Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Sci Transl Med. 2023 Aug 9;15(708):eabq1533. doi: 10.1126/scitranslmed.abq1533.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)-encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated. During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs. These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）病毒蛋白与宿主线粒体蛋白结合，可能抑制氧化磷酸化（OXPHOS）并刺激糖酵解。我们分析了 2019 年冠状病毒病（COVID-19）患者的鼻咽和尸检组织中的线粒体基因表达。在病毒滴度下降的鼻咽样本中，该病毒阻断了一组核 DNA（nDNA）编码的线粒体 OXPHOS 基因的转录，诱导 microRNA 2392 的表达，激活 HIF-1α 诱导糖酵解，并激活包括整合应激反应在内的宿主免疫防御。在 COVID-19 患者的尸检组织中，SARS-CoV-2 不再存在，肺中的线粒体基因转录已恢复。然而，在心脏的尸检组织中，nDNA 线粒体基因表达仍然受到抑制，在肾脏和肝脏中则受到较小程度的抑制，而线粒体 DNA 转录被诱导，宿主免疫防御途径被激活。在感染 SARS-CoV-2 的仓鼠肺部病毒载量达到峰值的早期，肺部的线粒体基因表达受到最小程度的干扰，但小脑的表达下调，纹状体的表达上调，尽管在大脑中未检测到 SARS-CoV-2。在感染 SARS-CoV-2 的小鼠中期，肺部的线粒体基因表达开始恢复。这些数据表明，当病毒滴度首次达到峰值时，会出现全身性宿主反应，随后病毒抑制线粒体基因转录并诱导糖酵解，从而导致抗病毒免疫防御的部署。即使病毒被清除且肺线粒体功能已恢复，心脏、肾脏、肝脏和淋巴结的线粒体功能仍受损，可能导致严重的 COVID-19 病理。
