1. Academic Validation
  2. Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming

Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming

  • J Exp Clin Cancer Res. 2025 Apr 7;44(1):114. doi: 10.1186/s13046-025-03372-0.
Su Jung Park 1 Claudia Cerella 2 3 Jin Mo Kang 1 Jinyoung Byun 4 David Kum 1 Barbora Orlikova-Boyer 2 3 Anne Lorant 2 5 Michael Schnekenburger 2 3 Ali Al-Mourabit 6 Christo Christov 7 Juyong Lee 4 8 Byung Woo Han 1 Marc Diederich 9
Affiliations

Affiliations

  • 1 Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2 Laboratoire de Biologie Moléculaire du Cancer, BAM3 Pavillon 2, 6A Rue Nicolas-Ernest Barblé, L-1210, Luxembourg, Luxembourg.
  • 3 Present address: Department of Cancer Research, Luxembourg Institute of Health (LIH), BAM Pavillon 2, 6A Rue Nicolas-Ernest Barblé, L-1210, Luxembourg, Luxembourg.
  • 4 College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 5 Present address: Luxembourg Centre for Systems Biomedicine, Bioinformatics Core, Roudeneck, 1, Boulevard du Jazz, Esch-sur-Alzette, L-4370, Luxembourg.
  • 6 CNRS, Institut de Chimie des Substances Naturelles, Université Paris-Saclay, Gif-Sur-Yvette, 91190, France.
  • 7 Service d'Histologie, Faculté de Médicine, Université de Lorraine, and INSERM U1256 NGERE, 54000, Nancy, France.
  • 8 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Medicine, Seoul National University, 1 Gwanak-Ro, Gwanak-Gu, Seoul, 08826, Korea.
  • 9 Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. marcdiederich@snu.ac.kr.
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.

Keywords

Drug resistance; Glutathione; Glycolysis; Metabolic reprogramming; Monocytic myeloid leukemia; OXPHOS.

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