The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model

Abstract

The conserved B-subunit of succinate dehydrogenase (SDH) participates in the TCA cycle and mitochondrial electron transport. The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL). In C. elegans, we generated an in vivo PPGL model (SDHB-1 Arg244His; equivalent to human Arg230His) which manifests delayed development, shortened lifespan, attenuated ATP production and reduced mitochondrial number. Although succinate is elevated in both missense and null sdhb-1(gk165) mutants, transcriptomic comparison suggests very different causal mechanisms that are supported by metabolic analysis where only Arg244His (not null) worms elevate lactate/pyruvate levels, pointing to a missense-induced, ‘Warburg’-like aberrant glycolysis. In silico predictions of the SDHA-B dimer structure demonstrate that Arg230His modifies the catalytic cleft despite the latter's remoteness from the mutation site. We hypothesise that Arg230His SDHB mutation rewires metabolism, reminiscent of metabolic reprogramming in cancer. Our tractable model provides a novel tool to investigate the metastatic propensity of this familial cancer and our approach may illuminate wider SDH pathology.

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“…These Arg244His SDHB mutants demonstrated elevated lactate/pyruvate levels, pointing to a missense-induced, Warburg-like aberrant glycolysis. Authors concluded that mutation in the amino acid sequence of SDHB rewires metabolism, resembling metabolic reprogramming in cancer [ 60 ]. Similar observations have been reported by other scientists who showed strong evidence that some mutations in SDH impair oxidative phosphorylation, which highly contributes to the Warburg metabolism switch observed in cancer cells [ 61 – 63 ].…”

Model systems in SDHx-related pheochromocytoma/paraganglioma

“…Sensitivity to hyperoxia. 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.…”

“…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. G71E mutants display oxygen hypersensitivity, decreased lifespan and brood size phenotypes.…”

“…Very recently, a copy of the human SDHB Arg230His mutation that presented in a Scottish family has been created in C. elegans (Arg244His in the worm) [ 84 ]. The findings are at an early stage, but the data show that (i) the enzyme is definitely defective, in that there is an abnormal build-up of succinate; (ii) the worm develops abnormally and is sterile but lives to a later larval stage than the L2-arrested SDHB-deletion worm; and (iii) shows a different pattern of metabolic rearrangement (reminiscent of Warburg effect) compared to the complete SDHB-deletion worm.…”

First person – Éva Saskői

“… ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Éva Saskői is first author on ‘ The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model ’, published in DMM. Éva is a PhD student in the lab of Krisztina Takács-Vellai at Eötvös Lorand University, Budapest, Hungary, investigating the developmental functions of tumor suppressor homologs in Caenorhabditis elegans .…”