Activation of the mTORC1/PGC-1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium
Activation of the mTORC1/PGC-1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium
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DOI：
10.1152/ajplung.00244.2018
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发表时间：
2019-06-01
影响因子：
4.9
通讯作者：
Romero, Freddy
中科院分区：
文献类型：
--
作者：
Summer, Ross;Shaghaghi, Hoora;Romero, Freddy
细胞衰老是细胞失去增殖能力但仍保持代谢活性的生物学过程。虽然最初被认为是限制癌症形成的保护机制，但现在认识到细胞衰老也有助于疾病的发展，包括常见的呼吸道疾病，如慢性阻塞性肺病和特发性肺纤维化。虽然许多因素与细胞衰老的发展有关，但线粒体功能障碍已成为一个重要的致病因素。在这项研究中，我们发现，由哺乳动物靶雷帕霉素/过氧化物酶体增殖物激活受体-γ复合物1 α/β（mTOR/PGC-1（-/-））轴驱动的线粒体生物合成途径在衰老的肺上皮细胞中显著上调。使用两种不同的模型，我们表明，这一途径的激活与增强线粒体生物合成的其他特征相关，包括增加每个细胞的线粒体数量，增加氧化磷酸化，增强线粒体活性氧（ROS）的产生。此外，我们发现，药物抑制mTORC 1复合物与雷帕霉素不仅恢复线粒体稳态，但也减少了细胞衰老的肺上皮细胞博莱霉素。同样，脑组织特异性抗氧化剂治疗也有效地抑制了这些细胞中的mTORC 1活化，同时减少了线粒体生物合成和细胞衰老。总之，这项研究提供了肺上皮细胞线粒体生物发生和细胞衰老之间的机制联系，并表明旨在阻断mTORC 1/PGC-1 α/β轴或减少ROS诱导的分子损伤的策略可能有效治疗衰老相关的肺部疾病。
Cellular senescence is a biological process by which cells lose their capacity to proliferate yet remain metabolically active. Although originally considered a protective mechanism to limit the formation of cancer, it is now appreciated that cellular senescence also contributes to the development of disease, including common respiratory ailments such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. While many factors have been linked to the development of cellular senescence, mitochondrial dysfunction has emerged as an important causative factor. In this study, we uncovered that the mitochondrial biogenesis pathway driven by the mammalian target of rapamycin/peroxisome proliferator-activated receptor-gamma complex 1 alpha/beta(mTOR/PGC-1(-/-)) axis is markedly upregulated in senescent lung epithelial cells. Using two different models, we show that activation of this pathway is associated with other features characteristic of enhanced mitochondrial biogenesis, including elevated number of mitochondrion per cell, increased oxidative phosphorylation, and augmented mitochondrial reactive oxygen species (ROS) production. Furthermore, we found that pharmacological inhibition of the mTORC1 complex with rapamycin not only restored mitochondrial homeostasis but also reduced cellular senescence to bleomycin in lung epithelial cells. Likewise, mitochondrial-specific antioxidant therapy also effectively inhibited mTORC1 activation in these cells while concomitantly reducing mitochondrial biogenesis and cellular senescence. In summary, this study provides a mechanistic link between mitochondrial biogenesis and cellular senescence in lung epithelium and suggests that strategies aimed at blocking the mTORC1/PGC-1 alpha/beta axis or reducing ROS-induced molecular damage could be effective in the treatment of senescence-associated lung diseases.