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同型胱氨酸尿症伴再甲基化缺陷患者的内质网应激与自噬

Endoplasmic Reticulum Stress and Autophagy in Homocystinuria Patients with Remethylation Defects.

作者信息

Martínez-Pizarro Ainhoa, Desviat Lourdes R, Ugarte Magdalena, Pérez Belén, Richard Eva

机构信息

Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid / Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, IDIPaz, Spain.

出版信息

PLoS One. 2016 Mar 9;11(3):e0150357. doi: 10.1371/journal.pone.0150357. eCollection 2016.

DOI:10.1371/journal.pone.0150357
PMID:26959487
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4784912/
Abstract

Proper function of endoplasmic reticulum (ER) and mitochondria is crucial for cellular homeostasis, and dysfunction at either site as well as perturbation of mitochondria-associated ER membranes (MAMs) have been linked to neurodegenerative and metabolic diseases. Previously, we have observed an increase in ROS and apoptosis levels in patient-derived fibroblasts with remethylation disorders causing homocystinuria. Here we show increased mRNA and protein levels of Herp, Grp78, IP3R1, pPERK, ATF4, CHOP, asparagine synthase and GADD45 in patient-derived fibroblasts suggesting ER stress and calcium perturbations in homocystinuria. In addition, overexpressed MAM-associated proteins (Grp75, σ-1R and Mfn2) were found in these cells that could result in mitochondrial calcium overload and oxidative stress increase. Our results also show an activation of autophagy process and a substantial degradation of altered mitochondria by mitophagy in patient-derived fibroblasts. Moreover, we have observed that autophagy was partially abolished by antioxidants suggesting that ROS participate in this process that may have a protective role. Our findings argue that alterations in Ca2+ homeostasis and autophagy may contribute to the development of this metabolic disorder and suggest a therapeutic potential in homocystinuria for agents that stabilize calcium homeostasis and/or restore the proper function of ER-mitochondria communications.

摘要

内质网（ER）和线粒体的正常功能对于细胞稳态至关重要，任何一个部位的功能障碍以及线粒体相关内质网膜（MAM）的扰动都与神经退行性疾病和代谢性疾病有关。此前，我们观察到患有导致高胱氨酸尿症的重甲基化障碍的患者来源成纤维细胞中活性氧（ROS）和凋亡水平升高。在此我们发现，患者来源的成纤维细胞中Herp、Grp78、IP3R1、磷酸化PERK（pPERK）、ATF4、CHOP、天冬酰胺合成酶和GADD45的mRNA和蛋白质水平升高，提示高胱氨酸尿症中存在内质网应激和钙紊乱。此外，在这些细胞中发现了过表达的MAM相关蛋白（Grp75、σ-1R和Mfn2），这可能导致线粒体钙超载和氧化应激增加。我们的结果还显示患者来源的成纤维细胞中自噬过程被激活，异常线粒体通过线粒体自噬大量降解。此外，我们观察到抗氧化剂部分消除了自噬，提示ROS参与了这一可能具有保护作用的过程。我们的研究结果表明，Ca2+稳态和自噬的改变可能促成这种代谢紊乱的发展，并提示对于稳定钙稳态和/或恢复内质网-线粒体通讯正常功能的药物，高胱氨酸尿症具有治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1f/4784912/446318ce4fbc/pone.0150357.g010.jpg
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