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Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells

ABSTRACT: Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells

PROVIDER: PRJNA511981 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8374240.fastq.gz	Fastqsanger.gz
	SRR8374241.fastq.gz	Fastqsanger.gz
	SRR8374242.fastq.gz	Fastqsanger.gz
	SRR8374233.fastq.gz	Fastqsanger.gz
	SRR8374243.fastq.gz	Fastqsanger.gz

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Project 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. The 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, reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis were examined. Additionally, metabolic profiling was conducted to analyze the 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, alongside 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, providing a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML

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Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells

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