G41S, Y48H, and A51V) affect its function. Furthermore, we provide an overview of the latest advanced technologies utilized for detecting cytochrome c, along with potential therapeutic approaches related to this protein. These strategies hold tremendous promise in personalized health care, presenting opportunities for targeted interventions in a wide range of conditions, including neurodegenerative disorders, cardiovascular diseases, and cancer.

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Fig. 1: Timeline in cytochrome c research.
Fig. 2: The structure of human cytochrome c.
Fig. 3: The subcellular-dependent functions of cytochrome c.
Fig. 4: The functions of cytochrome c in apoptosis, pyroptosis, and the persister phenotype.
Fig. 5: Cytochrome c-associated human diseases, detection, and therapeutic strategies for engineering precision nanoparticles (NPs).

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Acknowledgements

We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the manuscript. We are thankful to Dr. Douglas Green (St. Jude Hospital) for his critical review and invaluable contributions to the manuscript.

Funding

Research by X.S. was partly supported by an American Cancer Society grant (IRG-21-142-16), Simmons Comprehensive Cancer Center support grant (P30CA142543), and the Elsa U. Pardee Foundation (project ID: 21005817). Research by D.T. and R.K. was supported by grants from the National Institutes of Health (NIH; R01CA160417, R01CA229275, and R01CA211070). Research by Y.L. was supported by the NIH (R01CA265827 and R21CA259243), and Department of Defense (RA210084). Research by M.H. was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program (HT94252410073), NIH (R01NS120322 and U44NS125160), the Michigan Prostate SPORE Developmental Research Program, the National Science Foundation (MCB-2329629), and the Michigan Translational Research and Commercialization (MTRAC) Award. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the funding agencies, including the Department of Defense and NIH.

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Authors and Affiliations

  1. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA

    Zhuan Zhou, Rui Kang, Daolin Tang & Xinxin Song

  2. Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA

    Tasnim Arroum & Maik Hüttemann

  3. Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Xu Luo

  4. Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA

    Yong J. Lee

  5. Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI, 48201, USA

    Maik Hüttemann

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Contributions

ZZ, DT, and XS were involved in the conceptualization. All authors contributed to writing the manuscript. DT, MH, and XS further edited, reviewed, and approved the final manuscript for submission.

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Correspondence to Daolin Tang, Maik Hüttemann or Xinxin Song.

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Zhou, Z., Arroum, T., Luo, X. et al. Diverse functions of cytochrome c in cell death and disease. Cell Death Differ 31, 387–404 (2024). https://doi.org/10.1038/s41418-024-01284-8

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