Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates.
Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates.
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DOI：
10.1038/s41598-017-01678-4
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发表时间：
2017-05-10
影响因子：
4.6
通讯作者：
Abramov AY
中科院分区：
文献类型：
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作者：
Bartolome F;Esteras N;Martin-Requero A;Boutoleau-Bretonniere C;Vercelletto M;Gabelle A;Le Ber I;Honda T;Dinkova-Kostova AT;Hardy J;Carro E;Abramov AY
额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）患者中发现线粒体功能异常。编码 p62 蛋白的 p62 基因（也称为 SQSTM1）的突变在两种疾病中都有报道，支持 ALS/FTD 连续体的想法。在这项工作中，在 p62 基因携带两个独立致病性突变的 FTD 患者的成纤维细胞和 p62 敲低 (p62 KD) 人多巴胺能神经母细胞瘤细胞系 (SH-SY5Y) 中研究了 p62 在能量代谢中的作用。我们发现 p62 缺陷与复合物 I 线粒体呼吸受抑制有关，因为电子传递链缺乏 NADH。这种缺陷还与 NADPH 水平升高有关，反映了戊糖磷酸途径的更高激活，因为这伴随着更高的胞质还原型谷胱甘肽 (GSH) 水平。复合物 I 抑制导致线粒体膜电位降低和胞质 ROS 产生增加。转录因子 Nrf2 的药理激活可增加 p62 缺陷细胞中线粒体 NADH 水平并恢复线粒体膜电位。我们的结果表明，该表型是由功能丧失效应引起的，因为在突变成纤维细胞和 p62 KD 模型中都发现了类似的改变。这些发现强调了能量代谢在与 p62 缺乏相关的病理生理事件中的意义。
Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y). We found that p62 deficiency is associated with inhibited complex I mitochondrial respiration due to lack of NADH for the electron transport chain. This deficiency was also associated with increased levels of NADPH reflecting a higher activation of pentose phosphate pathway as this is accompanied with higher cytosolic reduced glutathione (GSH) levels. Complex I inhibition resulted in lower mitochondrial membrane potential and higher cytosolic ROS production. Pharmacological activation of transcription factor Nrf2 increased mitochondrial NADH levels and restored mitochondrial membrane potential in p62-deficient cells. Our results suggest that the phenotype is caused by a loss-of-function effect, because similar alterations were found both in the mutant fibroblasts and the p62 KD model. These findings highlight the implication of energy metabolism in pathophysiological events associated with p62 deficiency.