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Updated: May 26, 2025
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
D816V KIT mutation induces mitochondrial morphologic and functional changes through BNIP3 downregulation in human
Sabina Cisa-Wieczorek1, Maria Isabel Hernández-Alvarez2, Matilde Parreño3
1Laboratory of Hematology, Department of Hematology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona/IIB Sant Pau, Spain.
Abstract:
The KIT receptor is a transmembrane protein found on the surface of many different cell types. Mutant forms of KIT are drivers of myeloid neoplasms, including systemic mastocytosis. The KIT D816V mutation is the most common, leading to constitutive activation of the receptor and its downstream targets, and it is highly resistant to c-KIT inhibitors. Metabolic rewiring is a common trait in cancer. We analyzed the metabolic profile induced by the KIT D816 mutation, measuring mitochondrial parameters in two myeloid cell lines. We found that the KIT D816V mutation causes a significant increase in mitochondrial abundance and activity associated with superoxide production, which could promote DNA instability. Functional and morphologic changes in mitochondria were associated with reduced levels of BNIP3 protein expression. We also detected low BNIP3 levels in clinical acute myeloid leukemia samples harboring D816V mutations. In addition, we have found constitutive mTOR activation in mutated cells, a pathway that has been shown to regulate autophagy. Our data suggest that KIT D816V increases mitochondrial activity through downregulation of BNIP3 expression, which increases mitochondrial number through the autophagy pathway. Alterations in the cellular metabolism induced by the KIT D816V mutation could be therapeutically exploited.
Insights
The KIT D816V mutation in myeloid neoplasms significantly increases mitochondrial activity and abundance, potentially driving DNA instability. This occurs through reduced BNIP3 expression and altered autophagy, suggesting new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Mutant KIT receptor tyrosine kinase drives myeloid neoplasms.
- The KIT D816V mutation is common in systemic mastocytosis and resistant to inhibitors.
- Cancer cells exhibit metabolic rewiring, including altered mitochondrial function.
Purpose of the Study:
- To investigate the metabolic profile induced by the KIT D816V mutation.
- To analyze mitochondrial parameters and their functional consequences in myeloid cell lines.
- To explore the role of BNIP3 and autophagy in KIT D816V-mediated metabolic changes.
Main Methods:
- Analysis of mitochondrial abundance and activity in myeloid cell lines with KIT D816V.
- Measurement of superoxide production and assessment of mitochondrial morphology.
- Quantification of BNIP3 protein expression in cell lines and clinical samples.
- Investigation of mTOR pathway activation and its relation to autophagy.
Main Results:
- KIT D816V mutation significantly increases mitochondrial abundance and activity, correlating with superoxide production.
- Reduced BNIP3 protein expression was observed in mutated cells and clinical samples.
- Constitutive mTOR activation was detected, suggesting a role in regulating autophagy.
- KIT D816V appears to enhance mitochondrial activity via BNIP3 downregulation and autophagy-driven mitochondrial proliferation.
Conclusions:
- The KIT D816V mutation induces significant mitochondrial alterations in myeloid cells.
- Downregulation of BNIP3 and subsequent autophagy modulation contribute to increased mitochondrial mass.
- These metabolic changes represent potential therapeutic vulnerabilities in KIT D816V-driven cancers.
