Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts.
Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts.
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DOI：
10.1111/acel.12122
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发表时间：
2013-12
期刊：
影响因子：
7.8
通讯作者：
Sell C
中科院分区：
文献类型：
--
作者：
Lerner C;Bitto A;Pulliam D;Nacarelli T;Konigsberg M;Van Remmen H;Torres C;Sell C
线粒体和核基因的协调表达是维持线粒体正常功能所必需的。然而，确保这种协调的精确机制并没有很好地定义。我们发现从线粒体到细胞核的信号通过自噬和p62/SQSTM1转换的变化受到哺乳动物雷帕霉素靶蛋白（mTOR）活性的影响。降低mTOR活性增加自噬通量，增强线粒体膜电位，减少细胞内活性氧，延长复制寿命。这些影响似乎部分是由p62/SQSTM1和Keap1之间的相互作用介导的。这种相互作用允许核因子红细胞2样2 （NFE2L2，也称为核因子相关因子2或NRF2）的核积累，核呼吸因子1 （NRF1）的表达增加，核编码线粒体基因的表达增加，如线粒体转录因子A和线粒体编码基因参与氧化磷酸化。这些发现揭示了细胞内信号网络的一部分，该网络将线粒体更新与线粒体更新结合在一起，以维持细胞内的稳态，并提出了mTOR活性降低可能延长寿命的机制。
Coordinated expression of mitochondrial and nuclear genes is required to maintain proper mitochondrial function. However, the precise mechanisms that ensure this coordination are not well defined. We find that signaling from mitochondria to the nucleus is influenced by mammalian target of rapamycin (mTOR) activity via changes in autophagy and p62/SQSTM1 turnover. Reducing mTOR activity increases autophagic flux, enhances mitochondrial membrane potential, reduces reactive oxygen species within the cell, and increases replicative life span. These effects appear to be mediated in part by an interaction between p62/SQSTM1 and Keap1. This interaction allows nuclear accumulation of the nuclear factor erythroid 2-like 2 (NFE2L2, also known as nuclear factor related factor 2 or NRF2), increased expression of the nuclear respiratory factor 1 (NRF1), and increased expression of nuclear-encoded mitochondrial genes, such as the mitochondrial transcription factor A, and mitochondrial-encoded genes involved in oxidative phosphorylation. These findings reveal a portion of the intracellular signaling network that couples mitochondrial turnover with mitochondrial renewal to maintain homeostasis within the cell and suggest mechanisms whereby a reduction in mTOR activity may enhance longevity.
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影响因子：
7.8
作者：
Liu, L;Trimarchi, JR;Keefe, DL
通讯作者：
Keefe, DL
影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
11.4
作者：
Beyaert, R;Cuenda, A;Fiers, W
通讯作者：
Fiers, W
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje