Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2013 Jul 24;8(7):e69282. doi: 10.1371/journal.pone.0069282. Print 2013.
Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5'-UTRs that likely improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD(+) redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease.
原发性线粒体呼吸链（RC）疾病在病因和表现上具有异质性，但共同损害细胞能量代谢。RC 功能障碍导致全身细胞后果的机制尚不清楚。为了确定 RC 疾病的共同细胞反应，对人类原发性 RC 疾病骨骼肌和成纤维细胞转录组进行了综合基因、途径和系统生物学分析。在不同 RC 复合物和遗传病因的肌肉中，明显存在变化，这些变化与其他原发性 RC 疾病模型中的先前报道一致，涉及 RNA 处理、蛋白质翻译、运输和降解以及肌肉结构中涉及的基因的失调。还发现全局转录和转录后失调以高度组织特异性的方式发生。特别是，RC 疾病肌肉中细胞溶质核糖体蛋白的转录减少，提示合成代谢过程减少，线粒体核糖体蛋白的转录增加，5'-UTR 变短，可能提高翻译效率，以及含有富含 AU 的元素的 3'-UTR 稳定。RC 疾病成纤维细胞表现出一种非常相似的全局转录组失调模式，但方向相反。与这些转录效应平行，RC 疾病失调了涉及 FOXO、PPAR、sirtuins、AMPK 和 mTORC1 的综合营养感应信号网络，这些网络共同感知营养可用性并调节细胞生长。通过在 RC 抑制细胞中进行磷酸激酶免疫印迹分析，验证了营养感应信号网络中中心节点的改变活性。值得注意的是，用烟酰胺治疗 RC 突变成纤维细胞以增强 sirtuins 和 PPAR 活性也使 mTORC1 和 AMPK 信号正常化，恢复 NADH/NAD(+) 氧化还原平衡，并改善细胞呼吸能力。这些数据特别强调了一种共同的发病机制，该机制跨越了个体 RC 疾病的不同分子和生化病因，涉及全局转录组修饰。我们进一步将综合营养感应信号网络确定为一种共同的细胞反应，该反应介导并可能对原发性线粒体 RC 疾病的组织特异性后遗症进行靶向治疗。
