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)

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish
    JournalDisease Models & Mechanisms
    Early online date28 Aug 2020
    DOIs
    Publication statusE-pub ahead of print - 28 Aug 2020

    Keywords

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

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    Saskői, É., Hujber, Z., Nyírő, G., Likó, I., Mátyási, B., Petővári, G., Mészáros, K., Kovács, A. L., Patthy, L., Supekar, S., Fan, H., Sváb, G., Tretter, L., Sarkar, A., Nazir, A., Sebestyén, A., Patócs, A., Mehta, A., & Takács-Vellai, K. (2020). The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model. Disease Models & Mechanisms. https://doi.org/10.1242/dmm.044925