通过操纵NAD+/NADH比率来补充线粒体电子运输链
Denis V Titov1, Valentin Cracan1, Russell P Goodman2
1Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Broad Institute, Cambridge, MA, USA.
Science (New York, N.Y.)
|April 29, 2016
概括
电子传输链 (ETC) 的功能障碍会导致疾病. 这项研究表明,使用LbNOX酶增加人体细胞中的NAD+/NADH比率可以解决代谢问题,并表明减少压力有助于线粒体疾病.
科学领域:
- 生物化学
- 细胞生物学
- 人类生理学
背景情况:
- 电子传输链 (ETC) 的功能障碍与人类疾病有关.
- 已知病理因素之一是线粒体ATP的减少.
- 在疾病发病过程中,NAD+/NADH比率的作用不太清楚.
研究的目的:
- 研究改变的NAD+/NADH比对细胞代谢和信号的影响.
- 探索操纵人体细胞中特定的NAD+/NADH比率的治疗潜力.
- 阐明降解应激对线粒体病变的贡献.
主要方法:
- 作为一种遗传工具,利用了来自Lactobacillus brevis的形成水的NADH氧化酶 (LbNOX).
- 在细胞质或线粒体中对LbNOX进行特定表达的人类细胞工程.
- 评估了新陈代谢流,包括葡萄糖生成和信号通路.
主要成果:
- 在人体细胞中,LbNOX的表达成功地增加了分区特异性的NAD+/NADH比率.
- 恢复NAD ((+) /NADH平衡改善了与ETC受损相关的增殖和代谢缺陷.
- 关键代谢流程和信号对细胞和线粒体NAD+/NADH比率的依赖已被证明.
结论:
- 改变的NAD ((+) /NADH比率,表明还原性压力,在线粒体发病过程中起着重要作用.
- 使用LbNOX对细胞氧化还原状态进行有针对性的操纵是治疗ETC相关疾病的可行策略.
- LbNOX是研究氧化还原生物学和开发新疗法的一种有价值的工具.
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