Mitochondria and Mitochondrial DNA: Key Elements in the Pathogenesis and Exacerbation of the Inflammatory State Caused by COVID-19

Background and Objectives. The importance of mitochondria in inflammatory pathologies, besides providing energy, is associated with the release of mitochondrial damage products, such as mitochondrial DNA (mt-DNA), which may perpetuate inflammation. In this review, we aimed to show the importance of mitochondria, as organelles that produce energy and intervene in multiple pathologies, focusing mainly in COVID-19 and using multiple molecular mechanisms that allow for the replication and maintenance of the viral genome, leading to the exacerbation and spread of the inflammatory response. The evidence suggests that mitochondria are implicated in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which forms double-membrane vesicles and evades detection by the cell defense system. These mitochondrion-hijacking vesicles damage the integrity of the mitochondrion’s membrane, releasing mt-DNA into circulation and triggering the activation of innate immunity, which may contribute to an exacerbation of the pro-inflammatory state. Conclusions. While mitochondrial dysfunction in COVID-19 continues to be studied, the use of mt-DNA as an indicator of prognosis and severity is a potential area yet to be explored.

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Omegasomes: PI3P platforms that manufacture autophagosomes

Essays in Biochemistry ◽

10.1042/bse0550017 ◽

2013 ◽

Vol 55 ◽

pp. 17-27 ◽

Cited By ~ 40

Author(s):

Rebecca Roberts ◽

Nicholas T. Ktistakis

Keyword(s):

Molecular Mechanisms ◽

Protein Complexes ◽

Membrane Vesicles ◽

Double Membrane ◽

Survival Pathway ◽

Membrane Compartments ◽

Specific Control ◽

Phosphatidylinositol 3

Autophagy is a conserved survival pathway, which cells and tissues will activate during times of stress. It is characterized by the formation of double-membrane vesicles called autophagosomes inside the cytoplasm. The molecular mechanisms and the signalling components involved require specific control to ensure correct activation. The present chapter describes the formation of autophagosomes from within omegasomes, newly identified membrane compartments enriched in PI3P (phosphatidylinositol 3-phosphate) that serve as platforms for the formation of at least some autophagosomes. We discuss the signalling events required to nucleate the formation of omegasomes as well as the protein complexes involved.

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Peripheral Blood Mitochondrial DNA Levels Were Modulated by SARS-CoV-2 Infection Severity and Its Lessening Was Associated With Mortality Among Hospitalized Patients With COVID-19

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.754708 ◽

2021 ◽

Vol 11 ◽

Author(s):

José J. Valdés-Aguayo ◽

Idalia Garza-Veloz ◽

José R. Vargas-Rodríguez ◽

María C. Martinez-Vazquez ◽

Lorena Avila-Carrasco ◽

...

Keyword(s):

Mitochondrial Dna ◽

Peripheral Blood ◽

Mitochondrial Gene ◽

Mt Dna ◽

Qrt Pcr ◽

Potential Biomarker ◽

Inflammatory State ◽

Patient’S Outcome ◽

Severity Of The Disease ◽

Early Predictor

IntroductionDuring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the virus hijacks the mitochondria causing damage of its membrane and release of mt-DNA into the circulation which can trigger innate immunity and generate an inflammatory state. In this study, we explored the importance of peripheral blood mt-DNA as an early predictor of evolution in patients with COVID-19 and to evaluate the association between the concentration of mt-DNA and the severity of the disease and the patient’s outcome.MethodsA total 102 patients (51 COVID-19 cases and 51 controls) were included in the study. mt-DNA obtained from peripheral blood was quantified by qRT-PCR using the NADH mitochondrial gene.ResultsThere were differences in peripheral blood mt-DNA between patients with COVID-19 (4.25 ng/μl ± 0.30) and controls (3.3 ng/μl ± 0.16) (p = 0.007). Lower mt-DNA concentrations were observed in patients with severe COVID-19 when compared with mild (p= 0.005) and moderate (p= 0.011) cases of COVID-19. In comparison with patients with severe COVID-19 who survived (3.74 ± 0.26 ng/μl) decreased levels of mt-DNA in patients with severe COVID-19 who died (2.4 ± 0.65 ng/μl) were also observed (p = 0.037).ConclusionHigh levels of mt-DNA were associated with COVID-19 and its decrease could be used as a potential biomarker to establish a prognosis of severity and mortality of patients with COVID-19.

