Elevated type I interferon responses potentiate metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice.
Elevated type I interferon responses potentiate metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice.
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DOI：
10.1126/sciadv.abe7548
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发表时间：
2021-05
期刊：
影响因子：
13.6
通讯作者：
West AP
中科院分区：
文献类型：
--
作者：
Lei Y;Guerra Martinez C;Torres-Odio S;Bell SL;Birdwell CE;Bryant JD;Tong CW;Watson RO;West LC;West AP
IFN-I-NRF 2信号转导失衡驱动POLG突变小鼠的免疫代谢功能障碍、炎症和过早衰老。线粒体功能障碍是人类疾病中炎症反应的关键驱动因素。然而，目前还不清楚是否在线粒体先天免疫串扰的改变有助于线粒体疾病和衰老的病理生物学。使用聚合酶γ（POLG）突变模型的线粒体DNA不稳定性，我们报告说，异常激活的I型干扰素（IFN-I）先天免疫轴增强免疫代谢功能障碍，减少健康的跨度，并加速老化的突变小鼠。在机制上，升高的IFN-I信号传导抑制核因子红细胞2相关因子2（NRF 2）的活化，其增加氧化应激，增强促炎细胞因子应答，并加速代谢功能障碍。IFN-I信号传导的消融通过恢复NRF 2活性和减少有氧糖酵解来减弱炎症表型，这联合收割机减轻老年突变小鼠的心血管和骨髓功能障碍。这些发现进一步推进了我们对线粒体功能障碍如何塑造先天免疫反应的认识，并为理解POLG相关疾病和衰老中的线粒体驱动的免疫病理学提供了框架。
IFN-I–NRF2 signaling imbalances drive immunometabolic dysfunction, inflammation, and premature aging in POLG mutator mice. Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune cross-talk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces health span, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2–related factor 2 (NRF2), which increases oxidative stress, enhances proinflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyperinflammatory phenotypes by restoring NRF2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related disorders and aging.
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DOI：
10.1083/jcb.201701107
发表时间：
2017-12-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hos NJ;Ganesan R;Gutiérrez S;Hos D;Klimek J;Abdullah Z;Krönke M;Robinson N
通讯作者：
Robinson N
影响因子：
7.3
作者：
Davies, Thomas G.;Wixted, William E.;Kerns, Jeffrey K.
通讯作者：
Kerns, Jeffrey K.
影响因子：
3.8
作者：
Eom, Soyong;Lee, Ha Neul;Lee, Young-Mock
通讯作者：
Lee, Young-Mock
影响因子：
7.4
作者：
Erkens, Ralf;Kramer, Christian M.;Cortese-Krott, Miriam M.
通讯作者：
Cortese-Krott, Miriam M.
影响因子：
29
作者：
Ahlqvist, Kati J.;Hamalainen, Riikka H.;Suomalainen, Anu
通讯作者：
Suomalainen, Anu