@article{2921cd522c814529972470970e5f6a64,
title = "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 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{\textquoteright}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.",
keywords = "Cancer, C. elegans, Familial Paraganglioma Syndrome (FPS), TCA cycle, Succinate dehydrogenase, Warburg-like glycolysis, Familial paraganglioma syndrome",
author = "{\'E}va Sask{\H o}i and Zolt{\'a}n Hujber and G{\'a}bor Ny{\'i}r{\H o} and Istv{\'a}n Lik{\'o} and Barbara M{\'a}ty{\'a}si and G{\'a}bor Pet{\H o}v{\'a}ri and Katalin M{\'e}sz{\'a}ros and Kov{\'a}cs, {Attila L} and L{\'a}szl{\'o} Patthy and Shreyas Supekar and Hao Fan and Gergely Sv{\'a}b and L{\'a}szl{\'o} Tretter and Arunabh Sarkar and Aamir Nazir and Anna Sebesty{\'e}n and Attila Pat{\'o}cs and Anil Mehta and Krisztina Tak{\'a}cs-Vellai",
note = "Funding Information: We thank the Caenorhabditis Genetics Center (which is funded by the National Institutes of Health) for nematode strains, Chris Hopkins and Trisha Brock (Knudra Transgenics Service) for their expertise and effort to make some of the transgenic lines used in this work, and Professor G. W. Stewart for his comments on the manuscript. Funding Information: K.T.-V. and A.M. were supported by the Findacure Foundation/Russell Trust (PN1607/16). The work was supported by the Phaeo Para Cancer Charity (K10101B004), UK (who played no part in the publication itself). This work was completed in the ELTE Institutional Excellence Program, supported by the Hungarian Ministry of Human Capacities (Emberi Eroforr{\'a}sok Miniszt{\'e}riuma; 1783-3/2018/FEKUSTRAT). Recent research works at the 1st Department of Pathology and Experimental Cancer Research were funded by the Hungarian Scientific Research Fund (FK-128404), National Bionics Program (project no. ED_17-1-2017-0009) and the National Research, Development and Innovation Fund Hungary (Nemzeti Kutat{\'a}si Fejleszt{\'e}si {\'e}s Innov{\'a}ci{\'o}s Hivatal; NVKP_16-1-2016-0004) (A. Sebesty{\'e}n, G.P. and Z.H.). S.S. and H.F. gratefully acknowledge financial support from the Biomedical Research Council, Agency for Science, Technology and Research (A*STAR). The computational work for this article was performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg). Work performed at the Department of Medical Biochemistry, MTA-SE Laboratory for Funding Information: Neurobiochemistry, Semmelweis University was supported by the Hungarian Brain Research Program (KTIA_13_NAP-A-III/6 and 2017-1.2.1-NKP-2017-00002) and the Hungarian Academy of Sciences (Magyar Tudom{\'a}nyos Akad{\'e}mia; MTA TKI 02001). Publisher Copyright: {\textcopyright} 2020. Published by The Company of Biologists Ltd",
year = "2020",
month = oct,
day = "15",
doi = "10.1242/dmm.044925",
language = "English",
volume = "13",
journal = "Disease Models and Mechanisms (DMM)",
issn = "1754-8403",
publisher = "Company of Biologists Ltd",
number = "10",
}
