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Updated: Mar 20, 2026
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK
Paola Corazao-Rozas1,2,3, Pierre Guerreschi1,2,3, Fanny André1,2,3
1University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.
Abstract:
Although MAPK pathway inhibitors are becoming a promising anticancer strategy, they are insufficient to fully eliminate cancer cells and their long-term efficacy is strikingly limited in patients with BRAF-mutant melanomas. It is well established that BRAF inhibitors (BRAFi) hamper glucose uptake before the apparition of cell death. Here, we show that BRAFi induce an extensive restructuring of mitochondria including an increase in mitochondrial activity and biogenesis associated with mitochondrial network remodeling. Furthermore, we report a close interaction between ER and mitochondria in melanoma exposed to BRAFi. This physical connection facilitates mitochondrial Ca2+ uptake after its release from the ER. Interestingly, Mfn2 silencing disrupts the ER-mitochondria interface, intensifies ER stress and exacerbates ER stress-induced apoptosis in cells exposed to BRAFi in vitro and in vivo. This mitochondrial control of ER stress-mediated cell death is similar in both BRAF- and NRAS-mutant melanoma cells exposed to MEK inhibitors. This evidence reinforces the relevance in combining MAPK pathway inhibitors with mitochondriotropic drugs to improve targeted therapies.
Insights
BRAF inhibitors restructure mitochondria and enhance ER-mitochondria interactions in melanoma. Targeting these connections may improve MAPK pathway inhibitor efficacy for cancer therapy.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Mitogen-activated protein kinase (MAPK) pathway inhibitors show promise but have limited efficacy in BRAF-mutant melanomas.
- BRAF inhibitors (BRAFi) impede glucose uptake, preceding cancer cell death.
- Mitochondria play a crucial role in cellular processes and cancer progression.
Purpose of the Study:
- To investigate the effects of BRAFi on mitochondrial structure and function in melanoma.
- To explore the interplay between endoplasmic reticulum (ER) and mitochondria under BRAFi treatment.
- To identify novel therapeutic strategies by combining MAPK inhibitors with mitochondriotropic drugs.
Main Methods:
- Analysis of mitochondrial activity, biogenesis, and network remodeling in melanoma cells treated with BRAFi.
- Investigating the ER-mitochondria interface and calcium (Ca2+) transfer dynamics.
- Utilizing Mfn2 silencing to assess the role of the ER-mitochondria connection in apoptosis.
- In vitro and in vivo experiments on BRAF- and NRAS-mutant melanoma cells treated with BRAFi and MEK inhibitors.
Main Results:
- BRAFi induce significant mitochondrial restructuring, including increased activity, biogenesis, and network remodeling.
- A close physical interaction between ER and mitochondria is observed in BRAFi-treated melanoma, facilitating mitochondrial Ca2+ uptake.
- Disruption of the ER-mitochondria interface via Mfn2 silencing exacerbates ER stress and apoptosis.
- This mitochondrial regulation of ER stress-mediated cell death is conserved in NRAS-mutant melanoma treated with MEK inhibitors.
Conclusions:
- Mitochondrial dynamics and ER-mitochondria crosstalk are critical in melanoma response to MAPK inhibitors.
- Targeting the ER-mitochondria interface presents a potential strategy to overcome therapeutic resistance.
- Combining MAPK pathway inhibitors with mitochondriotropic drugs could enhance the efficacy of targeted melanoma therapies.
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