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1.
Ann Neurol ; 91(4): 568-574, 2022 04.
Article in English | MEDLINE | ID: covidwho-1680263

ABSTRACT

Coronavirus disease 2019 (COVID-19) severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2 infection) can lead to intensive care unit (ICU) admission and critical illness myopathy (CIM). We examined 3 ICU patients with COVID-19 who required mechanical ventilation for pneumonia and developed CIM. Pathological examination of the skeletal muscle biopsies revealed myopathic changes consistent with CIM, variable inflammation with autophagic vacuoles, SARS-CoV immunostaining + fibers/granules, and electron microscopy findings of mitochondrial abnormalities and coronavirus-like particles. Although mitochondrial dysfunction with compromised energy production is a critical pathogenic mechanism of non-COVID-19-associated CIM, in our series of COVID-19-associated CIM, myopathic changes including prominent mitochondrial damage suggest a similar mechanism and association with direct SARS-CoV-2 muscle infection. ANN NEUROL 2022;91:568-574.


Subject(s)
COVID-19/complications , COVID-19/virology , Critical Illness , Muscular Diseases/etiology , Muscular Diseases/virology , SARS-CoV-2 , Adult , Aged , Autophagy , Fatal Outcome , Female , Humans , Inflammation/pathology , Intensive Care Units , Male , Middle Aged , Mitochondria/pathology , Muscle, Skeletal/pathology , Vacuoles/pathology
2.
Am J Physiol Cell Physiol ; 322(2): C218-C230, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1673516

ABSTRACT

Selective autophagy of mitochondria, known as mitophagy, is a major quality control pathway in the heart that is involved in removing unwanted or dysfunctional mitochondria from the cell. Baseline mitophagy is critical for maintaining fitness of the mitochondrial network by continuous turnover of aged and less-functional mitochondria. Mitophagy is also critical in adapting to stress associated with mitochondrial damage or dysfunction. The removal of damaged mitochondria prevents reactive oxygen species-mediated damage to proteins and DNA and suppresses activation of inflammation and cell death. Impairments in mitophagy are associated with the pathogenesis of many diseases, including cancers, inflammatory diseases, neurodegeneration, and cardiovascular disease. Mitophagy is a highly regulated and complex process that requires the coordination of labeling dysfunctional mitochondria for degradation while simultaneously promoting de novo autophagosome biogenesis adjacent to the cargo. In this review, we provide an update on our current understanding of these steps in mitophagy induction and discuss the physiological and pathophysiological consequences of altered mitophagy in the heart.


Subject(s)
COVID-19/metabolism , Cardiovascular Diseases/metabolism , Cardiovascular System/metabolism , Mitochondria/metabolism , Mitophagy/physiology , Reactive Oxygen Species/metabolism , Animals , COVID-19/pathology , Cardiovascular Diseases/pathology , Cardiovascular System/pathology , Humans , Mitochondria/pathology , Phagocytosis/physiology
3.
Front Immunol ; 12: 799558, 2021.
Article in English | MEDLINE | ID: covidwho-1662582

ABSTRACT

The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16- monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1ß secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes.


Subject(s)
COVID-19/metabolism , Inflammasomes/metabolism , Lipopolysaccharide Receptors/metabolism , Monocytes/metabolism , Oxidative Stress/physiology , Receptors, IgG/metabolism , Aged , COVID-19/pathology , Caspase 1/metabolism , Female , GPI-Linked Proteins/metabolism , Humans , Interleukin-1beta/metabolism , Male , Middle Aged , Mitochondria/metabolism , Mitochondria/pathology , Monocytes/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Signal Transduction/physiology
4.
J Clin Invest ; 131(22)2021 11 15.
Article in English | MEDLINE | ID: covidwho-1518200

ABSTRACT

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non-COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.


