Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration
Open accessAbstract
Background: Colorectal cancer (CRC) can be classified into four molecular subtypes (CMS) among which CMS1 is associated with the best prognosis, while CMS4, the mesenchymal subtype, has the worst outcome. Although mitochondria are considered to be hubs of numerous signaling pathways, the study of mitochondrial metabolism has been neglected for many years. Mitochondrial Complex I (CI) plays a dual role, both in energy and reactive oxygen species (ROS) production. However, the possible contribution of CI to tumorigenesis in cancer remains unclear. The purpose of this study was to investigate the CI under the prism of the CMS classification of CRC in ex vivo models. Methods: Biochemical dosages, bioenergetics analysis and western-blot were used to characterize CI expression, function and redox balance in LoVo and MDST8 cell lines, belonging to CMS1 and CMS4 subgroups, respectively. Cell proliferation and migration were assessed by xCELLigence technology. Overproduction or scavenging of mitochondrial ROS (mtROS) were performed to analyze the effect of mtROS on proliferation, migration, and mesenchymal markers. Focal adhesion kinase (FAK) and its activation were analyzed by immunofluorescence. We assessed the distribution of two CI scores in CRC cohorts according to CMS classification and their relevance for patient survival. Results: We found that CI is downregulated in CMS4 cells and is associated with elevated mtROS. We establish for the first time that in these migrating cells, mtROS production is maintained at optimal levels not only through changes in CI activity but also by inactivation/acetylation of superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. We show that promoting or scavenging mtROS both mitigate CMS4 cells’ migration. Our results also point to a mtROS-mediated focal adhesion kinase (FAK) activation, which likely sustains their migratory phenotype. Using cohorts of CRC patients, we document that the expression of CI is downregulated in the CMS4 subgroup, and that low CI expression is associated with poor prognosis. Patients’ datasets reveal an inverse correlation between CI and the epithelial-mesenchymal transition (EMT) pathway. Conclusion: We showed that inhibition of CI contributes to heighten mtROS, which likely foster MDST8 migration and might account for the specific EMT signature of CMS4 tumors. These data reveal a novel role of mitochondrial CI in CRC, with biological consequences that may be targeted with anti- or pro-oxidant drugs in clinical practice.
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Elevated AKT3 and KIT, reduced mitochondrial respiratory complex I activity, and modified alternative splicing landscape are biological hallmarks of CMS4.
“Among other biological hallmarks of this subtype shown to contribute to CMS4 traits feature elevated AKT3 (42) and KIT (43), reduced mitochondrial respiratory complex I activity (44)—possibly resulting from KIT overexpression (43)—or modified alternative splicing landscape (45).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [44]
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Mouillet-Richard, S., Cazelles, A., Sroussi, M., Gallois, C., Taieb, J., & Laurent-Puig, P. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-3964 · Cited by 43 · see citing works
Self-citation
- Authors
- Bastin, J., Sroussi, M., Nemazanyy, I., Laurent-Puig, P., Mouillet-Richard, S., & Djouadi, F.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Djouadi, Fatima
- Venue
- Journal of Translational Medicine
- Published
- 2023-08-03
- Volume
- 21
- Issue
- 1
- Pages
- 522-522
- ISSN
- 1479-5876 (ISSN-L)
- PMC
- PMC10398918
- OpenAlex
- W4385514801
- Cited by
- 24
- References
- 43
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 5 · 2023: 2
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Translational Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Inserm
- SIRIC-Carpem (grant 2020 “Emergence, Innovation”)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- colorectal cancer, mitochondrial complex I, reactive oxygen species, molecular subtypes, cell migration, epithelial-mesenchymal transition, SOD2 acetylation, manganese superoxide dismutase, focal adhesion kinase, mitochondrial metabolism, cancer prognosis, LoVo cells, redox homeostasis, patient survival, oxidative stress
- MeSH terms
- Humans, Colorectal Neoplasms, Signal Transduction, Down-Regulation, Reactive Oxygen Species, Focal Adhesion Protein-Tyrosine Kinases
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