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The Molecular Interplay between Human Coronaviruses and Autophagy

Cells ◽

10.3390/cells10082022 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2022

Author(s):

Ankit Shroff ◽

Taras Y. Nazarko

Keyword(s):

Life Cycle ◽

Membrane Trafficking ◽

Molecular Mechanisms ◽

Membrane Vesicles ◽

Intracellular Protein ◽

Double Membrane ◽

The Past ◽

Trafficking Pathway ◽

Life Threatening ◽

Human Coronaviruses

Coronavirus disease 2019 (COVID-19), caused by a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has instantaneously emerged as a worldwide pandemic. However, humans encountered other coronaviruses in the past, and they caused a broad range of symptoms, from mild to life-threatening, depending on the virus and immunocompetence of the host. Most human coronaviruses interact with the proteins and/or double-membrane vesicles of autophagy, the membrane trafficking pathway that degrades and recycles the intracellular protein aggregates, organelles, and pathogens, including viruses. However, coronaviruses often neutralize and hijack this pathway to complete their life cycle. In this review, we discuss the interactions of human coronaviruses and autophagy, including recent data from SARS-CoV-2-related studies. Some of these interactions (for example, viral block of the autophagosome–lysosome fusion), while being conserved across multiple coronaviruses, are accomplished via different molecular mechanisms. Therefore, it is important to understand the molecular interplay between human coronaviruses and autophagy for developing efficient therapies against coronaviral diseases.

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Glycine-zipper motifs in hepatitis C virus nonstructural protein 4B are required for the establishment of viral replication organelles

Journal of Virology ◽

10.1128/jvi.01890-17 ◽

2017 ◽

pp. JVI.01890-17 ◽

Cited By ~ 5

Author(s):

David Paul ◽

Vanesa Madan ◽

Omar Ramirez ◽

Maja Bencun ◽

Ina Karen Stoeck ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Molecular Mechanisms ◽

Nonstructural Protein ◽

Membrane Vesicles ◽

Rna Replication ◽

Viral Rna ◽

Transmembrane Helices ◽

Double Membrane

Hepatitis C virus (HCV) RNA replication occurs in tight association with remodeled host cell membranes, presenting as cytoplasmic accumulations of single, double and multi membrane vesicles in infected cells. Formation of these so-called replication organelles is mediated by a complex interplay of host cell factors and viral replicase proteins. Of these, nonstructural protein 4B (NS4B), an integral transmembrane protein, appears to play a key role, but little is known about the molecular mechanisms how this protein contributes to organelle biogenesis. Using forward and reverse genetics we identified glycine-zipper motifs within transmembrane helices 2 and 3 of NS4B that are critically involved in viral RNA replication. Foerster resonance energy transfer analysis revealed the importance of the glycine-zippers in NS4B homo and heterotypic self-interactions. Additionally, ultrastructural analysis using electron microscopy unraveled a prominent role of glycine-zipper residues for the subcellular distribution and the morphology of HCV-induced double membrane vesicles. Notably, loss-of-function NS4B glycine-zipper mutants prominently induced single membrane vesicles with secondary invaginations that might represent an arrested intermediate state in double membrane vesicle formation. These findings highlight a so far unknown role of glycine residues within the membrane integral core domain for NS4B self-interaction and functional as well as structural integrity of HCV replication organelles.IMPORTANCERemodeling of the cellular endomembrane system leading to the establishment of replication organelles is a hallmark of positive-strand RNA viruses. In the case of hepatitis C virus (HCV), expression of the nonstructural proteins induces the accumulation of double membrane vesicles that likely arise from a concerted action of viral and co-opted cellular factors. However, the underlying molecular mechanisms are incompletely understood. Here, we identify glycine-zipper motifs within HCV nonstructural protein 4B (NS4B) transmembrane segments 2 and 3 that are crucial for the protein's self-interaction. Moreover, glycine residues within NS4B transmembrane helices critically contribute to the biogenesis of functional replication organelles and thus, efficient viral RNA replication. These results reveal how glycine-zipper motifs in NS4B contribute to structural and functional integrity of the HCV replication organelles and thus, viral RNA replication.

