Journal Article

DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma

Ji, Ning, Zhou, Yu, Wang, Zhen, Cai, Luyao, Li, Jing, Pan, Dan, Wang, Qing, Tang, Shouyi, Zhou, Hao, Zeng, Xin, Dong, Yunmei, Shen, Ying-qiang, Chen, Qianming

2024

Overview

Background Mitochondrial dynamics play a fundamental role in determining stem cell fate. However, the underlying mechanisms of mitochondrial dynamics in the stemness acquisition of cancer cells are incompletely understood. Methods Metabolomic profiling of cells were analyzed by MS/MS. The genomic distribution of H3K27me3 was measured by CUT&Tag. Oral squamous cell carcinoma (OSCC) cells depended on glucose or glutamine fueling TCA cycle were monitored by 13C-isotope tracing. Organoids and tumors from patients and mice were treated with DRP1 inhibitors mdivi-1, ferroptosis inducer erastin, or combination with mdivi-1 and erastin to evaluate treatment effects. Results Mitochondria of OSCC stem cells own fragment mitochondrial network and DRP1 is required for maintenance of their globular morphology. Imbalanced mitochondrial dynamics induced by DRP1 knockdown suppressed stemness of OSCC cells. Elongated mitochondria increased α-ketoglutarate levels and enhanced glutaminolysis to fuel the TCA cycle by increasing glutamine transporter ASCT2 expression. α-KG promoted the demethylation of histone H3K27me3, resulting in downregulation of SNAI2 associated with stemness and EMT. Significantly, suppressing DRP1 enhanced the anticancer effects of ferroptosis. Conclusion Our study reveals a novel mechanism underlying mitochondrial dynamics mediated cancer stemness acquisition and highlights the therapeutic potential of mitochondria elongation to increase the susceptibility of cancer cells to ferroptosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1059/2326 / 631/67/71 / Amino Acid Transport System ASC - antagonists & inhibitors / Amino Acid Transport System ASC - genetics / Amino Acid Transport System ASC - metabolism / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinoma, Squamous Cell - drug therapy / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - metabolism / Carcinoma, Squamous Cell - pathology / Cell fate / Cell Line, Tumor / Citric Acid Cycle - drug effects / Demethylation / Drug Resistance / Dynamins - antagonists & inhibitors / Dynamins - genetics / Dynamins - metabolism / Elongation / Epidemiology / Ferroptosis / Ferroptosis - drug effects / Glutamine / Glutamine - metabolism / Histones / Humans / Ketoglutaric acid / Ketoglutaric Acids - metabolism / Metabolomics / Mice / Minor Histocompatibility Antigens - genetics / Minor Histocompatibility Antigens - metabolism / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondrial Dynamics - drug effects / Molecular Medicine / Mouth Neoplasms - drug therapy / Mouth Neoplasms - genetics / Mouth Neoplasms - metabolism / Mouth Neoplasms - pathology / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Oncology / Oral cancer / Oral carcinoma / Oral squamous cell carcinoma / Organoids / Piperazines - pharmacology / Quinazolinones - pharmacology / Snail protein / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck - drug therapy / Squamous Cell Carcinoma of Head and Neck - genetics / Squamous Cell Carcinoma of Head and Neck - metabolism / Squamous Cell Carcinoma of Head and Neck - pathology / Stem cells / Tricarboxylic acid cycle