scholarly journals Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19

2021 ◽  
Vol 22 (15) ◽  
pp. 8180
Author(s):  
Shailendra Pratap Singh ◽  
Salomon Amar ◽  
Pinky Gehlot ◽  
Sanjib K. Patra ◽  
Navjot Kanwar ◽  
...  
Keyword(s):  
Cell Death ◽  
Essential Role ◽  
Viral Infections ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Innate Immune ◽  
Innate Immune Signaling ◽  
Promising Target ◽  
Intracellular Organelles ◽  
Viral Proliferation

Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.

scholarly journals The Mitochondrial Fission Regulator DRP1 Controls Post-Transcriptional Regulation of TNF-α

2021 ◽  
Vol 10 ◽  
Author(s):  
Fushan Gao ◽  
Mack B. Reynolds ◽  
Karla D. Passalacqua ◽  
Jonathan Z. Sexton ◽  
Basel H. Abuaita ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Critical Role ◽  
Innate Immune ◽  
Sterile Inflammation ◽  
Proinflammatory Response ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Tnf Α

The mitochondrial network plays a critical role in the regulation of innate immune signaling and subsequent production of proinflammatory cytokines such as IFN-β and IL-1β. Dynamin-related protein 1 (DRP1) promotes mitochondrial fission and quality control to maintain cellular homeostasis during infection. However, mechanisms by which DRP1 and mitochondrial dynamics control innate immune signaling and the proinflammatory response are incompletely understood. Here we show that macrophage DRP1 is a positive regulator of TNF-α production during sterile inflammation or bacterial infection. Silencing macrophage DRP1 decreased mitochondrial fragmentation and TNF-α production upon stimulation with lipopolysaccharide (LPS) or methicillin-resistant Staphylococcus aureus (MRSA) infection. The defect in TNF-α induction could not be attributed to changes in gene expression. Instead, DRP1 was required for post-transcriptional control of TNF-α. In contrast, silencing DRP1 enhanced IL-6 and IL-1β production, indicating a distinct mechanism for DRP1-dependent TNF-α regulation. Our results highlight DRP1 as a key player in the macrophage pro-inflammatory response and point to its involvement in post-transcriptional control of TNF-α production.

scholarly journals Viral Infection Modulates Mitochondrial Function

2021 ◽  
Vol 22 (8) ◽  
pp. 4260
Author(s):  
Xiaowen Li ◽  
Keke Wu ◽  
Sen Zeng ◽  
Feifan Zhao ◽  
Jindai Fan ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Viral Infection ◽  
Viral Infections ◽  
Mitochondrial Dynamics ◽  
Innate Immune ◽  
Host Cells ◽  
Mitochondrial Morphology ◽  
And Function ◽  
Antiviral Role

Mitochondria are important organelles involved in metabolism and programmed cell death in eukaryotic cells. In addition, mitochondria are also closely related to the innate immunity of host cells against viruses. The abnormality of mitochondrial morphology and function might lead to a variety of diseases. A large number of studies have found that a variety of viral infections could change mitochondrial dynamics, mediate mitochondria-induced cell death, and alter the mitochondrial metabolic status and cellular innate immune response to maintain intracellular survival. Meanwhile, mitochondria can also play an antiviral role during viral infection, thereby protecting the host. Therefore, mitochondria play an important role in the interaction between the host and the virus. Herein, we summarize how viral infections affect microbial pathogenesis by altering mitochondrial morphology and function and how viruses escape the host immune response.

scholarly journals Role of Mitochondria in Viral Infections

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 232
Author(s):  
Srikanth Elesela ◽  
Nicholas W. Lukacs
Keyword(s):  
Viral Infections ◽  
Mitochondrial Dynamics ◽  
The Body ◽  
Viral Diseases ◽  
Multiple Organs ◽  
Innate Immune Signaling ◽  
Mitochondrial Functions ◽  
Host Virus Interactions ◽  
Virus Interactions

