Mitochondria are multifaceted organelles representing the ‘powerhouse of cells’ for their function as bioenergetics and biosynthetic hubs. In addition, they play an essential role in the regulation of innate and adaptive immune responses, including host defences against viruses, as well as in inflammatory responses.¹ This peculiar role of mitochondria is principally because of the activation of adaptor mitochondrial proteins, known as mitochondrial antiviral signalling (MAVS) proteins. MAVS senses viral RNA and triggers the activation of the transcription factor NF‐kB or IFN pathways and autophagy, in order to clear the infection and avoid excessive inflammation respectively.¹

Several DNA or RNA viruses have evolved mechanisms to evade the interferon I‐mediated host immune responses by targeting mitochondria and, in particular, MAVS.² A paradigmatic example of the host innate immunity evasion is that of SARS‐CoV virus, closely related and homologous to SARS‐CoV‐2, whose open reading frame protein 9b (ORF9b) localized to the outer mitochondria membrane induces degradation of MAVS, with subsequent loss of the TNF receptor‐associated factor 3 (TRAF3) and 6 (TRAF6), leading to an impaired IFN responses in the infected cells.³ Recent findings demonstrated that SARS‐CoV‐2, such as SARS‐CoV virus, in addition to ORF7a and ORF8a, also expresses ORF9b⁴ that can associate with the mitochondrial protein TOM70, impairing antiviral responses.⁵ SARS‐CoV‐2 genome and RNA viral transcripts were also found localized into host mitochondria.⁴ These evidences supported the hypothesis that SARS‐CoV‐2 might modulate MAVS in order to evade host immune responses in favour of its replication cycle.

Innate and acquired immune responses are influenced by patient sex, with women having generally higher innate and cell‐mediated immune responses to pathogens than men.⁶ It is well known that sex chromosomes and sex hormones (ie oestrogen, progesterone and testosterone) cooperate in determining sex dimorphism in immune responses.⁷ Interestingly, recent findings suggested that differences in immune responses between men and women might also be caused by mitochondria, whose correct functioning is important for an adequate immune response and is influenced by sex.⁸ In fact, in mammals, mitochondrial DNA are maternal transmitted, and mitochondria are subjected to natural selection solely in females. Therefore, during the maturation of egg, defective mitochondria or those containing mutations harmful for the females are eliminated, whereas are ignored in males and can then become more deleterious for males than for females.⁸ This female‐biased mitochondrial ‘culling’ might be responsible of a lower quality and functioning of male mitochondria that, in turn, might explain, at least in part, the observed lower immune response in men than in women.

Researchers also pointed mitochondria as potential mediators of inflammatory responses, as well as key players in the establishment of hyperinflammatory states in virus‐infected cells. Inflammatory conditions, together with oxidative stress and cytokine storm, represent the main pathogenetic features of the ongoing global pandemic coronavirus disease 2019 (COVID‐19), caused by the recently discovered coronavirus SARS‐CoV‐2.

A typical feature of COVID‐19 is the oxidative stress conditions, created in the SARS‐CoV‐2‐infected cells by an excessive activation of the immune response, leading to an exacerbated inflammatory responses described as ‘cytokine storm’ and culminating in mitochondrial dysfunctions. Under these stressful conditions, dysfunctional and damaged mitochondria induced in turn inflammation, with subsequent modulation of immune responses.⁹ Severely damaged mitochondria increase reactive oxygen species (ROS) as well as pro‐inflammatory cytokine production, accompanied by release of mitochondrial DNA into the cytosol, leading to cell death, inflammation and tissue damage. Altogether these events contribute to exacerbate inflammation and lead to systemic damages, including ROS accumulation and oxidative stress, hyperferritinaemia, blood coagulation and thrombus formation,⁹ typically present in severe forms of COVID‐19.

The worldwide epidemiological analyses of COVID‐19 cases indicated that lethality is much higher in males than in females.¹⁰ Most of the COVID‐19 patients died for a severe respiratory tract infection, mainly the aged patient population. Unfortunately, effective strategies to treat or prevent COVID‐19 are lacking so far. Therefore, there is the need to consider and develop innovative approaches.

Therefore, taking into account these considerations, agents able to restore mitochondrial function could be useful at different level: (a) to better understand the COVID‐19 pathogenesis; (b) to identify new COVID‐19 diagnostic markers; (c) to antagonize the cascade of events after SARS‐CoV‐2 infection, responsible for the clinical picture, triggered by the imbalance towards oxidation, inflammation and cytokine storm; (d) and to develop potential new and sex‐specific strategies to manage and control COVID‐19.

