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ROS production by mitochondria: function or dysfunction?

Oncogene volume 43, pages 295–303 (2024)Cite this article

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Abstract

In eukaryotic cells, ATP generation is generally viewed as the primary function of mitochondria under normoxic conditions. Reactive oxygen species (ROS), in contrast, are regarded as the by-products of respiration, and are widely associated with dysfunction and disease. Important signaling functions have been demonstrated for mitochondrial ROS in recent years. Still, their chemical reactivity and capacity to elicit oxidative damage have reinforced the idea that ROS are the products of dysfunctional mitochondria that accumulate during disease. Several studies support a different model, however, by showing that: (1) limited oxygen availability results in mitochondria prioritizing ROS production over ATP, (2) ROS is an essential adaptive mitochondrial signal triggered by various important stressors, and (3) while mitochondria-independent ATP production can be easily engaged by most cells, there is no known replacement for ROS-driven redox signaling. Based on these observations and other evidence reviewed here, we highlight the role of ROS production as a major mitochondrial function involved in cellular adaptation and stress resistance. As such, we propose a rekindled view of ROS production as a primary mitochondrial function as essential to life as ATP production itself.

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Fig. 1: Schematic representation of the mitochondrial electron transport chain featuring complexes (I – IV) and electron carriers.
Fig. 2: ROS driven mechanism of DNA mutation.
Fig. 3: Mechanisms of HIF1/2α degradation and stabilization.
Fig. 4: Examples of ROS driven activation of anti-apoptotic signaling cascades.
Fig. 5: Examples of mitochondrial ROS-driven mechanisms of stem/progenitor cell differentiation.
Fig. 6: Mitochondrial ROS-driven chromatin remodeling.

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Acknowledgements

The authors are grateful for financial support from the U.S. National Cancer Institute (R01CA216882 to MGB), National Institute of Environmental Health Sciences (R01ES028149 and R56ES033398 to MGB), National Heart Lung and Blood Institute (R01HL163820 to MGB and BGN) and National Cancer Institute (P30CA06553, Cancer Center Support Grant). We are also grateful for support from the H Foundation, the Eric and Liz Lefkofsky Foundation and the Associate Board of the Lurie Cancer Center.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Northwestern University, Chicago, IL, USA

    Flavio R. Palma, Marcelo J. Sakiyama & Marcelo G. Bonini

  2. Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    Benjamin N. Gantner

  3. Department of Pharmacology, Ribeirao Preto College of Nursing, University of Sao Paulo, Sao Paulo, Brazil

    Cezar Kayzuka

  4. Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, India

    Sanjeev Shukla

  5. Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Sao Paulo, Brazil

    Riccardo Lacchini

  6. Department of Pathology and Laboratory Medicine, Larner School of Medicine, University of Vermont, Burlington, VT, USA

    Brian Cunniff

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  1. Flavio R. Palma
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  8. Marcelo G. Bonini
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Contributions

FRP, BNG, MJS, and BC wrote and edited the manuscript. FRP, MJS, and CK produced the figures and illustrations. SS and RL contributed text and references, critically reviewed and edited the manuscript. All authors discussed the ideas and searched the literature for relevant publications supporting the concepts reviewed in this manuscript.

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Correspondence to Marcelo G. Bonini.

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Competing interests

BC has a financial interest (research support, equity and consultant fees) in RS Oncology, a clinical stage biotechnology company developing therapies targeting mitochondrial activity and redox signaling in cancer.

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Palma, F.R., Gantner, B.N., Sakiyama, M.J. et al. ROS production by mitochondria: function or dysfunction?. Oncogene 43, 295–303 (2024). https://doi.org/10.1038/s41388-023-02907-z

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