How Covid-19 damages lungs explained

Authors: mINT oCTOBER 31, 2022

sYNOPSIS

SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following SARS-CoV in 2003 and MERS-CoV in 2012.

Covid-19: The virus attacks mitochondria, continuing an ancient battle that began in the primordial soup

Kingston (Canada), (The Conversation): Viruses and bacteria have a very long history. Because viruses can’t reproduce without a host, they’ve been attacking bacteria for millions of years. Some of those bacteria eventually became mitochondria, synergistically adapting to life within eukaryotic cells (cells that have a nucleus containing chromosomes).

Ultimately, mitochondria became the powerhouses within all human cells.

Fast-forward to the rise of novel coronaviruses like SARS-CoV-2, and the global spread of COVID-19. Approximately five per cent of people infected with SARS-CoV-2 suffer respiratory failure (low blood oxygen) requiring hospitalization. In Canada about 1.1 per cent of infected patients (almost 46,000 people) have died.

This is the story of how a team, assembled during the pandemic, recognized the mechanism by which these viruses were causing lung injury and lowering oxygen levels in patients: It is a throwback to the primitive war between viruses and bacteria — more specifically, between this novel virus and the evolutionary offspring of bacteria, our mitochondria.

SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following SARS-CoV in 2003 and MERS-CoV in 2012. We need to better understand how coronaviruses cause lung injury to prepare for the next pandemic.

How COVID-19 affects lungs

People with severe COVID-19 pneumonia often arrive at the hospital with unusually low oxygen levels. They have two unusual features distinct from patients with other types of pneumonia:

First, they suffer widespread injury to their lower airway (the alveoli, which is where oxygen is taken up).

Second, they shunt blood to unventilated areas of the lung, which is called ventilation-perfusion mismatch. This means blood is going to parts of the lung where it won’t get sufficiently oxygenated.

Together, these abnormalities lower blood oxygen. However, the cause of these abnormalities was unknown. In 2020, our team of 20 researchers at three Canadian universities set about to unravel this mystery. We proposed that SARS-CoV-2 worsened COVID-19 pneumonia by targeting mitochondria in airway epithelial cells (the cells that line the airways) and pulmonary artery smooth muscle cells.

We already knew that mitochondria are not just the powerhouse of the cell, but also its main consumers and sensors of oxygen. Mitochondria control the process of programmed cell death (called apoptosis), and they regulate the distribution of blood flow in the lung by a mechanism called hypoxic pulmonary vasoconstriction.

This mechanism has an important function. It directs blood away from areas of pneumonia to better ventilated lobes of the lung, which optimizes oxygen-uptake. By damaging the mitochondria in the smooth muscle cells of the pulmonary artery, the virus allows blood flow to continue into areas of pneumonia, which also lowers oxygen levels.

It appeared plausible that SARS-CoV-2 was damaging mitochondria. The results of this damage — an increase in apoptosis in airway epithelial cells, and loss of hypoxic pulmonary vasoconstriction — were making lung injury and hypoxemia (low blood oxygen) worse.

Our discovery, published in Redox Biology, explains how SARS-CoV-2, the coronavirus that causes COVID-19 pneumonia, reduces blood oxygen levels.

We show that SARS-CoV-2 kills airway epithelial cells by damaging their mitochondria. This results in fluid accumulation in the lower airways, interfering with oxygen uptake. We also show that SARS-CoV-2 damages mitochondria in the pulmonary artery smooth muscle cells, which inhibits hypoxic pulmonary vasoconstriction and lowers oxygen levels.

Attacking mitochondria

Coronaviruses damage mitochondria in two ways: by regulating mitochondria-related gene expression, and by direct protein-protein interactions. When SARS-CoV-2 infects a cell, it hijacks the host’s protein synthesis machinery to make new virus copies. However, these viral proteins also target host proteins, causing them to malfunction. We soon learned that many of the host cellular proteins targeted by SARS-CoV-2 were in the mitochondria.

Viral proteins fragment the mitochondria, depriving cells of energy and interfering with their oxygen-sensing capability. The viral attack on mitochondria starts within hours of infection, turning on genes that break the mitochondria into pieces (called mitochondrial fission) and make their membranes leaky (an early step in apoptosis called mitochondrial depolarization).

