Arduino Daniela M, Esteves A Raquel, Domingues A Filipa, Pereira Claudia M F, Cardoso Sandra M, Oliveira Catarina R
Centro de Neurociencias e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal.
BMB Rep. 2009 Nov 30;42(11):719-24. doi: 10.5483/bmbrep.2009.42.11.719.
Recent studies have revealed that endoplasmic reticulum (ER) disturbance is involved in the pathophysiology of neurodegenerative disorders, contributing to the activation of the ER stress-mediated apoptotic pathway. Therefore, we investigated here the molecular mechanisms underlying the ER-mitochondria axis, focusing on calcium as a potential mediator of cell death signals. Using NT2 cells treated with brefeldin A or tunicamycin, we observed that ER stress induces changes in the mitochondrial function, impairing mitochondrial membrane potential and distressing mitochondrial respiratory chain complex Moreover, stress stimuli at ER level evoked calcium fluxes between ER and mitochondria. Under these conditions, ER stress activated the unfolded protein response by an overexpression of GRP78, and also caspase-4 and-2, both involved upstream of caspase-9. Our findings show that ER and mitochondria interconnection plays a prominent role in the induction of neuronal cell death under particular stress circumstances.
最近的研究表明，内质网（ER）紊乱参与神经退行性疾病的病理生理过程，促使内质网应激介导的凋亡途径激活。因此，我们在此研究内质网-线粒体轴的分子机制，重点关注钙作为细胞死亡信号的潜在介质。使用经布雷菲德菌素A或衣霉素处理的NT2细胞，我们观察到内质网应激会诱导线粒体功能改变，损害线粒体膜电位并使线粒体呼吸链复合体受损。此外，内质网水平的应激刺激引发了内质网与线粒体之间的钙流动。在这些条件下，内质网应激通过GRP78的过表达激活了未折叠蛋白反应，还激活了半胱天冬酶-4和-2，二者均参与半胱天冬酶-9的上游过程。我们的研究结果表明，内质网与线粒体的相互连接在特定应激情况下诱导神经元细胞死亡中起重要作用。
