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

• Published in: Disease models & mechanisms 2020-10, Vol.13 (10)
• Main Authors: Saskői, Éva, Hujber, Zoltán, Nyírő, Gábor, Likó, István, Mátyási, Barbara, Petővári, Gábor, Mészáros, Katalin, Kovács, Attila L, Patthy, László, Supekar, Shreyas, Fan, Hao, Sváb, Gergely, Tretter, László, Sarkar, Arunabh, Nazir, Aamir, Sebestyén, Anna, Patócs, Attila, Mehta, Anil, Takács-Vellai, Krisztina
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - biosynthesis; Amino Acid Sequence; Animals; Binding sites; c. elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans Proteins - chemistry; Caenorhabditis elegans Proteins - genetics; Cancer; Citric Acid Cycle - genetics; Conserved Sequence; Dehydrogenases; Disease Models, Animal; Enzymes; familial paraganglioma syndrome; Gene Expression Profiling; Genes; Glycolysis - genetics; Humans; Iron-Sulfur Proteins - chemistry; Iron-Sulfur Proteins - genetics; Kinases; L-Lactate Dehydrogenase - antagonists & inhibitors; L-Lactate Dehydrogenase - metabolism; Metabolism; Metastasis; Mitochondria - metabolism; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - genetics; Mutation; Mutation - genetics; Nematodes; Neuroendocrine tumors; Paraganglioma - genetics; Phenotype; Protein Subunits - genetics; RNA Interference; succinate dehydrogenase; Succinate Dehydrogenase - chemistry; Succinate Dehydrogenase - genetics; tca cycle; Tumorigenesis; Tumors; warburg-like glycolysis
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.044925

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 , we generated an 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 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. 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.This article has an associated First Person interview with the first author of the paper.