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F2,6BP restores mitochondrial genome integrity in Huntington's disease
Anirban Chakraborty1, Santi M Mandal2, Mikita Mankevich2
1Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
The Journal of Biological Chemistry
|January 14, 2026
Summary
Huntington
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Genetics
Background:
- Impaired mitochondrial function and DNA damage are implicated in Huntington's disease (HD) progression.
- Polynucleotide kinase 3'-phosphatase (PNKP) activity is crucial for DNA repair but is reduced in HD.
- Reduced levels of fructose-2,6 bisphosphate (F2,6BP) are observed in HD mitochondria.
Purpose of the Study:
- To investigate the role of PNKP, PFKFB3, and F2,6BP in Huntington's disease pathogenesis.
- To explore the therapeutic potential of F2,6BP supplementation in HD models.
Main Methods:
- Analysis of mitochondrial extracts from HD patients and mouse models.
- Assay of PNKP enzyme activity and F2,6BP levels.
- Supplementation studies with F2,6BP in HD cell and Drosophila models.
- Assessment of mitochondrial genome integrity, membrane potential, and respiration.
Main Results:
- PNKP activity is significantly decreased in HD mitochondria due to lower F2,6BP levels.
- F2,6BP acts as a cofactor for PNKP, and its supplementation restores PNKP activity.
- F2,6BP supplementation improved mitochondrial function and reduced pathology in HD models.
Conclusions:
- Reduced F2,6BP impairs PNKP activity, leading to mitochondrial DNA damage in HD.
- F2,6BP supplementation represents a promising therapeutic strategy for Huntington's disease.
- Restoring PNKP activity via F2,6BP may ameliorate neurodegenerative symptoms in HD.
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