Host cell sensing and restoration of mitochondrial function and metabolism within Helicobacter pylori VacA intoxicated cells.
Host cell sensing and restoration of mitochondrial function and metabolism within Helicobacter pylori VacA intoxicated cells.
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DOI：
10.1128/mbio.02117-23
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发表时间：
2023-10-31
期刊：
影响因子：
6.4
通讯作者：
Blanke, Steven R.
中科院分区：
文献类型：
--
作者：
Seeger, Ami Y.;Zaidi, Faisal;Alhayek, Sammy;Jones, Rachel M.;Zohair, Huzaifa;Holland, Robin L.;Kim, Ik-Jung;Blanke, Steven R.
关键词：
幽门螺杆菌空泡毒素A(VacA)是一种细胞内作用蛋白外毒素，可导致宿主细胞内线粒体功能障碍和能量耗竭。尽管暴露于VacA会导致线粒体功能障碍，但最近的一项研究表明，在有限的VacA暴露后，线粒体功能和细胞ATP水平会以一种时间依赖的方式恢复。为研究宿主细胞检测和响应细胞内VacA的机制而进行的研究发现，一磷酸腺苷(AMP)激活的蛋白激酶(AMPK)是细胞能量状态依赖毒素变化的传感器。对VacA的反应激活AMPK被证明协调了线粒体动力学的改变，导致线粒体功能的恢复。具体地说，依赖于动力蛋白相关蛋白1(DRP-1)的线粒体分裂上调导致了丝状线粒体的可逆碎裂和线粒体相关VacA的时间依赖性减少，这表明碎片对于从线粒体中移除Vaca是重要的。DRP-1水平降低的细胞更容易受到VacA依赖的细胞死亡的影响，这表明线粒体动力学对于通过减少线粒体相关毒素来维持细胞活力是重要的。总之，这些研究支持一种模型，即细胞对VacA依赖的线粒体功能障碍的反应与宿主细胞对线粒体动力学的调节有关。这项研究为细胞识别和对细胞内作用的毒素调节宿主细胞功能的反应提供了新的见解，这可能与越来越多的病原微生物和病毒相关，这些病原微生物和病毒被发现将线粒体作为其毒力策略的一部分。幽门螺杆菌持续的人类胃部感染是胃恶性肿瘤发生的最重要的危险因素，而胃恶性肿瘤是全球癌症相关死亡的主要原因之一。幽门螺杆菌定植和胃病严重程度的一个重要毒力因子是外毒素VacA，它由细菌分泌，调节胃细胞的功能特性。VacA通过破坏线粒体发挥作用，线粒体通过破坏能量产生来损害宿主细胞的新陈代谢。在这里，我们证明了中毒的细胞有能力检测VacA介导的损伤，并协调线粒体功能的修复，从而恢复细胞的健康和活力。这项研究为细胞识别和对细胞内作用的毒素调节宿主细胞功能的反应提供了新的见解，这可能与越来越多的病原微生物和病毒相关，这些病原微生物和病毒被发现将线粒体作为其毒力策略的一部分。
Helicobacter pylori vacuolating cytotoxin A (VacA) is an intracellular-acting protein exotoxin that induces mitochondrial dysfunction and energy depletion within host cells. Although exposure to VacA results in mitochondrial dysfunction, one recent study revealed that, following limited exposure to VacA, mitochondrial function and cellular ATP levels were restored in a time-dependent manner. Studies performed to address the mechanism by which host cells detect and respond to intracellular VacA identified the adenosine monophosphate (AMP)-activated protein kinase (AMPK) as a sensor of toxin-dependent alterations in cellular energy status. Activation of AMPK in response to VacA was demonstrated to orchestrate alterations in mitochondrial dynamics which resulted in restoration of mitochondrial function. Specifically, upregulation of dynamin-related protein 1 (Drp-1)-dependent mitochondrial fission resulted in reversible fragmentation of filamentous mitochondria and time-dependent reduction in mitochondrial-associated VacA, suggesting that fragmentation is important for removal of VacA from mitochondria. Cells with reduced levels of Drp-1 were more susceptible to VacA-dependent cell death, suggesting that mitochondrial dynamics is important for maintaining cell viability through the reduction in mitochondrial-associated toxin. Collectively, these studies support a model that cellular recovery and survival in response to VacA-dependent mitochondrial dysfunction is linked to host cell modulation of mitochondrial dynamics. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies. Persistent human gastric infection with Helicobacter pylori is the single most important risk factor for development of gastric malignancy, which is one of the leading causes of cancer-related deaths worldwide. An important virulence factor for Hp colonization and severity of gastric disease is the protein exotoxin VacA, which is secreted by the bacterium and modulates functional properties of gastric cells. VacA acts by damaging mitochondria, which impairs host cell metabolism through impairment of energy production. Here, we demonstrate that intoxicated cells have the capacity to detect VacA-mediated damage, and orchestrate the repair of mitochondrial function, thereby restoring cellular health and vitality. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies.
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影响因子：
1.2
作者：
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通讯作者：
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影响因子：
3.4
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影响因子：
29
作者：
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DOI：
10.1083/jcb.200609061
发表时间：
2007-04-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gauthier NC;Monzo P;Gonzalez T;Doye A;Oldani A;Gounon P;Ricci V;Cormont M;Boquet P
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影响因子：
3.1
作者：
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通讯作者：
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