Targeting the Redox Balance Pathway Using Ascorbic Acid in sdhb Zebrafish Mutant Larvae

Area of Science:

• Biochemistry
• Oncology
• Zebrafish Models

Background:

• Mutations in succinate dehydrogenase β-subunit (SDHB) are linked to malignant phaeochromocytomas and paragangliomas (PPGLs).
• Therapeutic development for SDHB-associated PPGLs is limited by in vivo testing challenges.
• Mitochondrial dysfunction and reactive oxygen species (ROS) overproduction are implicated in SDHB-associated tumorigenesis.

Purpose of the Study:

• To investigate the utility of an SDHB zebrafish model for drug screening in PPGLs.
• To assess the efficacy of Vitamin C (ascorbic acid) in modulating ROS levels and survival in the SDHB zebrafish model.

Main Methods:

• Generated an SDHB zebrafish model exhibiting increased basal ROS levels.
• Conducted a semi high-throughput drug screening using varying Vitamin C dosages.
• Evaluated survival, ROS levels, and locomotor activity in response to Vitamin C treatment.

Main Results:

• Homozygous sdhb larvae showed elevated ROS levels compared to controls.
• Low-dose Vitamin C reduced ROS levels in sdhb larvae but did not impact lifespan.
• High-dose Vitamin C shortened the lifespan of sdhb larvae without affecting wild-type or heterozygous siblings.

Conclusions:

• The SDHB zebrafish model is validated as an effective tool for PPGL drug screening.
• Vitamin C's differential effects highlight the importance of dosage in therapeutic strategies.
• This model may facilitate the identification of novel therapeutic targets for SDHB-associated PPGLs.