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.
Highlights
Mitochondrial disorders can result from mutations affecting enzymes of oxidative metabolism [1,2,3,4]
We set out to determine whether C. elegans can be used as a genetic model of the succinate dehydrogenase (SDH)-loss cells present in human mitochondrial disorders including familial PPGL tumors
Seeking screenable phenotypes associated with SDH loss in worms, it was necessary to limit SDHx knockdown to a subpopulation of cells consistent with viability
Summary
Mitochondrial disorders can result from mutations affecting enzymes of oxidative metabolism [1,2,3,4]. And surprisingly, some cancers are caused by gain-of-function or loss-offunction mutations of genes encoding metabolic enzymes in susceptible tissues [5]. Up to 30% of PPGL tumors are hereditary [9]. All four subunits of the mitochondrial enzyme succinate dehydrogenase (SDH) have been identified as tumor suppressors in familial PPGL[10,11,12,13], with loss of heterozygosity accounting for tumorigenesis. Loss-of-function mutations of SDH subunits lead to dysfunctional complexes [15, 16]. The resulting TCA cycle dysfunction drives metabolic remodeling with dependence on glycolysis [17] and a profound
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