Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming
Abstract Background Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusio...
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BMC
2025-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03372-0 |
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| author | Su Jung Park Claudia Cerella Jin Mo Kang Jinyoung Byun David Kum Barbora Orlikova-Boyer Anne Lorant Michael Schnekenburger Ali Al-Mourabit Christo Christov Juyong Lee Byung Woo Han Marc Diederich |
| author_facet | Su Jung Park Claudia Cerella Jin Mo Kang Jinyoung Byun David Kum Barbora Orlikova-Boyer Anne Lorant Michael Schnekenburger Ali Al-Mourabit Christo Christov Juyong Lee Byung Woo Han Marc Diederich |
| author_sort | Su Jung Park |
| collection | DOAJ |
| description | Abstract Background Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis. Method This study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis. Additionally, metabolic profiling was conducted to analyze changes in metabolic pathways. Results TMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism along with changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells. Conclusion TMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies and provides a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML. Graphical Abstract |
| format | Article |
| id | doaj-art-aae2c1b44e94465488ff2841c9e01a31 |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-aae2c1b44e94465488ff2841c9e01a312025-08-20T02:17:13ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-04-0144112810.1186/s13046-025-03372-0Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogrammingSu Jung Park0Claudia Cerella1Jin Mo Kang2Jinyoung Byun3David Kum4Barbora Orlikova-Boyer5Anne Lorant6Michael Schnekenburger7Ali Al-Mourabit8Christo Christov9Juyong Lee10Byung Woo Han11Marc Diederich12Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National UniversityLaboratoire de Biologie Moléculaire du CancerResearch Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National UniversityCollege of Pharmacy, Seoul National UniversityResearch Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National UniversityLaboratoire de Biologie Moléculaire du CancerLaboratoire de Biologie Moléculaire du CancerLaboratoire de Biologie Moléculaire du CancerCNRS, Institut de Chimie des Substances Naturelles, Université Paris-SaclayService d’Histologie, Faculté de Médicine, Université de Lorraine, and INSERM U1256 NGERECollege of Pharmacy, Seoul National UniversityResearch Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National UniversityResearch Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National UniversityAbstract Background Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis. Method This study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis. Additionally, metabolic profiling was conducted to analyze changes in metabolic pathways. Results TMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism along with changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells. Conclusion TMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies and provides a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML. Graphical Abstracthttps://doi.org/10.1186/s13046-025-03372-0Metabolic reprogrammingOXPHOSGlycolysisDrug resistanceMonocytic myeloid leukemiaGlutathione |
| spellingShingle | Su Jung Park Claudia Cerella Jin Mo Kang Jinyoung Byun David Kum Barbora Orlikova-Boyer Anne Lorant Michael Schnekenburger Ali Al-Mourabit Christo Christov Juyong Lee Byung Woo Han Marc Diederich Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming Journal of Experimental & Clinical Cancer Research Metabolic reprogramming OXPHOS Glycolysis Drug resistance Monocytic myeloid leukemia Glutathione |
| title | Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming |
| title_full | Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming |
| title_fullStr | Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming |
| title_full_unstemmed | Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming |
| title_short | Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming |
| title_sort | tetrahydrobenzimidazole tmq0153 targets opa1 and restores drug sensitivity in aml via ros induced mitochondrial metabolic reprogramming |
| topic | Metabolic reprogramming OXPHOS Glycolysis Drug resistance Monocytic myeloid leukemia Glutathione |
| url | https://doi.org/10.1186/s13046-025-03372-0 |
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