In our experiments, we didn’t need to use a replicating virus to damage the mitochondria — simply introducing single SARS-CoV-2 proteins was enough to cause these adverse effects. This mitochondrial damage also occurred with other coronaviruses that we studied.

We are now developing drugs that may one day counteract COVID-19 by blocking mitochondrial fission and apoptosis, or by preserving hypoxic pulmonary vasoconstriction. Our drug discovery efforts have already enabled us to identify a promising mitochondrial fission inhibitor, called Drpitor1a.

Our team’s infectious diseases expert, Gerald Evans, notes that this discovery also has the potential to help us understand Long COVID. “The predominant features of that condition — fatigue and neurologic dysfunction — could be due to the lingering effects of mitochondrial damage caused by SARS-CoV-2 infection,” he explains.

The ongoing evolutionary battle

This research also has an interesting evolutionary angle. Considering that mitochondria were once bacteria, before being adopted by cells back in the primordial soup, our findings reveal an Alien versus Predator scenario in which viruses are attacking “bacteria.”

Bacteria are regularly attacked by viruses, called bacteriophages, that need a host to replicate in. The bacteria in turn fight back, using an ancient form of immune system called the CRISPR-cas system, that chops up the viruses’ genetic material. Humans have recently exploited this CRISPR-cas system for a Nobel Prize-winning gene editing discovery.

The ongoing competition between bacteria and viruses is a very old one; and recall that our mitochondria were once bacteria. So perhaps it’s not surprising at all that SARS-CoV-2 attacks our mitochondria as part of the COVID-19 syndrome.

Pandemic pivot

The original team members on this project are heart and lung researchers with expertise in mitochondrial biology. In early 2020 we pivoted to apply that in another field — virology — in an effort to make a small contribution to the COVID-19 puzzle.

The diverse team we put together also brought expertise in mitochondrial biology, cardiopulmonary physiology, SARS-CoV-2, transcriptomics, synthetic chemistry, molecular imaging and infectious diseases.

Our discovery owes a lot to our virology collaborators. Early in the pandemic, University of Toronto virologist Gary Levy offered us a mouse coronavirus (MHV-1) to work with, which we used to make a model of COVID-19 pneumonia. Che Colpitts, a virologist at Queen’s University, helped us study the mitochondrial injury caused by another human beta coronavirus, HCoV-OC43.

Finally, Arinjay Banerjee and his expert SARS-CoV-2 virology team at Vaccine and Infectious Disease Organization (VIDO) in Saskatoon performed key studies of human SARS-CoV-2 in airway epithelial cells. VIDO is one of the few Canadian centres equipped to handle the highly infectious SARS-CoV-2 virus.

Our team’s super-resolution microscopy expert, Jeff Mewburn, notes the specific challenges the team had to contend with.

“Having to follow numerous and extensive COVID-19 protocols, they were still able to exhibit incredible flexibility to retool and refocus our laboratory specifically on the study of coronavirus infection and its effects on cellular/mitochondrial functions, so very relevant to our global situation,” he said.

Our discovery will hopefully be translated into new medicines to counter future pandemics.

A New Study Pinpoints a Cause of Long-Haul COVID Symptoms

An Attack on Mitochondria?

Authors:  MAGGIE RYAN February 2, 2022

As the pandemic continues, long COVID-19 remains very prevalent (affecting between 31 and 69 percent of COVID-19 patients) and somewhat bewildering because there’s no clear connection between the severity of a patient’s initial symptoms and how long they might linger. That was one thing that Irina Petrache, MD, chief of the division of pulmonary, critical care, and sleep medicine at National Jewish Health in Denver, noticed early on in the pandemic. “As the first survivors of COVID emerged, it became clear that many of them suffered from prolonged illness,” Dr. Petrache tells POPSUGAR.

But when Dr. Petrache and her fellow researchers looked at 50 such patients at their hospital, they realized that “the vast majority of them did not have severe acute COVID,” she says. “They suffered from this acute viral infection at home, and they recovered without needing extra oxygen or needing to go to the hospital.”