Research data suggest that mitomiRs are a pool of miRNAs (cellular small non‐coding RNAs) identified in the mitochondrial fraction and directly targeting mitochondrial functions. Growing evidence highlights miRNAs as new and important regulators of infections and pathogenesis induced by a wide variety of DNA or RNA viral pathogens, including coronaviruses. Indeed, coronaviruses, like other respiratory and non‐respiratory viruses, have been reported to be able to alter the expression of several cellular miRNAs in favour of their replication cycle within the host, contributing to the pathogenesis of acute as well as chronic respiratory diseases, by eluding the cellular defence mechanisms.¹¹ Several of these miRNAs are associated with inflammation, aging and mitochondrial functions.¹² MitomiRs, in particular, have been demonstrated to regulate systemic energy homeostasis, oxidative capacity, ROS generation, inflammation and mitochondrial lipid metabolism. Thus, investigations on the potential modulation of immune and inflammatory responses in SARS‐CoV‐2‐infected cells by mitomiR could be interesting and helpful to better elucidate the molecular mechanisms involved in immune evasion by SARS‐CoV‐2 and in COVID‐19 pathogenesis.

The mitomiR 146a‐5p might represent one possible candidate for further investigations. Indeed, evidence demonstrated that miR‐146a‐5p expression was modulated following several viral infections, such as that induced by Japanese encephalitis virus, Dengue virus, avian infectious bronchitis virus, hepatitis B virus, influenza A virus and Borna disease virus 1. Its viral‐mediated overexpression has been reported to promote viral replication by inducing downregulation of IL‐1 receptor‐associated kinase‐2 (IRAK2) and TRAF6, with consequent suppression of inflammatory cell responses and cytokine production. Interestingly, miR‐146a has been found downregulated by oestrogens in murine splenic lymphocytes.¹³ Accordingly, a study conducted in Alzheimer's disease (AD) patients reported lower miR‐146a levels in females compared to males, both in AD patients and healthy non‐affected controls.¹⁴

Other intriguing candidates are the mitomiR‐221 and 19b, both located on the human X chromosome and sex hormones sensitive.¹⁵ MiR‐221 has been highlighted by researchers as a suppressor of innate antiviral immune responses. Indeed, overexpression of miR‐221 inhibited the induction of IFN‐I by MAVS.¹⁶ MiR‐19b has been found to potentiate inflammation in japanese encephalitis virus (JEV)‐infected human astrocytoma cell lines and in brain tissues of JEV‐infected mice.¹⁷ Unfortunately, nothing is known about the potential role of these miRs in respiratory viral infections, including coronaviruses. Only one study reported that respiratory syncytial virus (RSV)‐mediated inhibition of miR‐221 favours viral replication by interfering with the apoptotic death of infected cells.¹⁸ Another study showed that miR‐221 inhibition by the porcine epidemic diarrhoea coronavirus (PEDV) blocks NF‐kB pathway, enhancing virus replication.¹⁹

Therefore, in the light of the above, further studies on the role of mitomiRs would be indispensable to clarify both their possible role in the pathogenesis of COVID‐19 and their potential as sex‐specific disease biomarkers or therapeutic targets.

线粒体是多方面的细胞器，代表了“细胞的发电站”，因为它们具有作为生物能量学和生物合成中心的功能。此外，它们在调节先天性和适应性免疫反应（包括宿主对病毒的防御）以及炎症反应中发挥重要作用。¹线粒体的这种特殊作用主要是因为线粒体衔接蛋白的激活，称为线粒体抗病毒信号 (MAVS) 蛋白。MAVS 感知病毒 RNA 并触发转录因子 NF-kB 或 IFN 通路和自噬的激活，以分别清除感染和避免过度炎症。¹

一些 DNA 或 RNA 病毒已经进化出通过靶向线粒体，特别是 MAVS 来逃避干扰素 I 介导的宿主免疫反应的机制。²宿主先天免疫逃避的一个典型例子是 SARS-CoV 病毒，它与 SARS-CoV-2 密切相关和同源，其位于线粒体外膜的开放阅读框蛋白 9b (ORF9b) 诱导 MAVS 降解，与随后损失 TNF 受体相关因子 3 (TRAF3) 和 6 (TRAF6)，导致受感染细胞中的 IFN 反应受损。³最近的研究结果表明，SARS-CoV-2（如 SARS-CoV 病毒）除了 ORF7a 和 ORF8a 外，还表达可与线粒体蛋白 TOM70 结合的ORF9b ^{4 ，从而削弱抗病毒反应。5} SARS-CoV-2 基因组和 RNA 病毒转录本也被发现定位于宿主线粒体。⁴这些证据支持这样的假设，即 SARS-CoV-2 可能调节 MAVS 以逃避宿主免疫反应，从而有利于其复制周期。

先天性和获得性免疫反应受患者性别影响，女性对病原体的先天性和细胞介导的免疫反应通常高于男性。⁶众所周知，性染色体和性激素（即雌激素、孕激素和睾酮）共同决定免疫反应中的性别二态性。⁷有趣的是，最近的研究结果表明，男性和女性之间的免疫反应差异也可能是由线粒体引起的，线粒体的正确功能对于充分的免疫反应很重要，并且受性别影响。⁸事实上，在哺乳动物中，线粒体 DNA 是母体传播的，而线粒体仅在雌性中受到自然选择。因此，在卵子成熟过程中，有缺陷的线粒体或含有对雌性有害的突变的线粒体被消除，而在雄性中被忽略，然后对雄性的危害比对雌性更大。⁸这种偏向于女性的线粒体“剔除”可能是导致男性线粒体质量和功能较低的原因，而这反过来可能至少部分解释了观察到的男性免疫反应低于女性。