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Autophagy regulation by acetylation—implications for neurodegenerative diseases

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00556-4 ◽

2021 ◽

Vol 53 (1) ◽

pp. 30-41

Author(s):

Sung Min Son ◽

So Jung Park ◽

Marian Fernandez-Estevez ◽

David C. Rubinsztein

Keyword(s):

Neurodegenerative Diseases ◽

Posttranslational Modifications ◽

Molecular Mechanisms ◽

Membrane Vesicles ◽

Cell Types ◽

Double Membrane ◽

Physiological Processes ◽

Evolutionarily Conserved ◽

Development And Aging ◽

Catabolic Process

AbstractPosttranslational modifications of proteins, such as acetylation, are essential for the regulation of diverse physiological processes, including metabolism, development and aging. Autophagy is an evolutionarily conserved catabolic process that involves the highly regulated sequestration of intracytoplasmic contents in double-membrane vesicles called autophagosomes, which are subsequently degraded after fusing with lysosomes. The roles and mechanisms of acetylation in autophagy control have emerged only in the last few years. In this review, we describe key molecular mechanisms by which previously identified acetyltransferases and deacetylases regulate autophagy. We highlight how p300 acetyltransferase controls mTORC1 activity to regulate autophagy under starvation and refeeding conditions in many cell types. Finally, we discuss how altered acetylation may impact various neurodegenerative diseases in which many of the causative proteins are autophagy substrates. These studies highlight some of the complexities that may need to be considered by anyone aiming to perturb acetylation under these conditions.

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SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms21155475 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5475 ◽

Cited By ~ 11

Author(s):

Manuela Pennisi ◽

Giuseppe Lanza ◽

Luca Falzone ◽

Francesco Fisicaro ◽

Raffaele Ferri ◽

...

Keyword(s):

Nervous System ◽

Molecular Mechanisms ◽

Neuronal Damage ◽

Neurological Complications ◽

Neurological Manifestations ◽

Wide Range ◽

Inflammatory State ◽

Acute Polyneuropathy ◽

The Central Nervous System ◽

The Impact

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

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Linear plasmids that integrate into mitochondrial DNA in Neurospora

Genome ◽

10.1139/g89-027 ◽

1989 ◽

Vol 31 (1) ◽

pp. 155-159 ◽

Cited By ~ 31

Author(s):

H. Bertrand ◽

A. J. F. Griffiths

Keyword(s):

Mitochondrial Dna ◽

Rna Polymerase ◽

Dna Polymerase ◽

Inverted Repeats ◽

Insertion Sequences ◽

Long Terminal Repeats ◽

Linear Plasmids ◽

Mt Dna ◽

Common Features ◽

Mitochondrial Chromosome

In some field isolates of Neurospora from Hawaii and India, senescence is induced by integration of linear DNA plasmids, kalilo and maranhar, respectively, into mitochondrial (mt) DNA. Although the two plasmids show little homology at the DNA level, both have inverted long terminal repeats, and each potentially encodes a DNA polymerase and a RNA polymerase. Both plasmids generate very long inverted repeats of mtDNA at their ends upon integration into mitochondrial chromosomes. Hence, they appear to integrate by a mechanism that involves pairing of both ends of the plasmid with short stretches of homologous nucleotide sequences in mtDNA. This recombinogenic association apparently generates an origin for an unscheduled round of replication of mtDNA. In the process, the resulting two copies of the mitochondrial chromosome are joined to opposite ends of the plasmid. A model for the senescence-associated accumulation of mtDNAs with plasmid insertion sequences is proposed on the basis of common features that characterize senescence in a variety of filamentous fungi.Key words: Neurospora, senescence, plasmids, mitochondria.