Those 50 patients helped form the basis of a new preliminary study, coauthored by Dr. Petrache, that attempted to pinpoint the causes of long COVID. The researchers came away with a striking discovery: that the virus was damaging the mitochondria in the cells of long-COVID patients. The mitochondria (as you might remember from high school biology) is a crucial organelle within the cell, tasked with turning oxygen and other nutrients into ATP, which is the energy that your muscles use to move and contract. Mitochondria are essentially “little factories in all our cells that produce energy,” Dr. Petrache says. When they’re not working properly, it’s a bad sign.

Exercise Study Found Connection Between Long COVID and Mitochondria

In the study, researchers asked patients to undergo cardiopulmonary exercise testing, which involved exercising on either a stationary bike or a treadmill and slowly increasing the resistance or incline to the point of fatigue. As they exercised, researchers recorded “massive amounts of data,” Dr. Petrache says, from heart rate and blood pressure to the amount of oxygen and carbon dioxide in their inhalations and exhalations. They also took arterial blood samples to measure carbon dioxide and lactate (a byproduct substance produced during exercise) in the blood.

At first, the data didn’t seem to add up. The researchers saw that their patients were tiring more quickly than expected, but on the surface, their lungs, hearts, and muscles seemed to function correctly. It wasn’t until they looked on the cellular level that they realized what was happening. The abnormally fast rate at which lactate was rising, as well as clues from the gases that patients exhaled, suggested that the cause lay within the mitochondria.

“All these formulas and results pointed in the same direction: that there is something wrong with these little organelles,” Dr. Petrache says. “They’re just not working like they should be.”

How Does COVID-19 Affect Mitochondria?

Researchers don’t know the exact mechanism by which SARS-COV-2 (the virus that causes COVID-19) affects the mitochondria, though this is not the first study to point out a connection. One possibility is that when the virus particles break into a cell, it causes a “cascade of events” that damages the mitochondria; specifically, Dr. Petrache says, the virus can lead to the release of a substance called angiotensin which, when accumulated in this way, can “unlock” the mitochondria and damage it.

But Dr. Petrache notes that the pathway might be more indirect as well; the virus might affect the flow of oxygen in the bloodstream, which then deprives the mitochondria of fuel. It might also affect the life cycle of mitochondria, causing premature death to the organelles or slowing the production of new mitochondria.

Finding the exact mechanism of the mitochondria dysfunction is one of the next steps Dr. Petrache hopes to take. “All these permutations or possibilities are subject to research now,” she says. “We really want to pinpoint it.” To do that, they hope to expand their study, bringing in more long-COVID patients and adding a control group of people who recovered from their COVID-19 symptoms without a problem.

Additionally, though this test looked at muscle function in long-COVID patients, the researchers believe the same process could be related to other long-COVID symptoms, such as lung or neurological issues.

Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19

Authors: Davide Scozzi,1Marlene Cano,2Lina Ma,2Dequan Zhou,1Ji Hong Zhu,1Jane A. O’Halloran,3Charles Goss,4Adriana M. Rauseo,3Zhiyi Liu,1Sanjaya K. Sahu,2Valentina Peritore,5Monica Rocco,6Alberto Ricci,7Rachele Amodeo,8Laura Aimati,8Mohsen Ibrahim,1,5Ramsey Hachem,2Daniel Kreisel,1Philip A. Mudd,9Hrishikesh S. Kulkarni,2,10 and Andrew E. Gelman1,11

Abstract

Background

Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.

Methods

We measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.

Results

Circulating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.

Conclusion

These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934921/

UniProtKB – P59636 (ORF9B_SARS)

Protein: ORF9b protein database

Gene: 9b

Organism Severe acute respiratory syndrome coronavirus (SARS-CoV) Status Reviewed-Annotation score:-Experimental evidence at protein leveli

Functioni

Plays a role in the inhibition of host innate immune response by targeting the mitochondrial-associated adapter MAVS. Mechanistically, usurps the E3 ligase ITCH to trigger the degradation of MAVS, TRAF3, and TRAF6. In addition, causes mitochondrial elongation by triggering ubiquitination and proteasomal degradation of dynamin-like protein 1/DNM1L.1 Publication

Miscellaneous

The gene encoding this protein is included within the N gene (alternative ORF).

