TRANSCRIPT ANALYSIS OF SARS-CoV-2 INFECTED NASOPHARYNGEAL AND AUTOPSY SAMPLES REVEALS STRIKING DOWN-REGULATION OF MITOCHONDRIAL GENE EXPRESSION

SARS-CoV-2 infected cells manifest defects in mitochondrial oxidative phosphorylation (OXPHOS) and activation of HIF-1alpha. To determine the basis of these effects, we analyzed mitochondrial gene expression of COVID-19 nasopharyngeal and autopsy samples, and acute and late-stage infected hamsters and mice. This revealed that at initial lung peak viral titers, mitochondrial gene expression was minimally affected in the lung and viscera. Progression of the air way infection resulted in the down regulation of nuclear DNA (nDNA) genes for specific OXPHOS complex assembly modules, disrupted mitochondrial DNA (mtDNA) transcription, activation of HIF-1alpha, and host compensatory up regulation of uninhibited bioenergetic genes. Clearing of the virus resulted in up regulation of mitochondrial and HIF-1alpha gene expression in the autopsy lung, but the suppression of virtually all nDNA mitochondrial genes in the autopsy heart, even though mtDNA transcription was induced in all tissues. Hence, enhancing mitochondrial gene expression may mitigate the severity of COVID-19.