Sdhb, encoding succinate dehydrogenase subunit B, is a mitochondrial gene integral to the succinate dehydrogenase complex in the tricarboxylic acid (TCA) cycle and mitochondrial respiratory chain [5]. This complex is crucial for cellular energy production and metabolism, and Sdhb's function impacts various biological processes related to energy homeostasis and cell growth [5].

Germline pathogenic variants in Sdhb are strongly associated with an increased risk of developing pheochromocytomas and paragangliomas (PPGLs) [1,2,3,4]. Carriers of Sdhb germline pathogenic variants face a non-negligible risk of metastatic disease, second primary tumors, and mortality [2]. The penetrance of PPGLs in Sdhb pathogenic variant carriers increases with age, with risks reaching 24% by age 60 and 35% by age 80 for non-proband/non-index carriers [2]. Sdhb-associated PPGLs often show less differentiation, may produce only dopamine, and support tumor growth through high levels of the oncometabolite succinate, leading to pseudohypoxia and upregulation of hypoxia-related genes, promoting cancer cell growth, migration, invasiveness, and metastasis [1]. SDHB immunohistochemistry can predict Sdhb germline gene mutation and is closely associated with tumor progression and metastasis in PCC/PGL patients, with SDHB(-) staining indicating a poorer prognosis [6].

In conclusion, Sdhb is essential for mitochondrial energy-related functions. The study of Sdhb-associated germline pathogenic variants in genetic models, though not specifically KO/CKO mouse models in the provided references, has significantly enhanced our understanding of its role in the pathogenesis of PPGLs. This knowledge is crucial for early detection, risk assessment, and management strategies for patients at risk of these rare neuroendocrine tumors.