GO – Molecular functioni

GO – Biological processi

Keywordsi

Biological processHost-virus interactionInhibition of host innate immune response by virusInhibition of host MAVS by virusInhibition of host RLR pathway by virusViral immunoevasion

For In-depth Information of ORF-9b Protein: https://www.uniprot.org/uniprot/P59636

SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the AVS/TRAF3/TRAF6 signalosome

.J Immunol 2014 Sep 15;193(6):3080-9. doi: 10.4049/jimmunol.1303196. Epub 2014 Aug 18.

Chong-Shan Shi 1Hai-Yan Qi 2Cedric Boularan 1Ning-Na Huang 1Mones Abu-Asab 3James H Shelhamer 2John H Kehrl 4

Abstract

Coronaviruses (CoV) have recently emerged as potentially serious pathogens that can cause significant human morbidity and death. The severe acute respiratory syndrome (SARS)-CoV was identified as the etiologic agent of the 2002-2003 international SARS outbreak. Yet, how SARS evades innate immune responses to cause human disease remains poorly understood. In this study, we show that a protein encoded by SARS-CoV designated as open reading frame-9b (ORF-9b) localizes to mitochondria and causes mitochondrial elongation by triggering ubiquitination and proteasomal degradation of dynamin-like protein 1, a host protein involved in mitochondrial fission. Also, acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. This severely limits host cell IFN responses. Reducing either PCBP2 or AIP4 expression substantially reversed the ORF-9b-mediated reduction of MAVS and the suppression of antiviral transcriptional responses. Finally, transient ORF-9b expression led to a strong induction of autophagy in cells. The induction of autophagy depended upon ATG5, a critical autophagy regulator, but the inhibition of MAVS signaling did not. These results indicate that SARS-CoV ORF-9b manipulates host cell mitochondria and mitochondrial function to help evade host innate immunity. This study has uncovered an important clue to the pathogenesis of SARS-CoV infection and illustrates the havoc that a small ORF can cause in cells.

For More Information: https://pubmed.ncbi.nlm.nih.gov/25135833/

Inflammasome activation at the crux of severe COVID-19

Authors: Setu M. Vora,1,2Judy Lieberman,2,3 and Hao Wu1,2

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in life-threatening disease in a minority of patients, especially elderly people and those with co-morbidities such as obesity and diabetes. Severe disease is characterized by dysregulated cytokine release, pneumonia and acute lung injury, which can rapidly progress to acute respiratory distress syndrome, disseminated intravascular coagulation, multisystem failure and death. However, a mechanistic understanding of COVID-19 progression remains unclear. Here we review evidence that SARS-CoV-2 directly or indirectly activates inflammasomes, which are large multiprotein assemblies that are broadly responsive to pathogen-associated and stress-associated cellular insults, leading to secretion of the pleiotropic IL-1 family cytokines (IL-1β and IL-18), and pyroptosis, an inflammatory form of cell death. We further discuss potential mechanisms of inflammasome activation and clinical efforts currently under way to suppress inflammation to prevent or ameliorate severe COVID-19.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has so far infected more than 190 million people and caused death of more than 4.1 million people worldwide. The virus primarily infects the respiratory tract, causing fever, sore throat, anosmia and dyspnoea, but its tissue tropism still remains to be fully understood. As many as 10–15% of patients develop severe pneumonia, with some cases progressing to hypoxia and acute respiratory distress syndrome (ARDS), which requires mechanical ventilation in a critical care setting and has high mortality. Patients can also develop multi-organ failure, acute kidney injury and disseminated intravascular coagulation, among a host of other disorders111. Aside from supportive care, only a few treatments have been approved for COVID-19, and their reduction of mortality has been limited1214. Although several vaccines against SARS-CoV-2 have been approved and are being administered internationally, there will still be a significant number of infections owing to people who are not vaccinated in regions with inadequate access or acceptance of vaccination. In addition, while global vaccination efforts strive to meet the challenge of ending the pandemic, the appearance of immune-evasive viral variants and the unlikelihood of reaching immediate herd immunity underscore the continued need for additional treatments mitigating disease progression1519.

