Fehsel Karin
Neurobiochemical Research Unit, Department of Psychiatry, Medical Faculty, Heinrich-Heine-University, 240629 Düsseldorf, Germany.
Biomedicines. 2023 Aug 30;11(9):2421. doi: 10.3390/biomedicines11092421.
Impaired iron metabolism has been increasingly observed in many diseases, but a deeper, mechanistic understanding of the cellular impact of altered iron metabolism is still lacking. In addition, deficits in neuronal energy metabolism due to reduced glucose import were described for Alzheimer's disease (AD) and its comorbidities like obesity, depression, cardiovascular disease, and type 2 diabetes mellitus. The aim of this review is to present the molecular link between both observations. Insufficient cellular glucose uptake triggers increased ferritin expression, leading to depletion of the cellular free iron pool and stabilization of the hypoxia-induced factor (HIF) 1α. This transcription factor induces the expression of the glucose transporters (Glut) 1 and 3 and shifts the cellular metabolism towards glycolysis. If this first line of defense is not adequate for sufficient glucose supply, further reduction of the intracellular iron pool affects the enzymes of the mitochondrial electron transport chain and activates the AMP-activated kinase (AMPK). This enzyme triggers the translocation of Glut4 to the plasma membrane as well as the autophagic recycling of cell components in order to mobilize energy resources. Moreover, AMPK activates the autophagic process of ferritinophagy, which provides free iron urgently needed as a cofactor for the synthesis of heme- and iron-sulfur proteins. Excessive activation of this pathway ends in ferroptosis, a special iron-dependent form of cell death, while hampered AMPK activation steadily reduces the iron pools, leading to hypoferremia with iron sequestration in the spleen and liver. Long-lasting iron depletion affects erythropoiesis and results in anemia of chronic disease, a common condition in patients with AD and its comorbidities. Instead of iron supplementation, drugs, diet, or phytochemicals that improve energy supply and cellular glucose uptake should be administered to counteract hypoferremia and anemia of chronic disease.
在许多疾病中，铁代谢受损的情况越来越常见，但对于铁代谢改变对细胞的影响，仍缺乏更深入的机制性理解。此外，已有研究表明，阿尔茨海默病（AD）及其合并症如肥胖、抑郁症、心血管疾病和2型糖尿病，存在因葡萄糖摄取减少导致的神经元能量代谢缺陷。本综述的目的是阐述这两种现象之间的分子联系。细胞葡萄糖摄取不足会触发铁蛋白表达增加，导致细胞内游离铁池耗竭以及缺氧诱导因子（HIF）1α稳定。这种转录因子会诱导葡萄糖转运蛋白（Glut）1和3的表达，并使细胞代谢转向糖酵解。如果这第一道防线不足以提供足够的葡萄糖供应，细胞内铁池的进一步减少会影响线粒体电子传递链的酶，并激活AMP激活的蛋白激酶（AMPK）。该酶会触发Glut4转位至质膜以及细胞成分的自噬循环，以调动能量资源。此外，AMPK会激活铁蛋白自噬的自噬过程，该过程可提供血红素和铁硫蛋白合成所需的作为辅因子的游离铁。该途径的过度激活最终会导致铁死亡，这是一种特殊的铁依赖性细胞死亡形式，而AMPK激活受阻会持续减少铁池，导致低铁血症，并使铁在脾脏和肝脏中蓄积。长期的铁缺乏会影响红细胞生成，并导致慢性病贫血，这是AD及其合并症患者的常见病症。应使用改善能量供应和细胞葡萄糖摄取的药物、饮食或植物化学物质来对抗低铁血症和慢性病贫血，而不是补充铁剂。