Subject(s)
Basigin/physiology , COVID-19/immunology , Dexamethasone/pharmacology , SARS-CoV-2 , T-Lymphocytes/metabolism , Adult , COVID-19/metabolism , Cyclophilin A/physiology , Fatty Acids/metabolism , Female , Humans , Male , Middle Aged , Mitochondria/pathology , Reactive Oxygen Species/metabolism
5.
Histol Histopathol ; 36(9): 947-965, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1513241

ABSTRACT

Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) leads to multi-organ failure associated with a cytokine storm and septic shock. The virus evades the mitochondrial production of interferons through its N protein and, from that moment on, it hijacks the functions of these organelles. The aim of this study was to show how the virus kidnaps the mitochondrial machinery for its benefit and survival, leading to alterations of serum parameters and to nitrosative stress (NSS). In a prospective cohort of 15 postmortem patients who died from COVID-19, six markers of mitochondrial function (COX II, COX IV, MnSOD, nitrotyrosine, Bcl-2 and caspase-9) were analyzed by the immune colloidal gold technique in samples from the lung, heart, and liver. Biometric laboratory results from these patients showed alterations in hemoglobin, platelets, creatinine, urea nitrogen, glucose, C-reactive protein, albumin, D-dimer, ferritin, fibrinogen, Ca²âº, K⁺, lactate and troponin. These changes were associated with alterations in the mitochondrial structure and function. The multi-organ dysfunction present in COVID-19 patients may be caused, in part, by damage to the mitochondria that results in an inflammatory state that contributes to NSS, which activates the sepsis cascade and results in increased mortality in COVID-19 patients.


Subject(s)
COVID-19/pathology , Mitochondria/pathology , Nitrosative Stress/physiology , Aged , Female , Humans , Male , Middle Aged , SARS-CoV-2
6.
J Infect Dis ; 224(8): 1333-1344, 2021 10 28.
Article in English | MEDLINE | ID: covidwho-1493827

ABSTRACT

BACKGROUND: Lymphopenia is a key feature for adult patients with coronavirus disease 2019 (COVID-19), although it is rarely observed in children. The underlying mechanism remains unclear. METHODS: Immunohistochemical and flow cytometric analyses were used to compare the apoptotic rate of T cells from COVID-19 adults and children and apoptotic responses of adult and child T cells to COVID-19 pooled plasma. Biological properties of caspases and reactive oxygen species were assessed in T cells treated by COVID-19 pooled plasma. RESULTS: Mitochondria apoptosis of peripheral T cells were identified in COVID-19 adult patient samples but not in the children. Furthermore, increased tumor necrosis factor-α and interleukin-6 in COVID-19 plasma induced mitochondria apoptosis and caused deoxyribonucleic acid damage by elevating reactive oxygen species levels of the adult T cells. However, the child T cells showed tolerance to mitochondrial apoptosis due to mitochondria autophagy. Activation of autophagy could decrease apoptotic sensitivity of the adult T cells to plasma from COVID-19 patients. CONCLUSIONS: Our results indicated that the mitochondrial apoptosis pathway was activated in T cells of COVID-19 adult patients specifically, which may shed light on the pathophysiological difference between adults and children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ).


Subject(s)
COVID-19/complications , Lymphopenia/blood , SARS-CoV-2/immunology , T-Lymphocytes/pathology , Adolescent , Adult , Age Factors , Aged , Apoptosis/immunology , Autophagy , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Child , Child, Preschool , Humans , Infant , Lymphopenia/immunology , Lymphopenia/pathology , Lymphopenia/virology , Male , Middle Aged , Mitochondria/immunology , Mitochondria/pathology , Reactive Oxygen Species/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology
7.
Zh Nevrol Psikhiatr Im S S Korsakova ; 121(8): 25-29, 2021.
Article in Russian | MEDLINE | ID: covidwho-1395468

ABSTRACT

OBJECTIVE: To study the effectiveness of a course of intravenous administration of cytoflavin in combination with a standard rehabilitation program for post-COVID fatigue syndrome caused by mitochondrial dysfunction. MATERIAL AND METHODS: The dynamic examination of 45 patients with post-COVID syndrome at the second stage of rehabilitation was carried out. The patients were subdivided into 2 groups comparable in gender and age. The volume of lung damage in patients of both groups was also comparable at range of 25-80%. Twenty-four patients of the control group were treated with the standard post-COVID rehabilitation protocol: pulse magnetic therapy, inhalation therapy, aeroion therapy, infrared laser therapy, course aerobic training, psychotherapy, and standard drug therapy. Twenty-one patients of the main group additionally received intravenous administration of cytoflavin daily for 10 days. The dynamics of the scores on the Rehabilitation Routing Scale, HDRS, the Asthenic Status Scale, and the 6-minute walk test was analyzed. RESULTS AND CONCLUSION: The additional intravenous administration of cytoflavin at the complex rehabilitation of post-COVID syndrome can significantly improve the therapeutic results: it significantly improves the overall functional state, reduces depression and fatigue level and increases tolerance to physical exertion.