Most researchers agree that an inappropriate hyperinflammatory response lies at the root of many severe cases of COVID-19, driven by overexuberant inflammatory cytokine release. Consistently, co-morbidities, such as obesity, diabetes, heart disease, hypertension and ageing, which are prognostic of poor outcome, are associated with high basal inflammation7,11,20,21. It has been proposed since the beginning of the pandemic that these co-morbidities and the ensuing hyperinflammatory response may be aetiologically linked through overactive inflammasome signaling, which may account for the association of these co-morbidities with severe COVID-19 in the context of chronic inflammation as well as for COVID-19 progression in the context of a robust acute inflammatory response to infection2229. However, many of the studies that seek to understand the immune response to SARS-CoV-2 are based on RNA sequencing, often of thawed cells, and infected, activated or dying cells do not survive freeze–thaw well, which could skew results. Moreover, inflammasome activation does not directly induce transcriptional responses, and its detection is less straightforward than that of most other signaling pathways. Nonetheless, several studies are now accumulating that support direct (infection-induced) and indirect inflammasome activation and the critical role of inflammasomes in severe COVID-19. Here we discuss the available evidence, potential mechanisms and the implications for therapy.

Key to inflammation and innate immunity, are large, micrometer-scale multiprotein cytosolic complexes that assemble in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and trigger proinflammatory cytokine release as well as pyroptosis, a proinflammatory lytic cell death30,31 (Fig. 1). Upon activation by PAMPs or DAMPs, canonical inflammasome sensors — mainly in monocytes, macrophages and barrier epithelial cells — oligomerize and recruit the adaptor apoptosis-associated speck-like protein containing a CARD (ASC) to form inflammasome specks, within which the inflammatory caspase 1 is recruited and activated. Inflammasome sensors are activated in response to different triggers and differ in their overall specificities to PAMPs or DAMPs. NLRP3, the most broadly activated inflammasome sensor and a member of the nucleotide-binding domain- and leucine-rich repeat-containing protein (NLR) family, responds to an array of insults to the cell that cause cytosolic K+ efflux, Ca2+ cytosolic influx or release of mitochondrial reactive oxygen species (ROS)31,32. These insults include extracellular ATP, membrane permeabilization by pore-forming toxins and large extracellular aggregates such as uric acid crystals, cholesterol crystals and amyloids30. Other sensors, such as AIM2 and NLRC4, are tuned to recognize specific PAMPs and DAMPs, such as cytosolic double-stranded DNA and bacterial proteins, respectively31. In a parallel pathway, the mouse inflammatory caspase 11 and human caspase 4 and caspase 5 sense PAMPs and DAMPs such as bacterial lipopolysaccharide (LPS) that gain cytosolic access and endogenous oxidized phospholipids, leading directly to membrane damage or pyroptosis, and secondary K+ efflux followed by noncanonical NLRP3 inflammasome activation3336.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351223/

Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis

Authors: Keshav K. Singh,* Gyaneshwer Chaubey,* Jake Y. Chen, and Prashanth Suravajhala

Because of the ongoing pandemic around the world, the mechanisms underlying the SARS-CoV-2-induced COVID-19 are subject to intense investigation. Based on available data for the SARS-CoV-1 virus, we suggest how CoV-2 localization of RNA transcripts in mitochondria hijacks the host cell’s mitochondrial function to viral advantage. Besides viral RNA transcripts, RNA also localizes to mitochondria. SARS-CoV-2 may manipulate mitochondrial function indirectly, first by ACE2 regulation of mitochondrial function, and once it enters the host cell, open-reading frames (ORFs) such as ORF-9b can directly manipulate mitochondrial function to evade host cell immunity and facilitate virus replication and COVID-19 disease. Manipulations of host mitochondria by viral ORFs can release mitochondrial DNA (mtDNA) in the cytoplasm and activate mtDNA-induced inflammasome and suppress innate and adaptive immunity. We argue that a decline in ACE2 function in aged individuals, coupled with the age-associated decline in mitochondrial functions resulting in chronic metabolic disorders like diabetes or cancer, may make the host more vulnerable to infection and health complications to mortality. These observations suggest that distinct localization of viral RNA and proteins in mitochondria must play essential roles in SARS-CoV-2 pathogenesis. Understanding the mechanisms underlying virus communication with host mitochondria may provide critical insights into COVID-19 pathologies. An investigation into the SARS-CoV-2 hijacking of mitochondria should lead to novel approaches to prevent and treat COVID-19.

