Roe Andrew, Dowling Catríona M, D'Arcy Cian, Alencar Rodrigues Daniel, Wang Yu, Hiller Matthew, Keogh Carl, Hollinshead Kate E R, Garre Massimiliano, Cavanagh Brenton, Wynne Kieran, Liu Tianyan, Chen Zhixing, Kerr Emma, McIlroy Marie, H M Prehn Jochen, Schoen Ingmar, Chonghaile Tríona Ní
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
Nat Commun. 2025 Jul 28;16(1):6923. doi: 10.1038/s41467-025-61897-6.
Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity. In triple-negative breast cancer cells, HDAC6 inhibition or knockdown results in alterations to mitochondrial cristae structure, as detected by live-cell super-resolution STED nanoscopy and electron microscopy, along with the release of mitochondrial DNA. Mass-spectrometry immunoprecipitation reveals multiple mitochondrial HDAC6-interactors, with FH emerging as a top hit. Super-resolution 3D-STORM shows HDAC6 interactions with FH in mitochondrial networks, which increases after perturbation of HDAC6 activity with BAS-2. Treatment with BAS-2 leads to fumarate accumulation by C glucose labelling, along with downstream succination of proteins and cell death. Together, these results identify HDAC6 inhibition as a regulator of endogenous FH activity in tumour cells, and highlight it as a promising candidate for indirectly targeting tumour metabolism.
延胡索酸水合酶（FH）是线粒体代谢的关键节点，也是一种肿瘤抑制因子。尽管它在肿瘤发生和炎症中起着重要作用，但其调控机制仍知之甚少。在此，我们表明组蛋白去乙酰化酶6（HDAC6）调节FH活性。在三阴性乳腺癌细胞中，通过活细胞超分辨率受激发射损耗（STED）纳米显微镜和电子显微镜检测发现，HDAC6抑制或敲低会导致线粒体嵴结构改变，同时伴有线粒体DNA释放。质谱免疫沉淀揭示了多个与线粒体HDAC6相互作用的蛋白，其中FH是最主要的一个。超分辨率三维随机光学重建显微镜（3D-STORM）显示HDAC6与线粒体网络中的FH相互作用，在用BAS-2干扰HDAC6活性后这种相互作用增强。用BAS-2处理会通过C葡萄糖标记导致延胡索酸积累，同时引起蛋白质琥珀酰化及细胞死亡。总之，这些结果表明HDAC6抑制是肿瘤细胞内源性FH活性的调节因子，并突出其作为间接靶向肿瘤代谢的有前景的候选物。
