We recently reported that loss of calcium/calmodulin-dependent protein kinase kinase-2 (CAMKK2), a serine/threonine kinase activated by intracellular calcium, in mice leads to tissue-specific aberrant turnover of transferrin (TF), a receptor-mediated iron-transporter that supplies iron to tissues. Iron dyshomeostasis is associated with the pathogenesis of several diseases, making TF transport relevant to health. In this study, we used hemizygous CAMKK2 hypomorphic human endothelial cell (EA.hy926) clones to demonstrate that cells with reduced CAMKK2 exhibit increased TF uptake and transcytosis, and decreased intracellular trafficking to subcellular organelles compared to wild-type. The abnormal TF trafficking in CAMKK2 hypomorphic cells correlated with a reduction in intracellular iron content and defective glucose metabolism including glycolysis and mitochondrial respiration. CAMKK2 deficiency also caused reduction in GAPDH and VDAC1 protein level which correlated to defective bioenergetics function. These findings have identified a novel mechanistic link between abnormal calcium signaling, iron dyshomeostasis and metabolic dysfunction involving CAMKK2.

我们最近报道，小鼠体内钙/钙调蛋白依赖性蛋白激酶激酶-2（CAMKK2）（一种被细胞内钙激活的丝氨酸/苏氨酸激酶）的丢失会导致转铁蛋白（TF）（一种受体介导的铁）的组织特异性异常转换-向组织供应铁的转运蛋白。铁动态平衡与多种疾病的发病机理有关，使TF转运与健康相关。在这项研究中，我们使用半合子CAMKK2亚型的人内皮细胞（EA.hy926）克隆来证明，与野生型相比，具有减少的CAMKK2的细胞表现出增加的TF摄取和胞吞作用，并减少了细胞内向亚细胞器的运输。CAMKK2亚型细胞中的TF异常运输与细胞内铁含量降低和葡萄糖代谢缺陷（包括糖酵解和线粒体呼吸）有关。CAMKK2缺乏症还导致GAPDH和VDAC1蛋白质水平降低，这与有缺陷的生物能功能有关。这些发现确定了异常的钙信号传导，铁动态平衡和涉及CAMKK2的代谢功能障碍之间的新型机制联系。