研究人员还指出线粒体是炎症反应的潜在介质，以及在病毒感染细胞中建立高炎症状态的关键参与者。炎症状况，连同氧化应激和细胞因子风暴，代表了由最近发现的冠状病毒 SARS-CoV-2 引起的正在进行的 2019 年全球大流行冠状病毒病 (COVID-19) 的主要致病特征。

COVID-19 的一个典型特征是氧化应激条件，该条件是通过过度激活免疫反应在感染 SARS-CoV-2 的细胞中产生的，导致炎症反应加剧，称为“细胞因子风暴”并最终导致线粒体功能障碍. 在这些压力条件下，功能失调和受损的线粒体依次诱发炎症，随后调节免疫反应。⁹严重受损的线粒体会增加活性氧 (ROS) 以及促炎细胞因子的产生，同时线粒体 DNA 会释放到细胞质中，从而导致细胞死亡、炎症和组织损伤。总而言之，这些事件会加剧炎症并导致全身性损伤，包括 ROS 积累和氧化应激、高铁蛋白血症、凝血和血栓形成，⁹通常存在于严重的 COVID-19 形式中。

对 COVID-19 病例的全球流行病学分析表明，男性的致死率远高于女性。¹⁰大多数 COVID-19 患者死于严重的呼吸道感染，主要是老年人群。不幸的是，目前还缺乏治疗或预防 COVID-19 的有效策略。因此，有必要考虑和开发创新的方法。

因此，考虑到这些因素，能够恢复线粒体功能的药物可能在不同的水平上发挥作用：(a) 更好地了解 COVID-19 的发病机制；(b) 识别新的 COVID-19 诊断标志物；(c) 对抗 SARS-CoV-2 感染后由氧化、炎症和细胞因子风暴的失衡引发的导致临床表现的级联事件；(d) 并制定潜在的新的和针对特定性别的策略来管理和控制 COVID-19。

研究数据表明，mitomirs 是在线粒体部分中鉴定并直接靶向线粒体功能的 miRNA（细胞小非编码 RNA）库。越来越多的证据强调 miRNA 是由包括冠状病毒在内的多种 DNA 或 RNA 病毒病原体诱导的感染和发病机制的新的重要调节因子。事实上，据报道，与其他呼吸道和非呼吸道病毒一样，冠状病毒能够改变几种细胞 miRNA 的表达，有利于它们在宿主内的复制周期，从而导致急性和慢性呼吸道疾病的发病机制，通过逃避细胞防御机制。¹¹其中一些 miRNA 与炎症、衰老和线粒体功能有关。¹²特别是 MitomiRs 已被证明可以调节全身能量稳态、氧化能力、活性氧生成、炎症和线粒体脂质代谢。因此，对 mitomiR 对 SARS-CoV-2 感染细胞免疫和炎症反应的潜在调节作用的研究可能很有趣，有助于更好地阐明 SARS-CoV-2 免疫逃避和 COVID-19 发病机制中涉及的分子机制.

mitomiR 146a-5p 可能代表进一步研究的一个可能的候选者。事实上，有证据表明 miR-146a-5p 的表达在几种病毒感染后受到调节，例如由日本脑炎病毒、登革热病毒、禽传染性支气管炎病毒、乙型肝炎病毒、甲型流感病毒和博尔纳病病毒 1 诱导的病毒感染。据报道，介导的过表达通过诱导 IL-1 受体相关激酶 2 (IRAK2) 和 TRAF6 的下调来促进病毒复制，从而抑制炎症细胞反应和细胞因子的产生。有趣的是，已发现 miR-146a 在小鼠脾淋巴细胞中被雌激素下调。¹³因此，在阿尔茨海默病 (AD) 患者中进行的一项研究报告称，与男性相比，女性的 miR-146a 水平较低，无论是在 AD 患者中还是在健康的未受影响的对照组中。¹⁴

其他有趣的候选者是 mitomiR-221 和 19b，它们都位于人类 X 染色体上并且对性激素敏感。¹⁵ MiR-221 已被研究人员强调为先天抗病毒免疫反应的抑制剂。事实上，miR-221 的过表达抑制了 MAVS 对 IFN-I 的诱导。¹⁶已发现 MiR-19b 在日本脑炎病毒 (JEV) 感染的人类星形细胞瘤细胞系和 JEV 感染小鼠的脑组织中增强炎症。¹⁷不幸的是，对于这些 miR 在包括冠状病毒在内的呼吸道病毒感染中的潜在作用，我们一无所知。只有一项研究报告说，呼吸道合胞病毒 (RSV) 介导的 miR-221 抑制通过干扰受感染细胞的凋亡性死亡来促进病毒复制。¹⁸另一项研究表明，猪流行性腹泻冠状病毒 (PEDV) 抑制 miR-221 会阻断 NF-kB 通路，从而增强病毒复制。¹⁹

因此，鉴于上述情况，进一步研究 mitomiRs 的作用对于阐明它们在 COVID-19 发病机制中的可能作用以及它们作为性别特异性疾病生物标志物或治疗靶点的潜力是必不可少的。