Pyrroloquinoline Quinone, a Redox-Active o-Quinone, Stimulates Mitochondrial Biogenesis by Activating the SIRT1/PGC-1α Signaling Pathway
Pyrroloquinoline Quinone, a Redox-Active o-Quinone, Stimulates Mitochondrial Biogenesis by Activating the SIRT1/PGC-1α Signaling Pathway
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DOI：
10.1021/acs.biochem.7b01185
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发表时间：
2017-12-19
期刊：
影响因子：
2.9
通讯作者：
Akagawa, Mitsugu
中科院分区：
文献类型：
--
作者：
Saihara, Kazuhiro;Kamikubo, Ryosuke;Akagawa, Mitsugu
吡咯喹啉醌（PQQ）是一种氧化还原活性的邻醌，存在于各种食物和哺乳动物组织中，由于其增强线粒体生物发生的能力对健康有许多益处，因此受到越来越多的关注。然而，其潜在的分子机制仍不完全清楚。我们现在已经确定，小鼠NIH/3T3成纤维细胞暴露于生理相关浓度的PQQ显著刺激线粒体生物发生。NIH/3T3细胞在10-100 nM PQQ中暴露48小时，导致Mitotracker染色水平、线粒体DNA含量和线粒体编码的细胞色素c氧化酶亚基1 （MTCO1）蛋白水平升高。此外，我们观察到PQQ处理诱导过氧化物酶体增殖体激活受体- γ -辅助激活因子1 α (PGC-1 α)的去乙酰化，促进其核易位和靶基因表达，但不影响其蛋白水平，这意味着NAD（+）依赖性蛋白去乙酰化酶sirtuin 1 （SIRT1）的活性增加。事实上，使用SIRT1选择性抑制剂EX-527治疗，阻碍了PQQ刺激PGC-1 α介导的线粒体生物发生的能力。我们还发现PQQ处理引起细胞NAD（+）水平的浓度依赖性增加，但不引起总NAD（+）和NADH水平的浓度依赖性增加。我们的研究结果表明，pqq诱导的线粒体生物发生可归因于SIRT1/PGC-1 α信号通路的激活，通过增强细胞NAD（+）的形成。
Pyrroloquinoline quinone (PQQ), a redox-active o-quinone found in various foods and mammalian tissues, has received an increasing amount of attention because of a number of health benefits that can be attributed to its ability to enhance mitochondrial biogenesis. However, its underlying molecular mechanism remains incompletely understood. We have now established that the exposure of mouse NIH/3T3 fibroblasts to a physiologically relevant concentration of PQQ significantly stimulates mitochondrial biogenesis. The exposure of NIH/3T3 cells to 10-100 nM PQQ for 48 h resulted in increased levels of Mitotracker staining, mitochondrial DNA content, and mitochondrially encoded cytochrome c oxidase subunit 1 (MTCO1) protein. Moreover, we observed that PQQ treatment induces deacetylation of the peroxisome proliferator-activated receptor-gamma-coactivator 1 alpha (PGC-1 alpha) and facilitates its nuclear translocation and target gene expression but does not affect its protein levels, implying increased activity of the NAD(+)-dependent protein deacetylase sirtuin 1 (SIRT1). Indeed, treatment with a SIRT1 selective inhibitor, EX-527, hampered the ability of PQQ to stimulate PGC-1 alpha-mediated mitochondrial biogenesis. We also found that the PQQ treatment caused a concentration-dependent increase in the cellular NAD(+) levels, but not the total NAD(+) and NADH levels. Our results suggest that PQQ-inducible mitochondrial biogenesis can be attributed to activation of the SIRT1/PGC-1 alpha signaling pathway by enhancing cellular NAD(+) formation.