Studies with patients, animal models of human disease and hemopexin null mice have shown that the heme-binding protein hemopexin is vital for the protection of a variety of cell types and tissues against heme toxicity. The presence of hemopexin in all biological fluids examined to date indicates wide roles in abrogating heme toxicity in human tissues; and, thus, is clinically relevant. Heme-hemopexin endocytosis leads to coordinated trafficking of heme, iron and copper as heme traffics from endosomes to heme oxygenases (HOs) in the smooth endoplasmic reticulum and to the nucleus. This is safe redox-metal trafficking, without oxidative stress, as iron released from heme catabolism by HOs as well as copper taken up with heme-hemopexin move through the cell. To our knowledge, this coordinated metal trafficking has been described only for the hemopexin system and differs from the cell's response to non-protein bound heme, which can be toxic. We propose that defining how cells respond to heme-hemopexin endocytosis, a natural cytoprotective system, will aid our understanding of how cells adapt as they safely respond to increases in heme, Fe(II) and copper. This is relevant for many genetic hemolytic diseases and conditions, stroke and hemorrhage as well as neurodegeneration. Such analyses will help to define a pattern of events that can be utilized to characterize how dysfunctional redox and transition metal handling is linked to the development of pathology in disease states such as Alzheimer's disease when metal homeostasis is not restored; and potentially provide novel targets and approaches to improve therapies.

中文翻译：

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血红素和铁与铜的安全协调运输可以维持细胞稳态：血红素系统的模块。

对患者，人类疾病的动物模型和血红素无效小鼠的研究表明，血红素结合蛋白血红素对于保护各种细胞类型和组织免受血红素毒性至关重要。迄今为止，在所有检查过的生物液体中都存在血红素毒素，这表明在消除人体组织中的血红素毒性方面起着广泛的作用。因此具有临床意义。血红素-血红蛋白内吞作用导致血红素，铁和铜的协调运输，因为血红素从内体向平滑内质网中的血红素加氧酶（HOs）转运至细胞核。这是安全的氧化还原金属运输，没有氧化应激，因为HOs从血红素分解代谢中释放的铁以及被血红素-血红蛋白吸收的铜穿过细胞。据我们所知，这种协调的金属运输仅针对血红素系统进行了描述，与细胞对非蛋白质结合血红素的反应不同，后者可能是有毒的。我们建议，定义细胞对血红素-血红蛋白内吞作用（一种天然的细胞保护系统）的反应方式，将有助于我们了解细胞如何安全适应血红素，Fe（II）和铜的增加而适应。这与许多遗传性溶血性疾病和病症，中风和出血以及神经变性有关。这样的分析将有助于确定事件的模式，这些事件可用于表征功能障碍的氧化还原和过渡金属处理如何与疾病状态（如未恢复金属稳态的阿尔茨海默氏病）的病理发展联系起来；