# The Caenorhabditis elegans sdhb-1(R244H) Model Shows Characteristics of Human PPGL Tumor Cells

## TL;DR

A worm model with a specific SDHB mutation shows traits similar to human PPGL tumors, including mitochondrial dysfunction and pseudohypoxia.

## Contribution

A novel nematode model with the sdhb-1(R244H) mutation is shown to mimic human PPGL tumor characteristics.

## Key findings

- R244H mutants exhibit pseudohypoxia and increased reactive oxygen species due to reduced antioxidant enzyme levels.
- Mitophagy markers pink-1 and pdr-1 are downregulated in R244H mutants, indicating impaired mitophagy.
- Fluopyram treatment and structural analysis confirm residual activity in the SDH complex with the R244H mutation.

## Abstract

Pheochromocytomas and paragangliomas (PPGL) are classified as rare cancers but can be highly metastatic, particularly in individuals with inherited succinate dehydrogenase B (SDHB) mutations. As current therapies and the availability of SDHB-deficient animal models are both limited, we have previously constructed a nematode PPGL model, a transgenic worm carrying the R244H missense mutation equivalent to human R230H in the sdhb-1 gene. In this study, we show that R244H mutants display characteristics of PPGL tumors, such as pseudohypoxia activation and the accumulation of reactive oxygen species. The latter can be the result of compromised antioxidant machinery, as R244H mutants have reduced levels of cytosolic and mitochondrial superoxide dismutase enzymes. In addition, the expression of mitophagy markers pink-1 (PTEN-induced putative kinase) and pdr-1 (E3 ubiquitin-protein ligase parkin) were downregulated in R244H mutants, suggesting impaired mitophagy and reflecting the crucial role of mitochondrial health in PPGL pathology. Treatments by the SDH inhibitor fluopyram revealed that the SDH complex carrying the R244H mutation in subunit B displayed residual SDH activity, which was also confirmed by our structural analyses. We also observed a link between dopaminergic neuronal health and SDHB-1.