1. Modeling succinate dehydrogenase loss disorders in C. elegans through effects on hypoxia-inducible factor.
- Author
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Braun MM, Damjanac T, Zhang Y, Chen C, Hu J, and Maher LJ 3rd
- Subjects
- Adrenal Gland Neoplasms drug therapy, Adrenal Gland Neoplasms pathology, Amino Acids, Dicarboxylic pharmacology, Animals, Animals, Genetically Modified, Caenorhabditis elegans genetics, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins antagonists & inhibitors, Caenorhabditis elegans Proteins metabolism, Cell Hypoxia drug effects, Cell Hypoxia genetics, Disease Models, Animal, Drug Screening Assays, Antitumor methods, High-Throughput Screening Assays methods, Humans, Mutation, Paraganglioma drug therapy, Paraganglioma pathology, Pheochromocytoma drug therapy, Pheochromocytoma pathology, Succinate Dehydrogenase antagonists & inhibitors, Succinate Dehydrogenase metabolism, Succinic Acid metabolism, Adrenal Gland Neoplasms genetics, Caenorhabditis elegans Proteins genetics, Paraganglioma genetics, Pheochromocytoma genetics, Succinate Dehydrogenase genetics
- Abstract
Mitochondrial disorders arise from defects in nuclear genes encoding enzymes of oxidative metabolism. Mutations of metabolic enzymes in somatic tissues can cause cancers due to oncometabolite accumulation. Paraganglioma and pheochromocytoma are examples, whose etiology and therapy are complicated by the absence of representative cell lines or animal models. These tumors can be driven by loss of the tricarboxylic acid cycle enzyme succinate dehydrogenase. We exploit the relationship between succinate accumulation, hypoxic signaling, egg-laying behavior, and morphology in C. elegans to create genetic and pharmacological models of succinate dehydrogenase loss disorders. With optimization, these models may enable future high-throughput screening efforts., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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