Review SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19, 2024, Guarnieri et al.

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SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19
Guarnieri; Haltom; Albrecht; Lie; Olali; Widjaja; Ranshing; Angelin; Murdock; Wallace

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors.

This revealed that SARS-CoV2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression.

These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.

Link | PDF (Pharmacological Research) [Open Access]

 

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A comprehensive review.

This work was supported by DOD grant W81XWH-21-1-0128, the Bill & Melinda Gates Foundation grant # INV046722 grant and NIH grants AG078814and CA259635 awarded to D.C.W.

 

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Sections / subtitles —

SARS-CoV-2 reprograms host cell metabolism to enhance viral replication

• SARS-CoV-2 viral proteins manipulate mitochondrial physiology
• SARS-CoV-2 inhibits OXPHOS, increases mROS, stabilizes HIF-1α, and induces glycolysis
• Mitochondrial ROS, HIF-1α, and glycolysis induction
• SARS-CoV-2 induces de novo nucleic purine and pyrimidine synthesis
• SARS-CoV-2 requires de novo fatty acid synthesis
• SARS-CoV-2 infection alters levels of NAD+/NADP+
• SARS-CoV-2 requires glutaminolysis
• Inhibition of OXPHOS causes activation of innate immunity and the ISR

SARS-CoV-2 inhibition of mitochondrial biogenesis: Contribution to mortality and long-COVID

• SARS-CoV-2 impacts nuclear and mitochondrial transcription
• SARS-CoV-2 regulates OXPHOS transcription via Orf8, Orf10, and metabolic modulation of the epigenome

Suggesting —

Thus, inhibition of mitochondrial transcription by SARS-CoV-2 might occur as an indirect consequence of the production of diffusible factors that modulate the epigenome, perhaps due to the activation of the ISR or perturbation of the mitochondrial metabolite levels. By this scenario, SARS-CoV-2 polypeptides that bind to and inhibit mitochondrial proteins plus the vial induction of miRNA-2393, which inhibits mtDNA transcription, create an imbalance between OXPHOS nDNA and mtDNA proteins which activates the UPRMT. The UPRMT simulates OMA1 to cleave DELE1 which activates HRI of the ISR inhibiting cytosolic synthesis of mitochondrial proteins. The resulting disruption of OXPHOS alters the production of mitochondrial metabolites which act as substrates for the epigenomic modification enzymes.

Concluding —

This literature survey confirms that SARS-CoV-2 infection inhibits OXPHOS, increases mROS to stabilize HIF-1α and upregulates glycolysis and PPP to supply substrates for viral biogenesis. Alterations in mitochondrial physiology and mROS production also stimulate the mitochondria to elaborate mitochondrial DAMPs that activate the innate immune system and the ISR. Thus, perturbation of mitochondrial bioenergetics and mROS lie at the center of COVID-19 pathophysiology and the resulting alterations of mitochondrial metabolites could modify the epigenome to suppress OXPHOS gene expression even after viral genomes had been eliminated.

The most common manifestations of long-COVID [post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, heart palpitations, hormonal alterations, thirst (blood sugar alterations), chronic cough (inflammation), chest pain, and abnormal movements (cerebellar effects)] are also among the array of manifestations of known mitochondrial diseases. Consequently, the post-viral epigenomic suppression of OXPHOS gene expression may be an important factor in the pathophysiology of long-COVID. If so, the most effective metabolic therapies to mitigate acute and long-COVID could be to increase OXPHOS and decrease mROS.