Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration
Abstract 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 stu...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04341-x |
| _version_ | 1797752597121073152 |
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| author | Jean Bastin Marine Sroussi Ivan Nemazanyy Pierre Laurent-Puig Sophie Mouillet-Richard Fatima Djouadi |
| author_facet | Jean Bastin Marine Sroussi Ivan Nemazanyy Pierre Laurent-Puig Sophie Mouillet-Richard Fatima Djouadi |
| author_sort | Jean Bastin |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-12T17:06:43Z |
| format | Article |
| id | doaj.art-08da4395fe2b4e27ba67cb17740e7c9b |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-12T17:06:43Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-08da4395fe2b4e27ba67cb17740e7c9b2023-08-06T11:23:31ZengBMCJournal of Translational Medicine1479-58762023-08-0121111610.1186/s12967-023-04341-xDownregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migrationJean Bastin0Marine Sroussi1Ivan Nemazanyy2Pierre Laurent-Puig3Sophie Mouillet-Richard4Fatima Djouadi5Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris-CitéCentre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris-CitéPlate Plateforme d’étude du Métabolisme, SFR Necker, INSERM US24/CNRS UAR3633Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris-CitéCentre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris-CitéCentre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris-CitéAbstract 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.https://doi.org/10.1186/s12967-023-04341-xColorectal cancerMitochondriaComplex IReactive oxygen speciesSOD2Consensus Molecular Subtypes (CMS) |
| spellingShingle | Jean Bastin Marine Sroussi Ivan Nemazanyy Pierre Laurent-Puig Sophie Mouillet-Richard Fatima Djouadi Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration Journal of Translational Medicine Colorectal cancer Mitochondria Complex I Reactive oxygen species SOD2 Consensus Molecular Subtypes (CMS) |
| title | Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration |
| title_full | Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration |
| title_fullStr | Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration |
| title_full_unstemmed | Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration |
| title_short | Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration |
| title_sort | downregulation of mitochondrial complex i induces ros production in colorectal cancer subtypes that differently controls migration |
| topic | Colorectal cancer Mitochondria Complex I Reactive oxygen species SOD2 Consensus Molecular Subtypes (CMS) |
| url | https://doi.org/10.1186/s12967-023-04341-x |
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