Subject(s)
COVID-19 , Fatigue/rehabilitation , Mitochondria/pathology , COVID-19/rehabilitation , Fatigue/virology , Humans , Treatment Outcome
8.
Signal Transduct Target Ther ; 6(1): 308, 2021 08 18.
Article in English | MEDLINE | ID: covidwho-1364579

ABSTRACT

Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a major pathological feature of Coronavirus Disease 2019 (COVID-19) and a crucial determinant in COVID-19 prognosis. Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control. Here, we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α (HIF-1α) play key roles in the virus infection and pro-inflammatory responses. RNA sequencing shows that HIF-1α signaling, immune response, and metabolism pathways are dysregulated in COVID-19 patients. Clinical analyses indicate that HIF-1α production, inflammatory responses, and high mortalities occurr in elderly patients. HIF-1α and pro-inflammatory cytokines are elicited in patients and infected cells. Interestingly, SARS-CoV-2 ORF3a induces mitochondrial damage and Mito-ROS production to promote HIF-1α expression, which subsequently facilitates SARS-CoV-2 infection and cytokines production. Notably, HIF-1α also broadly promotes the infection of other viruses. Collectively, during SARS-CoV-2 infection, ORF3a induces HIF-1α, which in turn aggravates viral infection and inflammatory responses. Therefore, HIF-1α plays an important role in promoting SARS-CoV-2 infection and inducing pro-inflammatory responses to COVID-19.


Subject(s)
COVID-19/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Mitochondria/metabolism , SARS-CoV-2/metabolism , Signal Transduction , Viroporin Proteins/metabolism , A549 Cells , Animals , Chlorocebus aethiops , HEK293 Cells , HeLa Cells , Humans , Mitochondria/pathology , RNA-Seq , THP-1 Cells , Vero Cells
9.
J Infect Dis ; 224(8): 1333-1344, 2021 10 28.
Article in English | MEDLINE | ID: covidwho-1349787

ABSTRACT

BACKGROUND: Lymphopenia is a key feature for adult patients with coronavirus disease 2019 (COVID-19), although it is rarely observed in children. The underlying mechanism remains unclear. METHODS: Immunohistochemical and flow cytometric analyses were used to compare the apoptotic rate of T cells from COVID-19 adults and children and apoptotic responses of adult and child T cells to COVID-19 pooled plasma. Biological properties of caspases and reactive oxygen species were assessed in T cells treated by COVID-19 pooled plasma. RESULTS: Mitochondria apoptosis of peripheral T cells were identified in COVID-19 adult patient samples but not in the children. Furthermore, increased tumor necrosis factor-α and interleukin-6 in COVID-19 plasma induced mitochondria apoptosis and caused deoxyribonucleic acid damage by elevating reactive oxygen species levels of the adult T cells. However, the child T cells showed tolerance to mitochondrial apoptosis due to mitochondria autophagy. Activation of autophagy could decrease apoptotic sensitivity of the adult T cells to plasma from COVID-19 patients. CONCLUSIONS: Our results indicated that the mitochondrial apoptosis pathway was activated in T cells of COVID-19 adult patients specifically, which may shed light on the pathophysiological difference between adults and children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ).


Subject(s)
COVID-19/complications , Lymphopenia/blood , SARS-CoV-2/immunology , T-Lymphocytes/pathology , Adolescent , Adult , Age Factors , Aged , Apoptosis/immunology , Autophagy , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Child , Child, Preschool , Humans , Infant , Lymphopenia/immunology , Lymphopenia/pathology , Lymphopenia/virology , Male , Middle Aged , Mitochondria/immunology , Mitochondria/pathology , Reactive Oxygen Species/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology
10.
J Enzyme Inhib Med Chem ; 36(1): 1258-1267, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1263614

ABSTRACT

COVID-19, a pandemic disease caused by a viral infection, is associated with a high mortality rate. Most of the signs and symptoms, e.g. cytokine storm, electrolytes imbalances, thromboembolism, etc., are related to mitochondrial dysfunction. Therefore, targeting mitochondrion will represent a more rational treatment of COVID-19. The current work outlines how COVID-19's signs and symptoms are related to the mitochondrion. Proper understanding of the underlying causes might enhance the opportunity to treat COVID-19.


Subject(s)
COVID-19/drug therapy , COVID-19/pathology , Mitochondria/drug effects , Mitochondria/pathology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/metabolism , Humans , Mitochondria/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity
11.
Mol Neurobiol ; 58(9): 4575-4587, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1263176

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 or COVID-19 has been declared as a pandemic disease by the World Health Organization (WHO). Globally, this disease affected 159 million of the population and reported ~ 3.3 million deaths to the current date (May 2021). There is no definitive treatment strategy that has been identified, although this disease has prevailed in its current form for the past 18 months. The main challenges in the (SARS-CoV)-2 infections are in identifying the heterogeneity in viral strains and the plausible mechanisms of viral infection to human tissues. In parallel to the investigations into the patho-mechanism of SARS-CoV-2 infection, understanding the fundamental processes underlying the clinical manifestations of COVID-19 is very crucial for designing effective therapies. Since neurological symptoms are very apparent in COVID-19 infected patients, here, we tried to emphasize the involvement of redox imbalance and subsequent mitochondrial dysfunction in the progression of the COVID-19 infection. It has been articulated that mitochondrial dysfunction is very apparent and also interlinked to neurological symptoms in COVID-19 infection. Overall, this article provides an in-depth overview of redox imbalance and mitochondrial dysfunction involvement in aggravating COVID-19 infection and its probable contribution to the neurological manifestation of the disease.


Subject(s)
COVID-19/complications , Mitochondria/physiology , SARS-CoV-2/pathogenicity , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/metabolism , Central Nervous System/virology , Drug Repositioning , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Humans , Mice , Mitochondria/drug effects , Mitochondria/pathology , Models, Biological , Olfactory Nerve/virology , Organ Specificity , Oxidation-Reduction , Oxidative Stress/drug effects , Pandemics , SARS-CoV-2/physiology , Viral Proteins/physiology , Viral Tropism , Viremia/complications , Virulence , Virus Internalization
12.
Med Sci Monit ; 27: e933015, 2021 May 10.
Article in English | MEDLINE | ID: covidwho-1239178

ABSTRACT

Persistent comorbidities occur in patients who initially recover from acute coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 'Long COVID' involves the central nervous system (CNS), resulting in neuropsychiatric symptoms and signs, including cognitive impairment or 'brain fog' and chronic fatigue syndrome. There are similarities in these persistent complications between SARS-CoV-2 and the Ebola, Zika, and influenza A viruses. Normal CNS neuronal mitochondrial function requires high oxygen levels for oxidative phosphorylation and ATP production. Recent studies have shown that the SARS-CoV-2 virus can hijack mitochondrial function. Persistent changes in cognitive functioning have also been reported with other viral infections. SARS-CoV-2 infection may result in long-term effects on immune processes within the CNS by causing microglial dysfunction. This short opinion aims to discuss the hypothesis that the pathogenesis of long-term neuropsychiatric COVID-19 involves microglia, mitochondria, and persistent neuroinflammation.


Subject(s)
COVID-19/complications , Central Nervous System/pathology , Cognitive Dysfunction/etiology , Inflammation/pathology , Microglia/pathology , Mitochondria/pathology , COVID-19/pathology , Cognitive Dysfunction/pathology , Humans , Neurons/pathology , SARS-CoV-2
13.
Int J Mol Sci ; 22(3)2021 Jan 29.
Article in English | MEDLINE | ID: covidwho-1238895

ABSTRACT

This is a short review of the basic molecular mechanisms of ovarian aging, written with a particular focus on the use of this data to improve the diagnostic and therapeutic protocols both for women affected by physiological (age-related) ovarian decay and for those suffering premature ovarian insufficiency. Ovarian aging has a genetic basis that conditions the ovarian activity via a plethora of cell-signaling pathways that control the functions of different types of cells in the ovary. There are various factors that can influence these pathways so as to reduce their efficiency. Oxidative stress, often related to mitochondrial dysfunction, leading to the apoptosis of ovarian cells, can be at the origin of vicious circles in which the primary cause feeds back other abnormalities, resulting in an overall decline in the ovarian activity and in the quantity and quality of oocytes. The correct diagnosis of the molecular mechanisms involved in ovarian aging can serve to design treatment strategies that can slow down ovarian decay and increase the quantity and quality of oocytes that can be obtained for an in vitro fertilization attempt. The available treatment options include the use of antioxidants, melatonin, growth hormones, and mitochondrial therapies. All of these treatments have to be considered in the context of each couple's history and current clinical condition, and a customized (patient-tailored) treatment protocol is to be elaborated.


Subject(s)
Aging , Ovary/physiology , Ovary/physiopathology , Primary Ovarian Insufficiency/physiopathology , Animals , Apoptosis , Disease Management , Female , Humans , Mitochondria/genetics , Mitochondria/metabolism , Mitochondria/pathology , Mutation , Ovary/cytology , Oxidative Stress , Primary Ovarian Insufficiency/genetics , Primary Ovarian Insufficiency/metabolism , Primary Ovarian Insufficiency/therapy
14.
Cells ; 10(5)2021 05 04.
Article in English | MEDLINE | ID: covidwho-1223957

ABSTRACT

Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.


Subject(s)
COVID-19/diagnosis , Iron Overload/etiology , Liver Failure/etiology , Liver/pathology , Severity of Illness Index , Adult , Aged , Antiviral Agents , Biopsy , COVID-19/complications , COVID-19/mortality , COVID-19/therapy , Female , Ferritins/analysis , Hepatocytes/cytology , Hepatocytes/pathology , Humans , Iron/analysis , Iron/metabolism , Iron Overload/mortality , Iron Overload/pathology , Iron Overload/therapy , Liver/cytology , Liver/metabolism , Liver Failure/mortality , Liver Failure/pathology , Liver Failure/therapy , Liver Function Tests , Male , Middle Aged , Mitochondria/pathology , Positive-Pressure Respiration , SARS-CoV-2/isolation & purification
15.
Pharmacol Ther ; 224: 107825, 2021 08.
Article in English | MEDLINE | ID: covidwho-1117458

ABSTRACT

Coronaviruses (CoVs) are a group of single stranded RNA viruses, of which some of them such as SARS-CoV, MERS-CoV, and SARS-CoV-2 are associated with deadly worldwide human diseases. Coronavirus disease-2019 (COVID-19), a condition caused by SARS-CoV-2, results in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) associated with high mortality in the elderly and in people with underlying comorbidities. Results from several studies suggest that CoVs localize in mitochondria and interact with mitochondrial protein translocation machinery to target their encoded products to mitochondria. Coronaviruses encode a number of proteins; this process is essential for viral replication through inhibiting degradation of viral proteins and host misfolded proteins including those in mitochondria. These viruses seem to maintain their replication by altering mitochondrial dynamics and targeting mitochondrial-associated antiviral signaling (MAVS), allowing them to evade host innate immunity. Coronaviruses infections such as COVID-19 are more severe in aging patients. Since endogenous melatonin levels are often dramatically reduced in the aged and because it is a potent anti-inflammatory agent, melatonin has been proposed to be useful in CoVs infections by altering proteasomal and mitochondrial activities. Melatonin inhibits mitochondrial fission due to its antioxidant and inhibitory effects on cytosolic calcium overload. The collective data suggests that melatonin may mediate mitochondrial adaptations through regulating both mitochondrial dynamics and biogenesis. We propose that melatonin may inhibit SARS-CoV-2-induced cell damage by regulating mitochondrial physiology.


Subject(s)
COVID-19/drug therapy , Melatonin/pharmacology , Mitochondria/pathology , Aged , Animals , Antioxidants/administration & dosage , Antioxidants/pharmacology , COVID-19/complications , COVID-19/virology , Coronavirus Infections/complications , Coronavirus Infections/virology , Female , Humans , Melatonin/administration & dosage , Mitochondria/drug effects , Mitochondria/virology , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/virology , Virus Replication
16.
Int J Mol Sci ; 22(4)2021 Feb 18.
Article in English | MEDLINE | ID: covidwho-1110432

ABSTRACT

The mitochondrial respiratory chain is the main site of reactive oxygen species (ROS) production in the cell. Although mitochondria possess a powerful antioxidant system, an excess of ROS cannot be completely neutralized and cumulative oxidative damage may lead to decreasing mitochondrial efficiency in energy production, as well as an increasing ROS excess, which is known to cause a critical imbalance in antioxidant/oxidant mechanisms and a "vicious circle" in mitochondrial injury. Due to insufficient energy production, chronic exposure to ROS overproduction consequently leads to the oxidative damage of life-important biomolecules, including nucleic acids, proteins, lipids, and amino acids, among others. Different forms of mitochondrial dysfunction (mitochondriopathies) may affect the brain, heart, peripheral nervous and endocrine systems, eyes, ears, gut, and kidney, among other organs. Consequently, mitochondriopathies have been proposed as an attractive diagnostic target to be investigated in any patient with unexplained progressive multisystem disorder. This review article highlights the pathomechanisms of mitochondriopathies, details advanced analytical tools, and suggests predictive approaches, targeted prevention and personalization of medical services as instrumental for the overall management of mitochondriopathy-related cascading pathologies.


