Intimate associations between SARS-CoV-2 and mitochondria suggest new angles of attack

SARS-CoV-2与线粒体之间的密切联系表明新的攻击角度

by John Hewitt , Phys.org

约翰·休伊特（Phys.org）

Colorized scanning electron micrograph of a dying cell (blue) heavily infected with SARS-CoV-2 (yellow), the virus that causes COVID-19. Credit: NIAID Integrated Research Facility, Fort Detrick, Maryland.

严重感染SARS-CoV-2（黄色）的病毒（即将导致COVID-19的病毒）的垂死细胞（蓝色）的彩色扫描电子显微照片。图片提供：马里兰州Fort Detrick的NIAID综合研究设施。

As one wise pundit recently observed, "everybody is a virologist now." For the many people whose interest in biology formerly began and ended with "the mitochondria is the powerhouse of the cell," a second axiom can now be offered, namely, that the virus is the thief of power. In other words, what the mitochondria giveth, the virus taketh away.

正如一位明智的专家最近观察到的那样，“现在每个人都是病毒学家。”对于许多以前对生物学感兴趣的人来说，其始于和结束于“线粒体是细胞的动力源”，现在可以提供第二个公理，即病毒是力量的窃贼。换句话说，只要线粒体产生，病毒就会带走。

It is only through the massive oxidative capabilities of mitochondria that cells of the immune system can generate enough energy within a sufficiently short period of time to power an effective immune response. This response includes massive short- order construction projects where cascading waves of signaling factors, antibodies and the armies of clones that pump them out are hastily hardscrabbled together. It is this same power that a virus hijacks upon gaining entry to a cell to use for copying, transcribing and translating their genomes (not always in that specific order) to almost exponentially replicate and propel themselves through the body at large.

只有通过线粒体的强大氧化能力，免疫系统的细胞才能在足够短的时间内产生足够的能量，以驱动有效的免疫反应。这种回应包括大规模的短期建设项目，其中匆匆忙忙地拼凑了一系列信号因子，抗体和将其泵出的克隆军队。病毒具有进入细胞的劫持能力，即用于复制，转录和翻译其基因组（并非总是按照特定顺序），从而几乎以指数方式复制并推动自身进入整个人体。

It should therefore be no surprise that mitochondria and viruses are, at least in a molecular sense, quite well aware of each other. For example, it has been shown that the Orf9b accessory protein of SARS-CoV-2 interacts with the mitochondrial

因此，线粒体和病毒至少在分子意义上彼此非常清楚也就不足为奇了。例如，已显示SARS-CoV-2的Orf9b辅助蛋白与线粒体相互作用

transport protein TOM70, while Orf9c interacts with respiratory complex I. The Nonstructural protein 2 (NSP2) has been localized to nuclear and mitochondrial prohibitins which in turn form a 16-20 subunit ring at the inner membrane. Prohibits are also believed to act as viral receptors for the Chikungunya and Dengue 2 viruses.

转运蛋白TOM70，而Orf9c与呼吸道复合体I相互作用。非结构蛋白2（NSP2）已定位于核和线粒体禁止素，后者在内膜上又形成16-20个亚基环。人们还认为，禁忌可以作为基孔肯雅热和登革热2病毒的病毒受体。

In a paper recently published in the journal Frontiers in Aging Neuroscience, researchers from Texas Tech University explore the idea that some viruses, including SARS-CoV-2, could even replicate within mitochondria-derived structures. The authors say "mitochondria-derived" because in the absence of full dynamic imaging of double-membraned vesicle (DMV) formation within associated inclusions of mitochondria, endoplasmic reticulum (ER), golgi and virus, the necessary actions that seemingly must occur for the virus to complete its life cycle can only be inferred.

在最近发表在《衰老神经科学的前沿》杂志上的一篇论文中，得克萨斯理工大学的研究人员探索了这样一种想法，即包括SARS-CoV-2在内的某些病毒甚至可以在线粒体衍生的结构中复制。作者之所以说“源于线粒体”，是因为在线粒体，内质网（ER），高尔基体和病毒的相关夹杂物内没有完整的双膜囊泡（DMV）形成的完整动态成像的情况下，表面活性剂似乎必须发生病毒只能完成其生命周期的推断。

Mitochondria closely associated with the ER where they are embraced by external rings of contractile dynamin-related peptide (DRP1) molecules which squeeze them down to diameters small enough for spontaneous fusion and budding to occur. The authors note that in the original SARS-CoV-1, ORF-9b enhances mitochondrial fusion and reduces the levels of Drp1. Budding off DMVs packed with their own mtDNA nucleoids, which then fuse with the plasma membrane of the cell, is important business for mitochondria. Exporting these highly immunogenic lures are one

线粒体与内质网紧密相关，它们被可收缩的动力蛋白相关肽（DRP1）分子的外环所包围，从而将它们压缩到足够小的直径，以使其自发融合和发芽。作者注意到，在原始的SARS-CoV-1中，ORF-9b增强了线粒体融合并降低了Drp1的水平。堆积有自己的mtDNA核苷酸并随后与细胞质膜融合的DMV对线粒体而言是重要的业务。出口这些高度免疫原性的诱饵是其中之一

way white blood cells sacrifice their own, in a sense, to ramp up immune responses. This all sounds a little familiar—during its lifecycle, SARS viruses must clothe their own genetic material in suitable double membrane form before beginning its transcellular journal.

