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

Abstract

Patients with mutations in the β-subunit of the succinate dehydrogenase (SDHB) have the highest risk to develop incurable malignant phaeochromocytomas and paragangliomas (PPGLs). Therapy development is hindered by limited possibilities to test new therapeutic strategies in vivo. One possible molecular mechanism of SDHB-associated tumorigenesis originates in an overproduction of reactive oxygen species (ROS) due to mitochondrial dysfunction. Ascorbic acid (Vitamin C) has already been shown to act as anti-cancer agent in several clinical trials for various types of cancer. In this study, the potential of the sdhbrmc200 zebrafish model to study SDHB-associated PPGLs using a drug screening approach was investigated. First, we identified increased basal ROS levels in homozygous sdhb larvae compared to heterozygous and wild-type siblings. Using a semi high-throughput drug screening, the effectiveness of different dosages of anti- and pro-oxidant Vitamin C were assessed to evaluate differences in survival, ROS levels, and locomotor activity. Low-dosage levels of Vitamin C induced a decrease of ROS levels but no significant effects on lifespan. In contrast, high-dosage levels of Vitamin C shortened the lifespan of the homozygous sdhbrmc200 larvae while not affecting the lifespan of heterozygous and wild-type siblings. These results validated the sdhbrmc200 zebrafish model as a powerful drug screening tool that may be used to identify novel therapeutic targets for SDHB-associated PPGLs.

Animal and Cell Culture Models of PPGLs – Achievements and Limitations

“…In 2021, Dona et al published a Sdhb-KO model in zebrafish which led to loss of complex II activity and elevated succinate levels mimicking the features of SDHB-associated PPGLs in humans [70]. The researchers explored the impact of ascorbic acid on the redox balance of the Sdhb-KO zebrafish larvae, suggesting that the model is a potentially valuable tool to screen for drugs effective against SDHB-associated pseudohypoxic PPGLs [71]. This model opens new possibilities to understand the molecular mechanisms associated to SDHB deficiency, and to investigate novel therapeutic interventions for SDHB-related tumors.…”

Vitamin C as Scavenger of Reactive Oxygen Species during Healing after Myocardial Infarction

“…In the presence of succinate dehydrogenase, succinate converts into fumarate and reduces FAD to FADH 2 , which donates electrons to the Fe-S clusters, to ultimately be transferred to the reduced ubiquinol form of coenzyme Q [ 122 ] ( Figure 2 B). The dicarboxylate-binding site of complex II (II f site) is associated with electron leakage from ETC and ROS generation [ 123 , 124 ] ( Figure 2 B). In vitro research using isolated mitochondria suggested that the II f sites were reduced after the inhibition of complex II by atpenin A5 in myocardial ischemia [ 123 ].…”

New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas

“…Alterations in the mitochondrial respiratory chain and redox balance are major pathogenic factors in a subgroup of PPGL. The article by Dona et al presents a novel zebrafish model that could be efficiently used for the study of PPGL [ 16 ].…”