Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts, 2023, Guarnieri et al.

Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts
Joseph W. Guarnieri; Joseph M. Dybas; Hossein Fazelinia; Man S. Kim; Justin Frere; Yuanchao Zhang; Yentli Soto Albrecht; Deborah G. Murdock; Alessia Angelin; Larry N. Singh; Scott L. Weiss; Sonja M. Best; Marie T. Lott; Shiping Zhang; Henry Cope; Victoria Zaksas; Amanda Saravia-Butler; Cem Meydan; Jonathan Foox; Christopher Mozsary; Yaron Bram; Yared Kidane; Waldemar Priebe; Mark R. Emmett; Robert Meller; Sam Demharter; Valdemar Stentoft-Hansen; Marco Salvatore; Diego Galeano; Francisco J. Enguita; Peter Grabham; Nidia S. Trovao; Urminder Singh; Jeffrey Haltom; Mark T. Heise; Nathaniel J. Moorman; Victoria K. Baxter; Emily A. Madden; Sharon A. Taft-Benz; Elizabeth J. Anderson; Wes A. Sanders; Rebekah J. Dickmander; Stephen B. Baylin; Eve Syrkin Wurtele; Pedro M. Moraes-Vieira; Deanne Taylor; Christopher E. Mason; Jonathan C. Schisler; Robert E. Schwartz; Afshin Beheshti; Douglas C. Wallace

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis.

We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)–encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated.

During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs.

These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.

Link | PDF (Science Translational Medicine, paywalled)

 

Next thing they're going to say that the dysregulation persists in long covid because of something in the blood that just doesn't go away.

 

Stat article on the study:
Study mapping how SARS-CoV-2 disrupts mitochondria suggests a cause for long Covid

https://www.statnews.com/2023/08/09/long-covid-mitochondria-sars-cov-2/

 

In the murine part of their study —

We have a tag for GDF15.

 

This paper is not open-access but here are some of the available references from the introduction —

• A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection (2022, Nature European Journal of Human Genetics, open access)
• SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics (2021, iScience, open access)
• Immune system cells from COVID-19 patients display compromised mitochondrial-nuclear expression co-regulation and rewiring toward glycolysis (2021, iScience, open access)
• Role of miR-2392 in driving SARS-CoV-2 infection (2021, Cell Reports, open access, thread)
• Mitochondria and microbiota dysfunction in COVID-19 pathogenesis (2020, Mitochondrion, open access)
• Circulating levels of GDF-15 and calprotectin for prediction of in-hospital mortality in COVID-19 patients: A case series (2020, Journal of Infection, open access)
• Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis (2020, American Journal of Physiology-Cell Physiology, open access)
• ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis (2019, Molecular Cell, open access)
• eIF2B activator prevents neurological defects caused by a chronic integrated stress response (2019, eLife, open access)
• New mitochondrial DNA synthesis enables NLRP3 inflammasome activation (2018, Nature, Cached)
• The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes (2018, eLife, open access)
• Mitochondrial DNA in innate immune responses and inflammatory pathology (2017, Nature Reviews Immunology, Cached)
• Mitonuclear protein imbalance as a conserved longevity mechanism (2013, Nature, Cached)

 

The study is briefly discussed in today's TWiV Clinical update with Dr. Daniel Griffin and Prof. Vincent Racaniello wonders if this finding may be relevant for other viruses too.

 

Simon Décary on Twitter:
If I understand this paper right, this may be one of the most important piece of data to date to demonstrate how SARS-CoV-2 inhibits mitochondrial homeostasis, which could explain the pathophysiology of post-exertional malaise.

 

Eric Topol Long Covid: Mitochondria, the Big Miss, and Hope

quote:

This week there was news on Long Covid in two very different directions—emergence of strong data to support mitochondrial dysfunction as the basis for the condition in some people—and learning how the $1.15 billion allocation to the NIH RECOVER initiative has largely been wasted. In this edition of Ground Truths, I’ll review this news and offer a plan to get clinical trials testing treatments into high gear.

Sick Mitochondria as a Root Cause

When we published our review of Long Covid earlier this year, we highlighted the key established underpinnings as shown in the Figure below. As you’ll note, mitochondria was not one of them. There was a body of data emerging to support the role of mitochondria, as we asserted: ”Long COVID research has found mitochondrial dysfunction including loss of mitochondrial membrane potential and possible dysfunctional mitochondrial metabolism, altered fatty acid metabolism…” and that this had also been seen in myalgic encephalomyelitis(ME/CFS).

A new paper In Science Translational Medicine by leaders in mitochondria biology has advanced the case for direct interactions between SARS-CoV-2 and critical mitochondrial proteins for the potential basis of Long Covid—at least in some people.

 

Selected quotes from Introduction —

 

Selected quotes from Results —

Changes in OXPHOS gene transcription in COVID-19 human nasopharyngeal samples

Changes in OXPHOS gene transcription in COVID-19 human autopsy samples

 

Selected quotes from Results (cont'd) —

SARS-CoV-2 modulation of mitochondrial and glycolytic pathways in human nasopharyngeal and autopsy samples

SARS-CoV-2 modulation of HIF-1α, mTOR, and ISR pathways in human nasopharyngeal and autopsy samples

 

Selected quotes from Results (cont'd) —

miR-2392 induced by SARS-CoV-2 regulates mitochondrial mRNA function in human nasopharyngeal and autopsy samples

Metabolic flux in host cells in response to SARS-CoV-2 infection

 

Selected quotes from Discussion —

 

@DMissa any comment please?

 

I think this part needs to be repeated :