Model systems in SDHx-related pheochromocytoma/paraganglioma
Krisztina Takács-Vellai1, Zsolt Farkas2, Fanni Ősz2
1Department of Biological Anthropology, Eötvös Loránd University, Budapest, Hungary. krisztina.takacs@ttk.elte.hu.
Abstract:
Pheochromocytoma (PHEO) and paraganglioma (PGL) (together PPGL) are tumors with poor outcomes that arise from neuroendocrine cells in the adrenal gland, and sympathetic and parasympathetic ganglia outside the adrenal gland, respectively. Many follow germline mutations in genes coding for subunits of succinate dehydrogenase (SDH), a tetrameric enzyme in the tricarboxylic acid (TCA) cycle that both converts succinate to fumarate and participates in electron transport. Germline SDH subunit B (SDHB) mutations have a high metastatic potential. Herein, we review the spectrum of model organisms that have contributed hugely to our understanding of SDH dysfunction. In Saccharomyces cerevisiae (yeast), succinate accumulation inhibits alpha-ketoglutarate-dependent dioxygenase enzymes leading to DNA demethylation. In the worm Caenorhabditis elegans, mutated SDH creates developmental abnormalities, metabolic rewiring, an energy deficit and oxygen hypersensitivity (the latter is also found in Drosophila melanogaster). In the zebrafish Danio rerio, sdhb mutants display a shorter lifespan with defective energy metabolism. Recently, SDHB-deficient pheochromocytoma has been cultivated in xenografts and has generated cell lines, which can be traced back to a heterozygous SDHB-deficient rat. We propose that a combination of such models can be efficiently and effectively used in both pathophysiological studies and drug-screening projects in order to find novel strategies in PPGL treatment.
Insights
Model organisms reveal how succinate dehydrogenase (SDH) dysfunction causes pheochromocytoma and paraganglioma (PPGL). These models offer new avenues for developing effective PPGL treatments.
Area of Science:
- Biochemistry
- Oncology
- Genetics
Background:
- Pheochromocytoma (PHEO) and paraganglioma (PGL), collectively PPGL, are neuroendocrine tumors with poor prognoses.
- Many PPGL cases stem from germline mutations in succinate dehydrogenase (SDH) genes, crucial for the TCA cycle and electron transport.
- Mutations in SDH subunit B (SDHB) are linked to high metastatic potential in PPGL.
Purpose of the Study:
- To review the role of model organisms in understanding SDH dysfunction in PPGL.
- To highlight how these models aid in studying PPGL pathophysiology and drug discovery.
Main Methods:
- Review of studies utilizing model organisms like yeast (Saccharomyces cerevisiae), C. elegans, Drosophila melanogaster, zebrafish (Danio rerio), and rats.
- Examination of SDH dysfunction mechanisms, including succinate accumulation and its effects.
- Analysis of xenograft and cell line development from SDHB-deficient pheochromocytoma models.
Main Results:
- Yeast models show succinate accumulation inhibits dioxygenases, leading to DNA demethylation.
- C. elegans and D. melanogaster models exhibit developmental abnormalities, metabolic rewiring, energy deficits, and oxygen hypersensitivity.
- Zebrafish models display shorter lifespans and impaired energy metabolism due to sdhb mutations.
- Rats have been used to generate SDHB-deficient pheochromocytoma cell lines and xenografts.
Conclusions:
- Model organisms provide critical insights into the pathophysiology of SDH-related PPGL.
- A combination of diverse model systems can accelerate the development of novel therapeutic strategies for PPGL.
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