SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 11, 2024

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a ‘highly transmissible pathogen, leading to severe multi-organ damage. However, knowledge regarding SARS-CoV-2-induced cellular alterations limited. In this study, we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during early stage of viral infection. causes an increase in transmembrane potential via RNA-nucleocapsid cluster, thereby abnormally promoting elongation OXPHOS process, followed by enhancing ATP production. Furthermore, EGFR subsequently induces trafficking, contributing abnormal process propagation. Approved inhibitors remarkably reduce propagation, among which vandetanib exhibits highest antiviral efficacy. Treatment SARS-CoV-2-infected cells with decreases trafficking mitochondria restores aberrant elevation generation, resulting reduction oral administration hACE2 transgenic mice reduces propagation lung tissue mitigates inflammation. Vandetanib also potent activity against various variants concern, including alpha, beta, delta omicron, vitro culture experiments. Taken together, our findings provide novel insight into dynamics infection their roles robust suggesting attractive host target for combating COVID-19.

Language: Английский

---

Perturbation of the host cell Ca2+ homeostasis and ER-mitochondria contact sites by the SARS-CoV-2 structural proteins E and M

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(4)

Published: April 29, 2023

Abstract Coronavirus disease (COVID-19) is a contagious respiratory caused by the SARS-CoV-2 virus. The clinical phenotypes are variable, ranging from spontaneous recovery to serious illness and death. On March 2020, global COVID-19 pandemic was declared World Health Organization (WHO). As of February 2023, almost 670 million cases 6,8 deaths have been confirmed worldwide. Coronaviruses, including SARS-CoV-2, contain single-stranded RNA genome enclosed in viral capsid consisting four structural proteins: nucleocapsid (N) protein, ribonucleoprotein core, spike (S) envelope (E) membrane (M) embedded surface envelope. In particular, E protein poorly characterized viroporin with high identity amongst all β-coronaviruses (SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43) low mutation rate. Here, we focused our attention on study M proteins, found general perturbation host cell calcium (Ca 2+ ) homeostasis selective rearrangement interorganelle contact sites. vitro vivo biochemical analyses revealed that binding specific nanobodies soluble regions reversed observed phenotypes, suggesting might be an important therapeutic candidate not only for vaccine development, but also management COVID designing drug regimens that, so far, very limited.

Language: Английский

---

Mitochondrial oxidative stress, mitochondrial ROS storms in long COVID pathogenesis

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Dec. 22, 2023

Significance This review discusses the coronavirus disease 2019 (COVID-19) pathophysiology in context of diabetes and intracellular reactions by COVID-19, including mitochondrial oxidative stress storms, ROS long COVID. Recent advances The COVID is suffered ~10% COVID-19 patients. Even virus does not exist, patients suffer for even over a year, could be mitochondria dysregulation disease. Critical issues Patients who recover from can develop new or persistent symptoms multi-organ complications lasting weeks months, called underlying mechanisms involved still unclear. Once persist, they cause significant damage, leading to numerous, symptoms. Future directions A comprehensive map stages pathogenetic related effective drugs treat prevent it are required, which will aid development future treatments symptom relief.

Language: Английский

---

Metabolomics combined with network pharmacology reveals a role for astragaloside IV in inhibiting enterovirus 71 replication via PI3K-AKT signaling

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: June 10, 2024

Language: Английский

---

Visualization of BOK pores independent of BAX and BAK reveals a similar mechanism with differing regulation

Cell Death and Differentiation, Journal Year: 2022, Volume and Issue: 30(3), P. 731 - 741

Published: Oct. 26, 2022

Abstract BOK is a poorly understood member of the BCL-2 family proteins that has been proposed to function as pro-apoptotic, BAX-like effector. However, molecular mechanism and structural properties pores remain enigmatic. Here, we show thermal stability pore activity depends on presence its C-terminus well mitochondrial lipid cardiolipin. We directly visualized in liposomes by electron microscopy, which appeared similar those induced BAX, line with comparable oligomerization quantified single molecule imaging. In addition, super-resolution STED imaging revealed organized into dots ring-shaped assemblies apoptotic mitochondria, also reminiscent found for BAX BAK. Yet, unlike BAK, was limited partial localization independent unaffected other proteins. These results suggest that, while kept check subcellular instead interaction members, resulting are structurally

Language: Английский

---

Potential Beneficial Effects of Naringin and Naringenin on Long COVID—A Review of the Literature

Microorganisms, Journal Year: 2024, Volume and Issue: 12(2), P. 332 - 332

Published: Feb. 4, 2024

Coronavirus disease 2019 (COVID-19) caused a severe epidemic due to acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Recent studies have found that patients do not completely recover from infections, but instead, suffer variety of post-acute sequelae SARS-CoV-2 infection, known as long COVID. The effects COVID can be far-reaching, with duration up six months and range symptoms such cognitive dysfunction, immune dysregulation, microbiota dysbiosis, myalgic encephalomyelitis/chronic fatigue syndrome, myocarditis, pulmonary fibrosis, cough, diabetes, pain, reproductive thrombus formation. However, recent shown naringenin naringin palliative on various COVID-19 sequelae. Flavonoids naringenin, commonly in fruits vegetables, positive effects, including reducing inflammation, preventing viral providing antioxidants. This article discusses the molecular mechanisms clinical treating above diseases. It proposes them potential drugs for treatment COVID, it inferred exhibit extended medications, future likely serving nutraceuticals or supplements comprehensive alleviation manifestations complications.

