AI Article Synopsis
- Mitochondrial dynamics significantly influence the stemness of oral squamous cell carcinoma (OSCC) cells, with a focus on the role of the protein DRP1 in maintaining mitochondrial shape and function.
- DRP1 knockdown leads to imbalanced mitochondrial dynamics, reducing the stem cell characteristics of OSCC cells and altering metabolic pathways, particularly affecting α-ketoglutarate levels and glutaminolysis.
- Enhancing mitochondrial elongation through DRP1 suppression not only diminishes stemness but also increases the effectiveness of ferroptosis as a cancer treatment strategy, revealing potential therapeutic avenues.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11130175 | PMC |
| http://dx.doi.org/10.1038/s41416-024-02670-2 | DOI Listing |
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