LATEST! International Study Finds That SARS-CoV-2 Virus Inhibits Mitochondrial Gene Transcription, Increasing Risk Of Organ Failure And Death!
A new international study lead by researchers from the Children’s Hospital of Philadelphia and the COVID-19 International Research Team involving more than 25 research institutions spanning 4 countries ie United States, United Kingdom, Brazil and South Korea, has found that the SARS-CoV-2 coronavirus hijacks mitochondrial transcriptional machinery resulting in organ failure and death.
Disruptions and defects in mitochondrial oxidative phosphorylation (OXPHOS) have been reported in COVID-19 patients, but the timing and organs affected vary among reports.
The study team reveals 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.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.02.19.481089v1
The research team studied the effects of SARS-CoV-2 infection on the transcription of mitochondrial oxidative phosphorylation (OXPHOS), glycolysis, nutrient sensing, and stress response genes.
Corresponding author, Dr Douglas C. Wallace from the University of Pennsylvania told Thailand Medical News
, “It was found that 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.”
The study found that in most stages of COVID-19 disease, SARS-CoV-2 blocks distinct OXPHOS functions against which the host mounts a counter-attack, wherein the cells broadly upregulate unblocked OXPHOS gene functions.
This compensatory response is unfortunately is incapable of reviving the damage caused to the autopsied heart of deceased patients as it severely suppresses genes across all OXPHOS modules but it does save the patient’s lungs.
The study team collected about 700 nasopharyngeal swabs and about 40 autopsy cases from SARS-CoV-2-positive and negative individuals to examine early- and late-stage infection, respectively, in New York, USA.
The team 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.
The research team studied the mitochondrial transcription profiles in these samples to understand how COVID-19 dramatically inhibits OXPHOS functions.
This included calculating 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.
As with previous human nasopharyngeal and autopsy studies, it was found that high SARS-CoV-2 ribonucleic acid (RNA) levels inhibited transcription of mitochondrial genes associated with OXPHOS complexes I, II, III, IV, and V.
Furthermore, 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.
It was also found that 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.
Interestingly, 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.
The study team noted that SARS-CoV-2 manipulated the expression of the nasopharyngeal mtDNA transcripts.
The 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.
It was also found that 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.
Importantly, 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.
It should be noted that 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 study team also investigated the relationship between the initial SARS-CoV-2 protein inhibition of host mitochondrial proteins and the bioenergetic gene transcription in hamsters.
It was observed that mitochondrial gene expression was not impaired in the lung, heart, and kidney during early infection at peak lung viral titers.
Shockingly, however, brain mitochondrial gene expression was also affected, likely accounting for the commonly experienced brain fog during COVID-19.
Interestingly, 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.
The study findings demonstrated that the mitochondrial inhibitory effect observed during SARS-CoV-2 infection occurred at the transcriptional level.
The study team commented, “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 Coenzyme 10 (Q10), 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.”
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