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

Éva Saskői, Zoltán Hujber, Gábor Nyírő, István Likó, Barbara Mátyási, Gábor Petővári, Katalin Mészáros, Attila L Kovács, László Patthy, Shreyas Supekar, Hao Fan, Gergely Sváb, László Tretter, Arunabh Sarkar, Aamir Nazir, Anna Sebestyén, Attila Patócs, Anil Mehta, Krisztina Takács-Vellai (Lead / Corresponding author)

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    Abstract

    The conserved B-subunit of succinate dehydrogenase (SDH) participates in the tricarboxylic acid cycle (TCA) cycle and mitochondrial electron transport. The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL). In Caenorhabditis 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, whereby only Arg244His (not null) worms demonstrate elevated 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 hypothesize that the 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 could illuminate wider SDH pathology.

    Original languageEnglish
    Article numberdmm044925
    Number of pages15
    JournalDisease Models & Mechanisms
    Volume13
    Issue number10
    Early online date28 Aug 2020
    DOIs
    Publication statusPublished - 15 Oct 2020

    Keywords

    • Cancer
    • C. elegans
    • Familial Paraganglioma Syndrome (FPS)
    • TCA cycle
    • Succinate dehydrogenase
    • Warburg-like glycolysis
    • Familial paraganglioma syndrome

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