Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging
Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging
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DOI：
10.1073/pnas.192585799
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发表时间：
2002-11-12
影响因子：
11.1
通讯作者：
Ames, BN
中科院分区：
文献类型：
--
作者：
Atamna, H;Killilea, DW;Ames, BN
血红素，铁在细胞中的主要功能形式，通过亚铁螯合酶将亚铁插入原卟啉IX中在线粒体中合成。在两种人脑细胞系SHSY 5 Y（神经母细胞瘤）和U373（星形细胞瘤）以及大鼠原代海马神经元中，用亚铁螯合酶的选择性抑制剂N-甲基-原卟啉IX诱导血红素缺乏。脑细胞中的血红素缺乏减少线粒体复合物IV，激活一氧化氮合酶，改变淀粉样前体蛋白，破坏铁和锌的稳态。血红素缺乏导致的代谢后果似乎与阿尔茨海默病患者的神经元功能障碍相似。血红素缺乏的SHSY 5 Y或U373细胞分别在诱导分化或增殖时死亡。血红素在这些观察中的作用可能是由于其与特定蛋白质中的血红素调节基序相互作用或继发于受损的线粒体。血红素缺乏的常见原因包括衰老、铁和维生素B6缺乏以及暴露于有毒金属如铝。铁和维生素B6缺乏症尤其重要，因为它们很普遍，但它们也可以通过补充来预防。因此，血红素缺乏或失调可能是神经退行性过程的重要和可预防的组成部分。
Heme, a major functional form of iron in the cell, is synthesized in the mitochondria by ferrochelatase inserting ferrous iron into protoporphyrin IX Heme deficiency was induced with N-methyl-protoporphyrin IX, a selective inhibitor of ferrochelatase, in two human brain cell lines, SHSY5Y (neuroblastoma) and U373 (astrocytoma), as well as in rat primary hippocampal neurons. Heme deficiency in brain cells decreases mitochondrial complex IV, activates nitric oxide synthase, alters amyloid precursor protein, and corrupts iron and zinc homeostasis. The metabolic consequences resulting from heme deficiency seem similar to dysfunctional neurons in patients with Alzheimer's disease. Heme-deficient SHSY5Y or U373 cells die when induced to differentiate or to proliferate, respectively. The role of heme in these observations could result from its interaction with heme regulatory motifs in specific proteins or secondary to the compromised mitochondria. Common causes of heme deficiency include aging, deficiency of iron and vitamin B6, and exposure to toxic metals such as aluminum. iron and B6 deficiencies are especially important because they are widespread, but they are also preventable with supplementation. Thus, heme deficiency or dysregulation may be an important and preventable component of the neurodegenerative process.