Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways
Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways
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DOI：
10.1096/fj.07-9610com
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发表时间：
2008-03-01
期刊：
影响因子：
4.8
通讯作者：
Ames, Bruce N.
中科院分区：
文献类型：
--
作者：
Atamna, Hani;Nguyen, Andy;Ames, Bruce N.
亚甲基蓝(MB)在临床上用于治疗多种疾病已有近一个世纪的历史。我们发现，MB和其他二氨基吩噻嗪通过>；20群体倍增(PDLS)延长了组织培养中人IMR90成纤维细胞的寿命。MB通过增强线粒体功能在NM水平延缓IMR90的衰老。MB使线粒体复合体IV增加30%，使细胞耗氧量增加37%-70%，增加血红素合成，并逆转由过氧化氢或镉引起的过早衰老。MB还能诱导HepG2细胞中的2相抗氧化酶。黄素依赖的酶使用NAD(P)H将MB还原为亮亚甲基蓝(MBH2)，而细胞色素c将MBH2重新氧化为MB。对大鼠肝线粒体裂解产物的实验表明，MB/细胞色素c的比值对于MB的保护作用是重要的。我们认为，MB引起的细胞衰老延迟是由于线粒体中MB和MBH2之间的循环所致，这可能是线粒体比活性增加的部分原因。MB在氧化和还原状态之间的循环可能会阻止线粒体产生氧化剂。线粒体功能障碍和氧化应激被认为是导致细胞衰老和衰老的关键异常。MB可能有助于延缓阿尔茨海默病患者随年龄增长的线粒体功能障碍和复合体IV的减少。
Methylene blue (MB) has been used clinically for about a century to treat numerous ailments. We show that MB and other diaminophenothiazines extend the life span of human IMR90 fibroblasts in tissue culture by >20 population doubling (PDLs). MB delays senescence at nM levels in IMR90 by enhancing mitochondrial function. MB increases mitochondrial complex IV by 30%, enhances cellular oxygen consumption by 37-70%, increases heme synthesis, and reverses premature senescence caused by H2O2 or cadmium. MB also induces phase-2 antioxidant enzymes in hepG2 cells. Flavin-dependent enzymes are known to use NAD(P)H to reduce MB to leucomethylene blue (MBH2), whereas cytochrome c reoxidizes MBH2 to MB. Experiments on lysates from rat liver mitochondria suggest the ratio MB/cytochrome c is important for the protective actions of MB. We propose that the cellular senescence delay caused by MB is due to cycling between MB and MBH2 in mitochondria, which may partly explain the increase in specific mitochondrial activities. Cycling of MB between oxidized and reduced forms may block oxidant production by mitochondria. Mitochondrial dysfunction and oxidative stress are thought to be key aberrations that lead to cellular senescence and aging. MB may be useful to delay mitochondrial dysfunction with aging and the decrease in complex IV in Alzheimer disease.