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Vascular Dysfunction in Preeclampsia

Cells ◽

10.3390/cells10113055 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3055

Author(s):

Megan A. Opichka ◽

Matthew W. Rappelt ◽

David D. Gutterman ◽

Justin L. Grobe ◽

Jennifer J. McIntosh

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Treatment Options ◽

Cardiovascular Disorder ◽

Endothelial Damage ◽

Spiral Artery ◽

Mitochondrial Stress ◽

Inflammatory State ◽

Life Threatening

Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.

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Genome-wide interrogation of extracellular vesicle biology using barcoded miRNAs

eLife ◽

10.7554/elife.41460 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 7

Author(s):

Albert Lu ◽

Paulina Wawro ◽

David W Morgens ◽

Fernando Portela ◽

Michael C Bassik ◽

...

Keyword(s):

Nucleic Acid ◽

Molecular Mechanisms ◽

Membrane Vesicles ◽

Extracellular Vesicle ◽

Biologically Active ◽

Vesicle Release ◽

Guide Rnas ◽

Disease States ◽

Genome Wide ◽

First Time

Extracellular vesicles mediate transfer of biologically active molecules between neighboring or distant cells, and these vesicles may play important roles in normal physiology and the pathogenesis of multiple disease states including cancer. However, the underlying molecular mechanisms of their biogenesis and release remain unknown. We designed artificially barcoded, exosomal microRNAs (bEXOmiRs) to monitor extracellular vesicle release quantitatively using deep sequencing. We then expressed distinct pairs of CRISPR guide RNAs and bEXOmiRs, enabling identification of genes influencing bEXOmiR secretion from Cas9-edited cells. This approach uncovered genes with unrecognized roles in multivesicular endosome exocytosis, including critical roles for Wnt signaling in extracellular vesicle release regulation. Coupling bEXOmiR reporter analysis with CRISPR-Cas9 screening provides a powerful and unbiased means to study extracellular vesicle biology and for the first time, to associate a nucleic acid tag with individual membrane vesicles.

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PERIPHERAL BLOOD MITOCHONDRIAL DNA ALTERATION DURING SYSTEMIC LUPUS NEPHRITIS

Current Trends in Natural Sciences ◽

10.47068/ctns.2021.v10i19.055 ◽

2021 ◽

Vol 10 (19) ◽

pp. 416-421

Author(s):

Ruchi Upadhyay ◽

Ratika Srivastava

Keyword(s):

Mitochondrial Dna ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Peripheral Blood ◽

Normal Subjects ◽

Mitochondrial Genes ◽

Systemic Lupus ◽

Mt Dna ◽

Mitochondrial Dna Copy Number ◽

Genes Encoding

The investigation of mitochondrial DNA (Mt-DNA) alterations could impart light on the involvement of mitochondria in the pathophysiology of Systemic Lupus Erythematosus. The purpose of this study is to examine the peripheral blood mitochondrial DNA copy number variation in Lupus Nephritis patients and also to find out it’s correlation with amount of protein present in urine. The significant correlation could aid in the inspection of mitochondrial involvement, particularly in Lupus Nephritis. Two mitochondrial genes encoding MT-CYT and MT-TL1 were measured quantitatively by qRT-PCR in whole blood of 17 SLE patients and 15 healthy subjects with similar gender (female: male ratio) and age group. The amount of mitochondrial genes MT-CYT and MT-TL1 was 1.69 and 1.26 fold higher respectively in patients. The significantly higher amount of protein detected in lupus nephritis patients (129.4±116.4 mg/dl) in comparison to normal subjects (25.3 ±10.7 mg/dl). No significant correlation was established between Mt-DNA quantity and proteinuria. Alteration in mitochondrial genes reflects the possibilities of altered mitophagy or mitochondrial biosynthesis during SLE. These findings are required to be further validated by studying mitophagy and biogenesis during SLE in details.

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