Modulation of Mitochondrial Membrane Potential and ROS Generation by Nicotinamide in a Manner Independent of SIRT1 and Mitophagy.
Modulation of Mitochondrial Membrane Potential and ROS Generation by Nicotinamide in a Manner Independent of SIRT1 and Mitophagy.
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DOI：
10.14348/molcells.2017.0081
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发表时间：
2017-07-31
影响因子：
3.8
通讯作者：
Hwang ES
中科院分区：
文献类型：
--
作者：
Song SB;Jang SY;Kang HT;Wei B;Jeoun UW;Yoon GS;Hwang ES
烟酰胺（NAM）通过促进NAD+氧化还原稳态在生理学中起重要作用。重要的是，在高剂量下，它可以保护氧化应激下的细胞，并在各种疾病中显示出治疗效果。在我们以前的研究中，NAM降低了活性氧（ROS）水平，延长了原代人类细胞的细胞寿命。在处理过的细胞中，NAD+/NADH和SIRT 1活性水平增加，而线粒体含量通过自噬激活降低。剩余的线粒体标记有低超氧化物水平和高膜电位（Δ Δ μ m）;我们假设NAM的处理诱导了对去极化线粒体具有选择性的线粒体自噬激活，从而产生高水平的ROS。然而，SIRT 1介导的选择性线粒体自噬的证据从未被提供。这项研究试图解释NAM降低ROS水平和增加Δ m的机制。我们的研究结果表明，NAM和SIRT 1的激活对线粒体生理产生相当不同的影响。此外，未发现ROS和Δ λ m的变化通过自噬或SIRT激活介导。相反，NAM通过直接减少电子传递来抑制超氧化物的产生，并通过抑制线粒体渗透性转换孔的形成来增加Δ λ m。我们的研究结果剖析了细胞NAD+氧化还原调节的影响，并强调了线粒体以及细胞质中NAD+/NADH比率在维持线粒体质量中的重要性。
Nicotinamide (NAM) plays essential roles in physiology through facilitating NAD+ redox homeostasis. Importantly, at high doses, it protects cells under oxidative stresses, and has shown therapeutic effectiveness in a variety of disease conditions. In our previous studies, NAM lowered reactive oxygen species (ROS) levels and extended cellular life span in primary human cells. In the treated cells, levels of NAD+/NADH and SIRT1 activity increased, while mitochondrial content decreased through autophagy activation. The remaining mitochondria were marked with low superoxide levels and high membrane potentials (Δψm); we posited that the treatment of NAM induced an activation of mitophagy that is selective for depolarized mitochondria, which produce high levels of ROS. However, evidence for the selective mitophagy that is mediated by SIRT1 has never been provided. This study sought to explain the mechanisms by which NAM lowers ROS levels and increases Δψm. Our results showed that NAM and SIRT1 activation exert quite different effects on mitochondrial physiology. Furthermore, the changes in ROS and Δψm were not found to be mediated through autophagy or SIRT activation. Rather, NAM suppressed superoxide generation via a direct reduction of electron transport, and increased Δψm via suppression of mitochondrial permeability transition pore formation. Our results dissected the effects of cellular NAD+ redox modulation, and emphasized the importance of the NAD+/NADH ratio in the mitochondria as well as the cytosol in maintaining mitochondrial quality.