Heat shock protein 22 modulates NRF1/TFAM-dependent mitochondrial biogenesis and DRP1-sparked mitochondrial apoptosis through AMPK-PGC1α signaling pathway to alleviate the early brain injury of subarachnoid hemorrhage in rats.
Heat shock protein 22 modulates NRF1/TFAM-dependent mitochondrial biogenesis and DRP1-sparked mitochondrial apoptosis through AMPK-PGC1α signaling pathway to alleviate the early brain injury of subarachnoid hemorrhage in rats.
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DOI：
10.1016/j.redox.2021.101856
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发表时间：
2021-04
期刊：
影响因子：
11.4
通讯作者：
Duan C
中科院分区：
文献类型：
--
作者：
Fan H;Ding R;Liu W;Zhang X;Li R;Wei B;Su S;Jin F;Wei C;He X;Li X;Duan C
线粒体功能障碍已被广泛认为是蛛网膜下腔出血（SAH）引起的早期脑损伤（EBI）的一个有害因素，而EBI与神经功能预后不良密切相关。先前的研究表明，应激条件下热休克蛋白22 （hsp22）的增强是线粒体稳态、氧化应激和细胞凋亡的友好介质，从而加速神经系统的恢复。然而，没有研究证实hsp22是否在sah诱导的EBI中减轻线粒体应激和凋亡。我们的研究结果表明，内源性hsp22、p-AMPK/AMPK、PGC1α、TFAM、Nrf1和Drp1在SAH反应中在皮质神经元中显著上调，并伴有神经功能损伤、脑水肿、神经元变性、mtDNA和ATP水平降低、线粒体-细胞质色素c易位、氧化损伤和caspase 3参与的线粒体凋亡。然而，外源性hsp22维持神经功能，减少脑水肿，改善氧化应激和线粒体凋亡，这些作用高度依赖于PGC1α相关的线粒体生物发生/裂变，PGC1α siRNA的共同应用证明了这一点。此外，我们证明了用dorsomorphin阻断AMPK也会损害hsp22的神经保护作用，以及PGC1α及其相关途径分子的改变。这些数据表明，hsp22通过AMPK-PGC1α依赖的方式挽救线粒体功能发挥神经保护作用，通过正反馈调节TFAM/ nrf1诱导的线粒体生物发生，负反馈调节drp1触发的线粒体凋亡，进一步减轻氧化应激和脑损伤。通过hsp22促进生物发生和抑制线粒体过度裂变可能是缓解sah诱导的EBI的有效治疗方法。图示Hsp22通过AMPK-PGC1α信号通路调节线粒体生物发生和裂变，减轻SAH大鼠早期脑损伤。SAH蛛网膜下腔出血、Hsp22热休克蛋白22、AMPK腺苷5′单磷酸活化蛋白激酶、PGC1α过氧化物酶体增殖激活受体γ (PPARγ)辅激活因子1α、Drp1动力蛋白相关蛋白1、TFAM线粒体转录因子A、Nrf1核呼吸因子1、UCP2解偶联蛋白2、ROS活性氧、8-OHdG 8-羟基鸟嘌呤、MDA丙二醛、PCO蛋白羰基、Bcl-2 b细胞淋巴瘤-2、Bax Bcl-2相关X蛋白、小干扰核糖核酸。Hsp22在SAH后24小时在神经元中显著上调。Hsp22促进NRF1/ tfam依赖的线粒体生物发生。Hsp22抑制drp1引发的线粒体凋亡。AMPK-PGC1α通路参与hsp22介导的SAH后神经保护。调节线粒体的生物发生和裂变可能是治疗SAH的有效方法。
Mitochondrial dysfunction has been widely accepted as a detrimental factor in subarachnoid hemorrhage (SAH)-induced early brain injury (EBI), which is eminently related to poor neurologic function outcome. Previous studies have revealed that enhancement of heat shock protein 22 (hsp22) under conditions of stress is a friendly mediator of mitochondrial homeostasis, oxidative stress and apoptosis, thus accelerating neurological recovery. However, no study has confirmed whether hsp22 attenuates mitochondrial stress and apoptosis in the setting of SAH-induced EBI. Our results indicated that endogenous hsp22, p-AMPK/AMPK, PGC1α, TFAM, Nrf1 and Drp1 were significantly upregulated in cortical neurons in response to SAH, accompanied by neurologic impairment, brain edema, neuronal degeneration, lower level of mtDNA and ATP, mitochondria-cytosol translocation of cytochrome c, oxidative injury and caspase 3-involved mitochondrial apoptosis. However, exogenous hsp22 maintained neurological function, reduced brain edema, improved oxidative stress and mitochondrial apoptosis, these effects were highly dependent on PGC1α-related mitochondrial biogenesis/fission, as evidenced by co-application of PGC1α siRNA. Furthermore, we demonstrated that blockade of AMPK with dorsomorphin also compromised the neuroprotective actions of hsp22, along with the alterations of PGC1α and its associated pathway molecules. These data revealed that hsp22 exerted neuroprotective effects by salvaging mitochondrial function in an AMPK-PGC1α dependent manner, which modulates TFAM/Nrf1-induced mitochondrial biogenesis with positive feedback and DRP1-triggered mitochondrial apoptosis with negative feedback, further reducing oxidative stress and brain injury. Boosting the biogenesis and repressing excessive fission of mitochondria by hsp22 may be an efficient treatment to relieve SAH-elicited EBI. The schematic diagram demonstrating that Hsp22 modulates mitochondrial biogenesis and fission through AMPK-PGC1α signaling pathway to alleviate the early brain injury after SAH in rats. SAH subarachnoid hemorrhage, Hsp22 heat shock protein 22, AMPK Adenosine 5'monophosphate-activated protein kinase, PGC1α peroxisome proliferative activated receptor γ (PPARγ) coactivator 1α, Drp1 dynamin-related protein 1, TFAM mitochondrial transcription factor A, Nrf1 nuclear respiratory factor 1, UCP2 uncoupling protein 2, ROS reactive oxygen species, 8-OHdG 8-hydroxyguanine, MDA malondialdehyde, PCO protein carbonyl, Bcl-2 B-cell lymphoma-2, Bax Bcl-2 associated X protein, siRNA small interfering ribonucleic acid. Hsp22 is notably upregulated in neurons at 24 h after SAH. Hsp22 boosts the NRF1/TFAM-dependent mitochondrial biogenesis. Hsp22 represses DRP1-sparked mitochondrial apoptosis. AMPK-PGC1α pathway is involved in hsp22-mediated neuroprotection after SAH. Modulation of mitochondrial biogenesis and fission may be efficient for treating SAH.
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影响因子：
11.4
作者：
Mo J;Enkhjargal B;Travis ZD;Zhou K;Wu P;Zhang G;Zhu Q;Zhang T;Peng J;Xu W;Ocak U;Chen Y;Tang J;Zhang J;Zhang JH
通讯作者：
Zhang JH
影响因子：
4.5
作者：
Meyer JN;Leuthner TC;Luz AL
通讯作者：
Luz AL
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DOI：
10.1016/j.bbrc.2020.04.002
发表时间：
2020-06-11
影响因子：
3.1
作者：
Guo, Ai;Li, Kai;Xiao, Qian
通讯作者：
Xiao, Qian
影响因子：
3.5
作者：
Ekstrand, MI;Falkenberg, M;Larsson, NG
通讯作者：
Larsson, NG
影响因子：
5.6
作者：
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通讯作者：
Chuang YC