Viral diseases account for an increasing proportion of deaths worldwide. Viruses maneuver host cell machinery in an attempt to subvert the intracellular environment favorable for their replication. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections. Viruses affect mitochondrial functions and impact mitochondrial metabolism, and innate immune signaling. Resurgence of host-virus interactions in recent literature emphasizes the key role of mitochondria and host metabolism on viral life processes. Mitochondrial dysfunction leads to damage of mitochondria that generate toxic compounds, importantly mitochondrial DNA, inducing systemic toxicity, leading to damage of multiple organs in the body. Mitochondrial dynamics and mitophagy are essential for the maintenance of mitochondrial quality control and homeostasis. Therefore, metabolic antagonists may be essential to gain a better understanding of viral diseases and develop effective antiviral therapeutics. This review briefly discusses how viruses exploit mitochondrial dynamics for virus proliferation and induce associated diseases.

scholarly journals Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways

2017 ◽  
Vol 8 (10) ◽  
pp. e3078-e3078 ◽  
Author(s):  
Puja Kumari ◽  
Irene Saha ◽  
Athira Narayanan ◽  
Sathish Narayanan ◽  
Akinori Takaoka ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Essential Role ◽  
Innate Immune ◽  
Immune Signaling ◽  
Innate Immune Signaling

scholarly journals Peroxiredoxin 5 Inhibits Glutamate-Induced Neuronal Cell Death through the Regulation of Calcineurin-Dependent Mitochondrial Dynamics in HT22 Cells

2019 ◽  
Vol 39 (20) ◽  
Author(s):  
Mi Hye Kim ◽  
Hong Jun Lee ◽  
Sang-Rae Lee ◽  
Hyun-Shik Lee ◽  
Jae-Won Huh ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Glutamate Toxicity ◽  
Ht22 Cells ◽  
Peroxidase Enzyme ◽  
The Central Nervous System

ABSTRACT Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca2+ influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca2+/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca2+/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca2+/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.

Abstract 393: MCL-1 Promotes Survival and Influences Mitochondrial Dynamics in Cardiac Myocytes

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alexandra G Moyzis ◽  
Robert L Thomas ◽  
Jennifer Kuo ◽  
Åsa B Gustafsson
Keyword(s):  
Cell Death ◽  
Cardiac Myocytes ◽  
Apoptotic Cell ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Apoptotic Cell Death ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Morphology ◽  
Rapid Degradation

The BCL-2 family proteins are important regulators of mitochondrial structure and integrity. MCL-1 is an anti-apoptotic BCL-2 protein that is highly expressed in the myocardium compared to the other anti-apoptotic proteins BCL-2 and BCL-X L. Recently, we reported that MCL-1 is essential for myocardial homeostasis. Cardiac-specific deletion of MCL-1 in mice led to rapid mitochondrial dysfunction, hypertrophy, and lethal cardiomyopathy. Surprisingly, MCL-1 deficient myocytes did not undergo apoptotic cell death. Instead, the cells displayed signs of mitochondrial deterioration and necrotic cell death, suggesting that MCL-1 has an additional role in maintaining mitochondrial function in cardiac myocytes. Similarly, deletion of MCL-1 in fibroblasts caused rapid mitochondrial fragmentation followed by cell death at 72 hours. Interestingly, the MCL-1 deficient fibroblasts retained cytochrome c in the mitochondria , confirming that the cells were not undergoing apoptotic cell death. We have also identified that MCL-1 localizes to the mitochondrial outer membrane (OM) and the matrix in the myocardium and that the two forms respond differently to stress. MCL-1 OM was rapidly degraded after myocardial infarction or fasting, whereas MCL-1 Matrix levels were maintained. Similarly, starvation of MEFs resulted in rapid degradation of MCL-1 OM , whereas MCL-1 Matrix showed delayed degradation. Treatment with the mitochondrial uncoupler FCCP led to rapid degradation of both forms. This suggests that the susceptibility to degradation is dependent on its localization and the nature of the stress. Our data also suggests that these two forms perform distinct functions in regulating mitochondrial morphology and survival. Overexpression of MCL-1 Matrix promoted mitochondrial fusion in fibroblasts under baseline conditions and protected cells against FCCP-mediated mitochondrial fission and clearance by autophagosomes. Thus, our data suggest that MCL-1 exists in two separate locations where it performs different functions. MCL-1 Matrix promotes mitochondrial fusion, which protects cells against excessive mitochondrial clearance during unfavorable conditions.