Subject(s)
Energy Metabolism , Mitochondria/pathology , Mitochondrial Diseases/pathology , Oxidative Stress , Animals , Carcinogenesis/pathology , Humans , Mitochondria/metabolism , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/metabolism , Neurodegenerative Diseases/diagnosis , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Precision Medicine , Reactive Oxygen Species/metabolism
17.
Cell Death Dis ; 11(12): 1042, 2020 12 08.
Article in English | MEDLINE | ID: covidwho-969908

ABSTRACT

COVID-19, caused by SARS-CoV-2, is an acute and rapidly developing pandemic, which leads to a global health crisis. SARS-CoV-2 primarily attacks human alveoli and causes severe lung infection and damage. To better understand the molecular basis of this disease, we sought to characterize the responses of alveolar epithelium and its adjacent microvascular endothelium to viral infection under a co-culture system. SARS-CoV-2 infection caused massive virus replication and dramatic organelles remodeling in alveolar epithelial cells, alone. While, viral infection affected endothelial cells in an indirect manner, which was mediated by infected alveolar epithelium. Proteomics analysis and TEM examinations showed viral infection caused global proteomic modulations and marked ultrastructural changes in both epithelial cells and endothelial cells under the co-culture system. In particular, viral infection elicited global protein changes and structural reorganizations across many sub-cellular compartments in epithelial cells. Among the affected organelles, mitochondrion seems to be a primary target organelle. Besides, according to EM and proteomic results, we identified Daurisoline, a potent autophagy inhibitor, could inhibit virus replication effectively in host cells. Collectively, our study revealed an unrecognized cross-talk between epithelium and endothelium, which contributed to alveolar-capillary injury during SARS-CoV-2 infection. These new findings will expand our understanding of COVID-19 and may also be helpful for targeted drug development.


Subject(s)
COVID-19/pathology , Cell Communication/physiology , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Cell Line , Coculture Techniques , Down-Regulation , Endothelial Cells/cytology , Endothelial Cells/metabolism , Endothelial Cells/virology , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Microscopy, Electron, Transmission , Mitochondria/pathology , Mitochondria/virology , Proteome/metabolism , Proteomics/methods , Pulmonary Alveoli/cytology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Serine Endopeptidases/metabolism , Up-Regulation
20.
Neuroscientist ; 27(4): 331-339, 2021 08.
Article in English | MEDLINE | ID: covidwho-797803

ABSTRACT

The coronavirus disease 2019 (COVID-19) is a pandemic disease, originated in Wuhan City, China. It is caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and its biology is still poorly understood. Currently, there are no vaccines and drugs/or agents that can reduce severity of this new disease. Recent data suggest that patients with age-related comorbidities, including cardiovascular disease, diabetes, obesity, hypertension, chronic kidney disease, and dementia are highly susceptible to severe respiratory illness due to coronavirus infection. Recent research also revealed that aged individuals with elevated baseline inflammation cause defects in T and B cells, leading to decreased body's immune response to viral infection. In the current article, we discuss the effects of SARS-CoV-2 on age-related chronic diseases, such as diabetes, obesity, and Alzheimer's disease. Our article also highlights the interaction between coronavirus and immune cells, and how COVID-19 alters mitochondrial activities in host cells. Based on new and compelling evidence, we propose that mitochondrial fission is inhibited while fusion is promoted, causing mitochondrial elongation and providing a receptive intracellular environment for viral replication in infected cells. Further research is still needed to understand the cross talk between viral replication in mitochondria and disease progression in patients with COVID-19.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Dementia/immunology , Dementia/pathology , Diabetes Complications/immunology , Diabetes Complications/pathology , Diabetes Mellitus/immunology , Diabetes Mellitus/pathology , Immune System/pathology , Mitochondria/pathology , Mitochondrial Dynamics , Obesity/immunology , Obesity/pathology , Humans , Immunity, Cellular
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