Targeted Down Regulation Of Core Mitochondrial Genes During SARS-CoV-2 Infection

Abstract

Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been reported in COVID-19 patients, but the timing and organs affected vary among reports. Here, we reveal the dynamics of COVID-19 through transcription profiles in nasopharyngeal and autopsy samples from patients and infected rodent models. While mitochondrial bioenergetics is repressed in the viral nasopharyngeal portal of entry, it is up regulated in autopsy lung tissues from deceased patients. In most disease stages and organs, discrete OXPHOS functions are blocked by the virus, and this is countered by the host broadly up regulating unblocked OXPHOS functions. No such rebound is seen in autopsy heart, results in severe repression of genes across all OXPHOS modules. Hence, targeted enhancement of mitochondrial gene expression may mitigate the pathogenesis of COVID-19.

Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism

“…In line with the detected enrichment of accessible binding motifs for the inflammatory TF family, supervised hierarchical clustering further showed that SARS-CoV-2 infection induced the transcription of IFN-stimulated genes. In accordance with reported SARS-CoV-2-mediated impairment of mitochondrial biogenesis (Guarnieri et al, 2022), downregulated genes in SARS-CoV-2-infected samples were significantly associated (among others) with the downregulation of pathways driving mitochondrial oxidative phosphorylation (OXPHOS). The upregulation of chromatin silencing and nucleosome assembly pathways at the proteomic level in SARS-CoV-2-infected samples is consistent with SARS-CoV-2-ORF8-mediated chromatin compaction (Kee et al, 2021) and may represent the epigenomic mechanism underlying SARS-CoV-2-mediated host-shutoff (Finkel et al, 2021).…”

Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight

“…However, this change was seen only in Calu-3 cells, which are lung epithelial cells but not seen in Caco-2 and Huh-7 cells, indicating that different cell types may show different alterations in carbon metabolism upon the viral infection. Most recent targeted transcriptome analysis revealed impairment of mitochondrial OXPHOS and antioxidant gene expression in clinical samples of nasopharyngeal, heart, kidney and liver tissues, which was correlated with enhanced mtROS which stabilises HIF-1α [ 80 ], which is known to induce glycolysis [ 81 ] and repress mitochondrial oxygen consumption [ 82 ] as well. The study also confirms with the help of clinical autopsy samples that, with reducing viral load, mitochondrial integrity is rescued that repairs tissue damage.…”

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model

“…Differentially expressed gene lists were created using the DESeq2 R package (58) by comparing injury and Sham conditions, with or without P110 treatment. Gene set enrichment analyses (GSEA) were performed using the desktop software (https://www.gsea-msigdb.org/gsea/index.jsp) (59, 60) using MitoCarta3.0 (61) and custom curated mitochondrial pathway (62) databases. Heatmaps were generated using the pheatmap R package.…”