Modeling succinate dehydrogenase loss disorders in C. elegans through effects on hypoxia-inducible factor

Braun, Megan M.; Damjanac, Tamara; Zhang, Yuxia; Chen, Chuan; Hu, Jinghua; Maher, Jim

doi:10.1371/journal.pone.0227033

Cited by 5 publications

(8 citation statements)

References 41 publications

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“…Succinate accumulation, damaged oxygen consumption [ 83 , 84 ] Cell-specific sdhb-1(RNAi) C. elegans Cell-specific sdhb-1(RNAi) Also used DMOG to suppress SDH. Crosses with HIF mutants [ 85 ] Copy of human mutation in SDHB C. elegans Arg244His point mutant (corresponding to Arg230His in human SDHB ) Succinate accumulation, damaged oxygen consumption, increased pyruvate and lactate levels, increased LDH activity. Sterile adults [ 84 ] mev-1 C. elegans G71E in SDHC mev-1 was discovered in a worm screen for oxygen sensitivity.…”

Section: Model Systemsmentioning

confidence: 99%

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Model systems in SDHx-related pheochromocytoma/paraganglioma

Takács‐Vellai

Farkas

Ősz

et al. 2021

Cancer Metastasis Rev

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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.

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Section: Model Systemsmentioning

confidence: 99%

“…Another worm group used convergent genetic and pharmacological approaches to study the effect of SDH deficits on the HIF system in the worm [ 85 ]. One effect of HIF activation in the worm is a delay in egg-laying, or ‘egg retention’.…”

Section: Model Systemsmentioning

confidence: 99%

Model systems in SDHx-related pheochromocytoma/paraganglioma

Takács‐Vellai

Farkas

Ősz

et al. 2021

Cancer Metastasis Rev

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“…Current hypotheses focus on the roles of accumulating succinate as an oncometabolite, augmented damage by reactive oxygen species (ROS), and hypersuccinylation ( Ishii et al 2005 , Selak et al 2005 , Smestad et al 2018 ). ROS production has been shown to increase in SDH loss model organisms, but it is unclear how much protein and DNA damage results ( Adachi et al 1998 , Ishii et al 2005 , Smith et al 2007 , Braun et al 2019 ). Recent work has shown that the loss of SDHB in particular disrupts iron homeostasis, leading to exacerbated ROS generation and hallmarks of the tumor phenotype such as pseudohypoxia and DNA hypermethylation.…”

Section: Introductionmentioning

confidence: 99%

A suppressor of dioxygenase inhibition in a yeast model of SDH deficiency

Beimers

Braun

Schwinefus

et al. 2022

Endocrine-Related Cancer

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A fascinating class of familial paraganglioma (PGL) neuroendocrine tumors is driven by loss of the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) resulting in succinate accumulation as an oncometabolite, and other metabolic derangements. Here we exploit a S. cerevisiae yeast model of SDH loss where accumulating succinate, and possibly reactive oxygen species, poison a dioxygenase enzyme required for sulfur scavenging. Using this model we performed a chemical suppression screen for compounds that relieve dioxygenase inhibition. After testing 1280 pharmaceutically-active compounds we identified meclofenoxate HCL, and its hydrolysis product, dimethylaminoethanol (DMAE), as suppressors of dioxygenase intoxication in SDH-loss yeast cells. We show that DMAE acts to alter metabolism so as to normalize the succinate:2-ketoglutarate ratio, improving dioxygenase function. This work raises the possibility that oncometabolite effects might be therapeutically suppressed by drugs that rewire metabolism to reduce the flux of carbon into pathological metabolic pathways.

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“…In an attempt to envision therapeutics and probe PGL mechanisms, several model systems, including Caenorhabditis elegans, zebrafish, rodents, mammalian cell lines, and the yeast Saccharomyces cerevisiae have been used in lieu of conventional cancer models (Bancos et al, 2013;Braun et al, 2019;Dona et al, 2021;Lussey-Lepoutre et al, 2018;Smestad et al, 2017;Smith et al, 2007). Yeast models of PGL have exploited the conserved mitochondrial role of SDH for studies of metabolic disorders (Bancos et al, 2013;Kregiel, 2012;Lussey-Lepoutre et al, 2018;Smith et al, 2007).…”

Section: Words Introductionmentioning

confidence: 99%

“…Current hypotheses focus on the roles of accumulating succinate as an oncometabolite, augmented damage by reactive oxygen species (ROS), and hypersuccinylation (Ishii et al, 2005;Selak et al, 2005;Smestad et al, 2018). ROS production has been shown to increase in SDH-loss model organsims, but it is unclear how much protein and DNA damage results (Adachi et al, 1998;Braun et al, 2019;Ishii et al, 2005;Smith et al, 2007). There is evidence that inherent oxidative stress enhances PGL sensitivity to additional oxidative damage (Liu et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

A chemical screen for suppressors of dioxygenase inhibition in a yeast model of familial paraganglioma

Beimers

Braun

Schwinefus

et al. 2021

Preprint

Self Cite

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A fascinating class of familial paraganglioma (PGL) neuroendocrine tumors is driven by loss of the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) resulting in succinate accumulation as an oncometabolite, and other metabolic derangements. Here we exploit a S. cerevisiae yeast model of SDH loss where accumulating succinate, and possibly reactive oxygen species, poison a dioxygenase enzyme required for sulfur scavenging. Using this model we performed a chemical suppression screen for compounds that relieve dioxygenase inhibition. After testing 1280 pharmaceutically-active compounds we identified meclofenoxate HCL, and its hydrolysis product, dimethylaminoethanol (DMAE), as suppressors of dioxygenase intoxication in SDH-loss cells. We show that DMAE acts to alter metabolism so as to normalize the succinate:2-ketoglutarate ratio, improving dioxygenase function. This work raises the possibility that oncometabolite effects might be therapeutically suppressed by drugs that rewire metabolism to reduce the flux of carbon into pathological metabolic pathways.

show abstract

Modeling succinate dehydrogenase loss disorders in C. elegans through effects on hypoxia-inducible factor

Cited by 5 publications

References 41 publications

Model systems in SDHx-related pheochromocytoma/paraganglioma

Model systems in SDHx-related pheochromocytoma/paraganglioma

A suppressor of dioxygenase inhibition in a yeast model of SDH deficiency

A chemical screen for suppressors of dioxygenase inhibition in a yeast model of familial paraganglioma

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