Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
Int J Biochem Cell Biol. 2021 May;134:105949. doi: 10.1016/j.biocel.2021.105949. Epub 2021 Feb 17.
Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours. So far, over 20 causative genes have been identified, of which the most frequent and strongest indicator for malignancies are mutations in succinate dehydrogenase subunit B. No curative therapy is available for patients with metastases resulting in poor prognosis. Therapy development has been hindered by lack of suitable model systems. The succinate dehydrogenase complex is located in the inner membrane of the mitochondria and plays a crucial role in the oxidative phosphorylation chain and the tricarboxylic acid-cycle. Succinate dehydrogenase deficiency results in accumulation of the oncometabolite succinate inducing hypoxia inducible factor stabilization, deoxyribonucleic acid and histone methylation inhibition, and impaired production of adenosine triphosphate. It remains unknown which combination of pathways and/or triggers are decisive for metastases development. In this review, the role of mitochondria in malignant succinate dehydrogenase subunit B-associated phaeochromocytomas and paragangliomas and implications for mitochondria as therapeutic target are discussed.
嗜铬细胞瘤和副神经节瘤是罕见的神经内分泌肿瘤。到目前为止，已经发现了 20 多个致病基因，其中琥珀酸脱氢酶亚基 B 的突变是恶性肿瘤最常见和最强的指标。对于发生转移的患者，目前尚无治愈性治疗方法，预后不良。由于缺乏合适的模型系统，治疗药物的开发受到了阻碍。琥珀酸脱氢酶复合物位于线粒体内膜，在氧化磷酸化链和三羧酸循环中起着至关重要的作用。琥珀酸脱氢酶缺乏会导致致癌代谢物琥珀酸的积累，从而诱导缺氧诱导因子稳定、脱氧核糖核酸和组蛋白甲基化抑制以及三磷酸腺苷产生受损。目前尚不清楚哪些途径和/或触发因素对转移的发展起决定性作用。在这篇综述中，讨论了线粒体在恶性琥珀酸脱氢酶亚基 B 相关嗜铬细胞瘤和副神经节瘤中的作用，以及线粒体作为治疗靶点的意义。