scholarly journals Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity

2016 ◽  
Vol 213 (11) ◽  
pp. 2365-2382 ◽  
Author(s):  
Brooke A. Napier ◽  
Sky W. Brubaker ◽  
Timothy E. Sweeney ◽  
Patrick Monette ◽  
Greggory H. Rothmeier ◽  
...  
Keyword(s):  
Cell Death ◽  
Cleavage Product ◽  
Innate Immune ◽  
Sepsis Severity ◽  
Human Sepsis ◽  
Proinflammatory Mediators ◽  
Mapk Activity ◽  
Innate Immune Signaling ◽  
Genome Wide ◽  
Dependent Cell

Cell death and release of proinflammatory mediators contribute to mortality during sepsis. Specifically, caspase-11–dependent cell death contributes to pathology and decreases in survival time in sepsis models. Priming of the host cell, through TLR4 and interferon receptors, induces caspase-11 expression, and cytosolic LPS directly stimulates caspase-11 activation, promoting the release of proinflammatory cytokines through pyroptosis and caspase-1 activation. Using a CRISPR-Cas9–mediated genome-wide screen, we identified novel mediators of caspase-11–dependent cell death. We found a complement-related peptidase, carboxypeptidase B1 (Cpb1), to be required for caspase-11 gene expression and subsequent caspase-11–dependent cell death. Cpb1 modifies a cleavage product of C3, which binds to and activates C3aR, and then modulates innate immune signaling. We find the Cpb1–C3–C3aR pathway induces caspase-11 expression through amplification of MAPK activity downstream of TLR4 and Ifnar activation, and mediates severity of LPS-induced sepsis (endotoxemia) and disease outcome in mice. We show C3aR is required for up-regulation of caspase-11 orthologues, caspase-4 and -5, in primary human macrophages during inflammation and that c3aR1 and caspase-5 transcripts are highly expressed in patients with severe sepsis; thus, suggesting that these pathways are important in human sepsis. Our results highlight a novel role for complement and the Cpb1–C3–C3aR pathway in proinflammatory signaling, caspase-11 cell death, and sepsis severity.

scholarly journals Long noncoding RNAAVANpromotes antiviral innate immunity by interacting with TRIM25 and enhancing the transcription of FOXO3a

2019 ◽  
Author(s):  
Chengcai Lai ◽  
Lihui Liu ◽  
Qinghua Liu ◽  
Sijie Cheng ◽  
Keyu Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza A ◽  
Virus Production ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Forkhead Box ◽  
Innate Immune Signaling ◽  
Promising Target ◽  
Antiviral Innate Immunity

AbstractAccumulating evidence has shown that long noncoding RNAs (lncRNAs) are involved in several biological processes, including immune responses. However, the role of lncRNAs in antiviral innate immune responses remains largely unexplored. Here, we identify an uncharacterized human lncRNA from influenza A virus (IAV) patients, antivirus and activate neutrophil (AVAN), that is significantly up-regulated upon virus infection. Mechanistically, nuclear lncRNA-AVANpositively regulates the transcription of forkhead box O3A (FOXO3a) by associating with its promoter and inducing chromatin remodeling to promote neutrophil chemotaxis. Furthermore, we also found that cytoplasmic lncRNA-AVANdirectly binds tripartite motif containing 25 (TRIM25) and enhances the association of TRIM25 and Retinoic acid inducible gene-1 proteins (RIG-I) and the ubiquitylation of RIG-I, thereby promoting TRIM25- and RIG-I-mediated antiviral innate immune signaling. More importantly, we enforced the expression of AVAN in transgenic mice and found that it significantly alleviated IAV virulence and virus production. Collectively, these findings highlight the potential clinical implications of lncRNA-AVANas a key positive regulator of the antiviral innate immune response and a promising target for developing broad antiviral therapeutics.

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