Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway.
Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway.
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KML001对人T细胞端粒损伤可通过p53-PGC-1α途径诱导线粒体功能障碍。
DOI：
10.1038/s41419-020-03238-7
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发表时间：
2020-12-02
影响因子：
9
通讯作者：
Yao ZQ
中科院分区：
文献类型：
--
作者：
Schank M;Zhao J;Wang L;Li Z;Cao D;Nguyen LN;Dang X;Khanal S;Nguyen LNT;Thakuri BKC;Ogbu SC;Lu Z;Zhang J;Wu XY;Morrison ZD;El Gazzar M;Ning S;Moorman JP;Yao ZQ
端粒侵蚀和线粒体功能障碍是衰老细胞的显著特征，细胞功能进行性下降。端粒损伤是否诱导人T淋巴细胞线粒体功能障碍，这是适应性宿主免疫抗感染和恶性肿瘤的主要组成部分，目前尚不清楚。我们最近发现，端粒靶向药物KML 001对端粒完整性的破坏，通过端粒DNA损伤反应（DDR）诱导T细胞衰老和凋亡。在这项研究中，我们使用KML 001进一步研究端粒损伤在衰老T细胞线粒体失调中的作用和机制。我们证明，通过KML 001靶向端粒诱导线粒体功能障碍，表现为线粒体肿胀增加和线粒体膜电位降低，氧化磷酸化，线粒体DNA含量，线粒体呼吸，耗氧量，糖酵解和ATP能量产生。从机制上讲，我们发现KML 001诱导的端粒DDR激活了p53信号，这反过来又抑制了过氧化物酶体增殖物激活受体-γ共激活因子1 α（PGC-1α）和核呼吸因子1（NRF-1）的表达，导致T细胞线粒体功能障碍。这些结果在端粒和线粒体生物学之间建立了直接联系，为人类T细胞衰老网络提供了新的线索，并证明了p53-PGC-1α-NRF-1轴在端粒DDR的设置中有助于线粒体功能障碍。这项研究表明，靶向这一轴可能提供一种替代的，新的方法来预防端粒损伤介导的线粒体和T细胞功能障碍，以对抗广泛的免疫衰老相关的人类疾病。
Telomere erosion and mitochondrial dysfunction are prominent features of aging cells with progressive declines of cellular functions. Whether telomere injury induces mitochondrial dysfunction in human T lymphocytes, the major component of adaptive host immunity against infection and malignancy, remains unclear. We have recently shown that disruption of telomere integrity by KML001, a telomere-targeting drug, induces T cell senescence and apoptosis via the telomeric DNA damage response (DDR). In this study, we used KML001 to further investigate the role and mechanism of telomere injury in mitochondrial dysregulation in aging T cells. We demonstrate that targeting telomeres by KML001 induces mitochondrial dysfunction, as evidenced by increased mitochondrial swelling and decreased mitochondrial membrane potential, oxidative phosphorylation, mitochondrial DNA content, mitochondrial respiration, oxygen consumption, glycolysis, and ATP energy production. Mechanistically, we found that the KML001-induced telomeric DDR activated p53 signaling, which in turn repressed the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1), leading to T cell mitochondrial dysfunction. These results, forging a direct link between telomeric and mitochondrial biology, shed new light on the human T cell aging network, and demonstrate that the p53-PGC-1α-NRF-1 axis contributes to mitochondrial dysfunction in the setting of telomeric DDR. This study suggests that targeting this axis may offer an alternative, novel approach to prevent telomere damage-mediated mitochondrial and T cell dysfunctions to combat a wide range of immune aging-associated human diseases.
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影响因子：
14.9
作者：
Babicki S;Arndt D;Marcu A;Liang Y;Grant JR;Maciejewski A;Wishart DS
通讯作者：
Wishart DS
影响因子：
2
作者：
Arkus, N
通讯作者：
Arkus, N
影响因子：
29
作者：
Li, Yinyin;Shen, Yi;Weyand, Cornelia M.
通讯作者：
Weyand, Cornelia M.
DOI：
10.1097/mco.0b013e3282f0dbfb
发表时间：
2007-11-01
影响因子：
3.1
作者：
Conley, Kevin E.;Marcinek, David J.;Villarin, Jason
通讯作者：
Villarin, Jason
影响因子：
4.8
作者：
Boulares, AH;Yakovlev, AG;Smulson, M
通讯作者：
Smulson, M