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.

中文翻译：

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SDHB Arg230His 突变导致家族性副神经节瘤，改变新的秀丽隐杆线虫模型中的糖酵解。


琥珀酸脱氢酶 (SDH) 的保守 B 亚基参与 TCA 循环和线粒体电子传递。 SDHB 中的 Arg230His 突变会导致遗传性嗜铬细胞瘤/副神经节瘤 (PPGL)。在秀丽隐杆线虫中，我们生成了体内PPGL 模型（SDHB-1 Arg244His；相当于人类 Arg230His），该模型表现出发育延迟、寿命缩短、ATP 产生减弱和线粒体数量减少。尽管琥珀酸在错义和空sdhb-1(gk165)突变体中均升高，但转录组比较表明，代谢分析支持非常不同的因果机制，其中只有 Arg244His（非空）蠕虫提高乳酸/丙酮酸水平，指出错义诱导的，“Warburg”样异常糖酵解。 SDHA-B 二聚体结构的计算机预测表明，Arg230His 可以修饰催化裂口，尽管后者距离突变位点较远。我们假设 Arg230His SDHB 突变会重新连接代谢，让人想起癌症中的代谢重编程。我们的易处理模型提供了一种新的工具来研究这种家族性癌症的转移倾向，我们的方法可能会阐明更广泛的 SDH 病理学。