Mutations in any of the genes encoding the four subunits of succinate dehydrogenase (SDH), a mitochondrial membrane-bound enzyme complex that is involved in both the tricarboxylic acid cycle and the electron transport chain, can lead to a variety of disorders. Recognized conditions with such mutations include Leigh syndrome and hereditary tumors such as pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma, and gastrointestinal stromal tumor. Tumors appear in SDH mutation carriers with dominant inheritance due to loss of heterozygosity in susceptible cells. Here, we describe a mouse model intended to reproduce hereditary PPGL through Cre-mediated loss of SDHC in cells that express tyrosine hydroxylase (TH), a compartment where PPGL is known to originate. We report that while there is modest expansion of TH+ glomus cells in the carotid body upon SDHC loss, PPGL is not observed in such mice, even in the presence of a conditional dominant negative p53 protein and chronic hypoxia. Instead, we report an unexpected phenotype of nondiabetic obesity beginning at about 20 weeks of age. We hypothesize that this obesity is caused by TH+ cell loss or altered phenotype in key compartments of the central nervous system responsible for regulating feeding behavior, coupled with metabolic changes due to loss of peripheral catecholamine production.

中文翻译：

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线粒体复合物 II 缺陷的条件小鼠模型中的意外肥胖，而不是肿瘤发生

任何编码琥珀酸脱氢酶 (SDH) 四个亚基的基因发生突变，SDH 是一种线粒体膜结合酶复合物，参与三羧酸循环和电子传递链，可导致多种疾病。具有此类突变的公认病症包括 Leigh 综合征和遗传性肿瘤，例如嗜铬细胞瘤和副神经节瘤 (PPGL)、肾细胞癌和胃肠道间质瘤。由于易感细胞中杂合性的丧失，肿瘤出现在具有显性遗传的 SDH 突变携带者中。在这里，我们描述了一种小鼠模型，该模型旨在通过 Cre 介导的表达酪氨酸羟化酶 (TH) 的细胞中 SDHC 的丢失来复制遗传性 PPGL，这是已知 PPGL 的来源。我们报告说，虽然在 SDHC 损失后颈动脉体中 TH+ 球细胞适度扩增，但在此类小鼠中未观察到 PPGL，即使存在条件显性失活 p53 蛋白和慢性缺氧也是如此。相反，我们报告了从大约 20 周龄开始的非糖尿病性肥胖的意外表型。我们假设这种肥胖是由负责调节摄食行为的中枢神经系统关键区室中的 TH+ 细胞丢失或表型改变以及由于外周儿茶酚胺产生的丧失引起的代谢变化引起的。