In a recent study posted to the bioRxiv* pre-print server, researchers studied the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the transcription of mitochondrial oxidative phosphorylation (OXPHOS), glycolysis, nutrient sensing, and stress response genes.
Study: Targeted Down Regulation Of Core Mitochondrial Genes During SARS-CoV-2 Infection. Image Credit: Terelyuk/Shutterstock
SARS-CoV-2 infection, by inhibiting mitochondrial bioenergetics, activates an excessive, systemic inflammatory response, including a ‘cytokine storm’; however, it more adversely impacts the vital human organs, including the heart and brain, since these organs are highly reliant on mitochondrial energy production.
In most stages of coronavirus disease 2019 (COVID-19), SARS-CoV-2 blocks distinct OXPHOS functions against which the host mounts a counter-attack, wherein the cells broadly upregulate unblocked OXPHOS gene functions. Unfortunately, although this compensatory response is incapable of reviving the damage caused to the autopsied heart of deceased patients as it severely suppresses genes across all OXPHOS modules, it saves the patient’s lungs.
About the study
In the present study, researchers collected ~700 nasopharyngeal swabs and ~40 autopsy cases from SARS-CoV-2-positive and negative individuals to examine early- and late-stage infection, respectively, in New York, USA.
They also examined SARS-CoV-2-infected hamsters and mice to analyze and validate the observed changes in mitochondrial bioenergetic gene expression at early and mid-stages of infection in humans.
They studied the mitochondrial transcription profiles in these samples to understand how COVID-19 dramatically inhibits OXPHOS functions. To this end, they calculated the relative expression levels of host genes in ribonucleic acid sequencing (RNA-seq) data from study specimens, using the curated cellular bioenergetics genes, plus the genes and 40 pathway lists from MitoCarta and MitoPathway.
Findings
As revealed during human nasopharyngeal and autopsy studies, high SARS-CoV-2 ribonucleic acid (RNA) levels inhibited transcription of mitochondrial genes associated with OXPHOS complexes I, II, III, IV, and V.
In addition, SARS-CoV-2 infection inhibited an array of other mitochondrial functions, including fatty acid oxidation, mitochondrial fatty acid synthesis (mtFASII), antioxidant defenses, translational machinery, cytosolic protein import, mitochondrial deoxyribonucleic acid (mtDNA) biogenesis, and intermediate metabolism. Intriguingly, the autopsied lungs showed an up-regulation of mitochondrial gene expression.
Further, SARS-CoV-2 manipulated the master transcriptional regulator of the OXPHOS enzyme modules, i.e., nuclear DNA (nDNA) OXPHOS genes. It is worth noting here that the OXPHOS enzyme complexes are assembled from multiple nDNA and mtDNA-coded protein subunits, and to achieve the exact stoichiometric ratio for each sub-enzyme module, the modular genes work in tightly regulated coordination.
The host cells counter this phenomenon by coordinated up-regulation of nDNA mitochondrial gene expression. Subsequently, they up-regulate the synthesis of cytochrome C oxidase 2 (SCO2), a complex IV assembly gene.
Further, the authors noted that SARS-CoV-2 manipulated the expression of the nasopharyngeal mtDNA transcripts. SARS-CoV-2 genome coded three sequences homologous to the seed sequences of microRNA (miR)-2392. At high viral loads, there was enough RNA that mimicked miR-2392 resulting in inhibition of mtDNA transcription. The altered gene expression of the mammalian target of rapamycin (mTOR) nutrient-sensing pathway genes with the energy-sensing kinases further supported SARS-CoV-2 manipulation of these regulatory genes.
Inside the host cells, inhibition of OXPHOS and limited antioxidant defenses resulted in increased mitochondrial reactive oxygen species (mROS) that stabilized hypoxia-inducing factor 1-α (HIF-1α). It redirected metabolites away from the mitochondrial oxidation, toward glycolysis to generate viral precursors. The imbalance in nDNA and mtDNA polypeptides also activated the mitochondrial unfolded protein (UPRMT), which activated the integrated stress response (ISR), resulting in a bias of protein synthesis away from cellular maintenance and toward vial biogenesis.
Autopsy data confirmed that these processes depended on viral titers because as soon as viral titers declined, normal mitochondrial function resurged to repair tissue damage. However, if the virally-induced inhibition was too severe, it resulted in irreversible damage to the autopsied heart, kidney, and liver, ensuing organ failure resulting in death.
The authors also investigated the relationship between the initial SARS-CoV-2 protein inhibition of host mitochondrial proteins and the bioenergetic gene transcription in hamsters. They observed that mitochondrial gene expression was not impaired in the lung, heart, and kidney during early infection at peak lung viral titers. Surprisingly, however, brain mitochondrial gene expression was affected, likely accounting for the commonly experienced brain fog during COVID-19.
In the later stages of lung infection in hamsters, an upsurge of bioenergetic gene expression occurred in the autopsied lung, which removed the virus from the lungs.
Conclusions
To summarize, the study findings demonstrated that the mitochondrial inhibitory effect observed during SARS-CoV-2 infection occurred at the transcriptional level.
Therefore, an approach that would effectively mitigate the adverse effects of SARS-CoV-2 must simultaneously combine stimulation of mitochondrial function with inhibition of mROS production. For instance, SARS-CoV-2-infected monocytes treated with antioxidants, such as N-acetylcysteine (NAC) and MitoQ, will have reduced levels of mROS, thereby leading to a reduction in the HIF-1α, pro-inflammatory messenger ribonucleic acid (mRNA) levels, and finally, the viral load.
*Important notice
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
