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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.
Experimental Hematology
|February 22, 2025
Summary
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.