Language: Английский

---

Unveiling the Role of Protein Kinase C θ in Porcine Epidemic Diarrhea Virus Replication: Insights from Genome-Wide CRISPR/Cas9 Library Screening

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3096 - 3096

Published: March 7, 2024

Porcine epidemic diarrhea virus (PEDV), a member of the Alpha-coronavirus genus in Coronaviridae family, induces acute diarrhea, vomiting, and dehydration neonatal piglets. This study aimed to investigate genetic dependencies PEDV identify potential therapeutic targets by using single-guide RNA (sgRNA) lentiviral library screen host factors required for infection. Protein kinase C θ (PKCθ), calcium-independent PKC family localized cell membrane, was found be crucial factor The investigation infection limited Vero porcine epithelial cell-jejunum 2 (IPEC-J2) due defective interferon production poor replication IPEC-J2. Therefore, identifying suitable cells is crucial. findings this reveal that human embryonic kidney (HEK) 293T L929 cells, but not IPEC-J2 were investigating PKCθ played significant role endocytosis PEDV, regulated expression phosphorylation PKCθ. Apoptosis involved replication, as activated PKCθ-B-cell lymphoma (BCL-2) ovarian killer (BOK) axis HEK293T increase viral via mitochondrial apoptosis. demonstrated suitability identified essential These provide valuable insights development strategies drug

Language: Английский

---

Taurine Improved Autism-Like Behaviours and Defective Neurogenesis of the Hippocampus in BTBR Mice through the PTEN/mTOR/AKT Signalling Pathway

Folia Biologica, Journal Year: 2024, Volume and Issue: 70(1), P. 45 - 52

Published: Jan. 1, 2024

Effective treatment of patients with autism spectrum disorder (ASD) is still absent so far. Taurine exhibits therapeutic effects towards the autism-like behaviour in ASD model animals. Here, we determined mechanism taurine effect on hippocampal neurogenesis genetically inbred BTBR T + tf/J (BTBR) mice, a proposed ASD. In this mouse model, explored oral supplementation ASD-like behaviours an open field test, elevated plus maze, marble burying self-grooming and three-chamber test. The mice were divided into four groups normal controls (WT) models (BTBR), who did or not receive 6-week water (WT, WT+ Taurine, BTBR, BTBR+Taurine). Neurogenesis-related by Ki67 immunofluorescence staining. Western blot analysis was performed to detect expression phosphatase tensin homologue deleted from chromosome 10 (PTEN)/mTOR/AKT pathway-associated proteins. Our results showed that improved behaviour, increased proliferation cells, promoted PTEN expression, reduced phosphorylation mTOR AKT tissue mice. conclusion, partially inherited which may be associa­ted improving defective neural precursor cell enhancing PTEN-associated pathway tissue.

Language: Английский

---

The role of programmed cell death in organ dysfunction induced by opportunistic pathogens

Critical Care, Journal Year: 2025, Volume and Issue: 29(1)

Published: Jan. 24, 2025

Sepsis is a life-threatening condition resulting from pathogen infection and characterized by organ dysfunction. Programmed cell death (PCD) during sepsis has been associated with the development of multiple dysfunction syndrome (MODS), impacting various physiological systems including respiratory, cardiovascular, renal, neurological, hematological, hepatic, intestinal systems. It well-established that infections lead to immune dysregulation, which subsequently contributes MODS in sepsis. However, recent evidence suggests sepsis-related opportunistic pathogens can directly induce failure promoting PCD parenchymal cells each affected organ. This study provides an overview damaged induction host pathogens, proposing innovative strategies for preventing

Language: Английский

---

SARS-CoV-2 enhances complement-mediated endothelial injury via suppression of membrane complement regulatory proteins

Emerging Microbes & Infections, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Complement hyperactivation and thrombotic microangiopathy are closely associated with severe COVID-19. Endothelial dysfunction is a key mechanism underlying microangiopathy. To address the relationship between endothelial injury, complement activation of COVID-19, we wonder whether, if so, what how SARS-CoV-2 factors make cells (ECs) sensitive to complement-mediated cytotoxicity. We revealed that multiple proteins enhanced cytotoxicity ECs via inhibiting membrane regulatory (CRPs) enhancing deposition recognizing component FCN1. By screening CRISPR/Cas9-gRNA libraries, identified ADAMTS9, SYAP1 HIGD1A as intrinsic regulators CD59 on were inhibited by M, NSP16 ORF9b proteins. IFN-γ, GM-CSF IFN-α upregulated CD55 CD59, which IFN-γ antagonized inhibition three So, deficiency weakened protection CRPs against injury may be during infection. Our findings illustrated regulation attack self-cells infection immune responses, providing insights for potential targets treating

Language: Английский

---