在某种意义上，白细胞会牺牲自己的细胞以增强免疫反应。这一切听起来有些耳熟，在其生命周期中，SARS病毒必须以合适的双膜形式覆盖自己的遗传物质，然后才能开始其跨细胞日记。

In a another paper recently published in Scientific Reports, Pinchas Cohen and his team compared mitochondrial-COVID interactions to those of other viruses including respiratory syncytial virus, seasonal influenza A virus and human parainfluenza virus

在最近发表在《科学报告》上的另一篇论文中，Pinchas Cohen和他的团队将线粒体与COVID的相互作用与其他病毒的相互作用进行了比较，包括呼吸道合胞病毒，季节性A型流感病毒和人副流感病毒

3. One important finding was that in SARS-CoV-2, the levels of respiratory complex I components were reduced. Reduced complex I activity can also reduce levels of reactive oxygen species (ROS). The authors describe how host innate immunity is regulated by mitochondrial antiviral signaling proteins (MAVS). Under normal conditions, these MAVs interact with mitochondrial fusion factors like MFN2. However, after infection, mitochondria are tethered to the ER by MFN-2, whereupon the MAVS interacts with important kinases, namely, TANK binding kinase 1, IKKA, and IKKB.

3.一个重要发现是，在SARS-CoV-2中，呼吸道复合物I组分的水平降低了。降低的复杂I活性也可以降低活性氧（ROS）的水平。作者介绍了线粒体抗病毒信号蛋白（MAVS）如何调节宿主固有免疫力。在正常情况下，这些MAV与线粒体融合因子（如MFN2）相互作用。但是，感染后，线粒体通过MFN-2束缚在ER上，于是MAVS与重要的激酶（TANK结合激酶1，IKKA和IKKB）相互作用。

Other new research shows that SARS-CoV-2 virus may go even further, suggesting that in peripheral blood mononuclear cells of patients with COVID-19, the virus deliberately manipulates the metabolic functions of mitochondria to their own advantage. In particular, the authors show increases in the mitokine FGF-21, and also increases in glycolysis. They propose that since FGF-21 correlates with disease severity, it could serve as a biomarker for COVID-19-related mitochondrial dysfunction. Since mitochondria play a key role in the initiation and development of

其他新的研究表明，SARS-CoV-2病毒可能会进一步传播，这表明在COVID-19患者的外周血单核细胞中，该病毒故意操纵线粒体的代谢功能以发挥自身的优势。尤其是，作者显示出丝氨酸激酶FGF-21的增加，以及糖酵解的增加。他们认为，由于FGF-21与疾病的严重程度相关，因此它可以作为COVID-19相关线粒体功能障碍的生物标志物。由于线粒体在启动和发展中起着关键作用

cytokine storm, specific mitochondrial pathways in immune cells might be targeted clinically.

对于细胞因子风暴，免疫细胞中特定的线粒体途径可能是临床目标。

To get some more perspective, it is worth mentioning a few other important details regarding the SARS-CoV-2 genome. At around 30 kilobases long, it is twice the size of mtDNA, and over three times as long as the HIV genome. HIV is also a positive sense RNA virus; however, it is double-stranded, and integrates within the host cell genome. Although SARS-CoV-2 normally completes its life cycle in the cytoplasm, some recent evidence suggests that it, too, can be reverse-transcribed and integrated into nuclear DNA. While mtDNA is normally entirely circulatized (save perhaps in some heart muscle cells), SARS-CoV-2 can sometimes be circularized into circRNAs of many different sizes, although the implications of this are unknown. Like host nuclear DNA and mtDNA, the SARS-CoV-2 genome also contains unique G- quadruplex formations. These often enigmatic structural formations at specific guanine repeats are also potential therapeutic targets.

为了获得更多的观点，值得一提的是有关SARS-CoV-2基因组的其他一些重要细节。它长约30千个碱基，是mtDNA的两倍，是HIV基因组的三倍以上。艾滋病毒也是一种正向RNA病毒。然而，它是双链的，并整合在宿主细胞基因组内。尽管SARS-CoV-2通常在细胞质中完成其生命周期，但最近的一些证据表明，它也可以逆转录并整合到核DNA中。虽然通常将mtDNA完全环化（也许可以保存在某些心肌细胞中），但SARS-CoV-2有时可以环化为许多不同大小的circRNA，尽管其含义尚不清楚。像宿主核DNA和mtDNA一样，SARS-CoV-2基因组也包含独特的G-四链体形成。这些在特定鸟嘌呤重复序列上通常是难以理解的结构形成也是潜在的治疗靶标。

No SARS cabinet of curiosities would be complete without some ode to the still largely inexplicable furin cleavage site (FCS). While a few recombination

没有对仍然很大程度上无法解释的弗林蛋白酶切割位点（FCS）的某些颂歌，SARS的好奇心就不会完整。虽然几重组

theories have been bantered about, the actual mechanism is still an open question. For inspiration to answer this vexing question, we offer the charming and now famous genetics how-to video from the Cambridge iGEM Institute.

理论已经开玩笑了，实际的机制仍然是一个悬而未决的问题。为了回答这个棘手的问题，我们提供了来自剑桥iGEM研究所的迷人而又著名的遗传学入门视频。

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