Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
Biotechnology Laboratory, Department of Diagnostics, Civic Hospital of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy.
Mol Neurobiol. 2016 Oct;53(8):5542-74. doi: 10.1007/s12035-015-9473-y. Epub 2015 Oct 14.
Mounting evidence indicates that the lysosome-autophagy pathway plays a critical role in iron release from ferritin, the main iron storage cellular protein, hence in the distribution of iron to the cells. The recent identification of nuclear receptor co-activator 4 as the receptor for ferritin delivery to selective autophagy sheds further light on the understanding of the mechanisms underlying this pathway. The emerging view is that iron release from ferritin through the lysosomes is a general mechanism in normal and tumour cells of different tissue origins, but it has not yet been investigated in brain cells. Defects in the lysosome-autophagy pathway are often involved in the pathogenesis of neurodegenerative disorders, and brain iron homeostasis disruption is a hallmark of many of these diseases. However, in most cases, it has not been established whether iron dysregulation is directly involved in the pathogenesis of the diseases or if it is a secondary effect derived from other pathogenic mechanisms. The recent evidence of the crucial involvement of autophagy in cellular iron handling offers new perspectives about the role of iron in neurodegeneration, suggesting that autophagy dysregulation could cause iron dyshomeostasis. In this review, we recapitulate our current knowledge on the routes through which iron is released from ferritin, focusing on the most recent advances. We summarise the current evidence concerning lysosome-autophagy pathway dysfunctions and those of iron metabolism and discuss their potential interconnections in several neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases; amyotrophic lateral sclerosis; and frontotemporal lobar dementia.
越来越多的证据表明，溶酶体-自噬途径在铁从铁蛋白（主要的细胞铁储存蛋白）中释放以及铁向细胞分配中起着关键作用。最近发现核受体辅激活因子 4 是铁蛋白递送至选择性自噬的受体，这进一步阐明了该途径的机制。目前的观点是，铁从铁蛋白通过溶酶体释放是不同组织来源的正常和肿瘤细胞中的一种普遍机制，但尚未在脑细胞中进行研究。溶酶体-自噬途径的缺陷常与神经退行性疾病的发病机制有关，而脑内铁稳态失调是许多此类疾病的标志。然而，在大多数情况下，尚未确定铁失调是否直接参与疾病的发病机制，或者它是否是源自其他致病机制的继发效应。最近有证据表明自噬在细胞铁处理中起着关键作用，这为铁在神经退行性变中的作用提供了新的视角，表明自噬失调可能导致铁稳态失调。在这篇综述中，我们回顾了铁从铁蛋白中释放的途径的现有知识，重点介绍了最新进展。我们总结了有关溶酶体-自噬途径功能障碍和铁代谢的现有证据，并讨论了它们在几种神经退行性疾病（如阿尔茨海默病、帕金森病和亨廷顿病；肌萎缩侧索硬化症；以及额颞叶痴呆）中的潜在相互关系。