For More Information: https://journals.physiology.org/doi/full/10.1152/ajpcell.00224.2020

SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2

Authors: Yuyang LeiJiao ZhangCara R. SchiavonMing HeLili ChenHui ShenYichi ZhangQian YinYoshitake ChoLeonardo AndradeGerald S. ShadelMark HepokoskiTing LeiHongliang WangJin ZhangJason X., et. al.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection relies on the binding of S protein (Sprotein (Spike glycoprotein) to ACE (angiotensin-converting enzyme) 2 in the host cells. Vascular endothelium can be infected by SARS-CoV-2,1 which triggers mitochondrial reactive oxygen species production and glycolytic shift.2 Paradoxically, ACE2 is protective in the cardiovascular system, and SARS-CoV-1 S protein promotes lung injury by decreasing the level of ACE2 in the infected lungs.3 In the current study, we show that S protein alone can damage vascular endothelial cells (ECs) by downregulating ACE2 and consequently inhibiting mitochondrial function.

For More Information: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.121.318902

COVID-19: A Mitochondrial Perspective

Authors: Pankaj Prasun 1

Coronavirus disease 2019 (COVID-19) is the worst public health crisis of the century. Although we have made tremendous progress in understanding the pathogenesis of this disease, a lot more remains to be learned. Mitochondria appear to be important in COVID-19 pathogenesis because of its role in innate antiviral immunity, as well as inflammation. This article examines pathogenesis of COVID-19 from a mitochondrial perspective and tries to answer some perplexing questions such as why the prognosis is so poor in those with obesity, metabolic syndrome, or type 2 diabetes. Although effective vaccines and antiviral drugs will be the ultimate solution to this crisis, a better understanding of disease mechanisms will open novel avenues for treatment and prevention.

For More Information: https://pubmed.ncbi.nlm.nih.gov/33872068/

Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis

Authors: Keshav K. Singh,* Gyaneshwer Chaubey,* Jake Y. Chen, and Prashanth Suravajhala

Because of the ongoing pandemic around the world, the mechanisms underlying the SARS-CoV-2-induced COVID-19 are subject to intense investigation. Based on available data for the SARS-CoV-1 virus, we suggest how CoV-2 localization of RNA transcripts in mitochondria hijacks the host cell’s mitochondrial function to viral advantage. Besides viral RNA transcripts, RNA also localizes to mitochondria. SARS-CoV-2 may manipulate mitochondrial function indirectly, first by ACE2 regulation of mitochondrial function, and once it enters the host cell, open-reading frames (ORFs) such as ORF-9b can directly manipulate mitochondrial function to evade host cell immunity and facilitate virus replication and COVID-19 disease. Manipulations of host mitochondria by viral ORFs can release mitochondrial DNA (mtDNA) in the cytoplasm and activate mtDNA-induced inflammasome and suppress innate and adaptive immunity. We argue that a decline in ACE2 function in aged individuals, coupled with the age-associated decline in mitochondrial functions resulting in chronic metabolic disorders like diabetes or cancer, may make the host more vulnerable to infection and health complications to mortality. These observations suggest that distinct localization of viral RNA and proteins in mitochondria must play essential roles in SARS-CoV-2 pathogenesis. Understanding the mechanisms underlying virus communication with host mitochondria may provide critical insights into COVID-19 pathologies. An investigation into the SARS-CoV-2 hijacking of mitochondria should lead to novel approaches to prevent and treat COVID-19.

For More Information: https://journals.physiology.org/doi/full/10.1152/ajpcell.00224.2020