scholarly journals HIF-1, the Warburg Effect, and Macrophage/Microglia Polarization Potential Role in COVID-19 Pathogenesis

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Elisabetta Ferraro ◽  
Maria Germanò ◽  
Rocco Mollace ◽  
Vincenzo Mollace ◽  
Natalia Malara
Keyword(s):  
Potential Role ◽  
Immune Reaction ◽  
Hypoxia Inducible Factor ◽  
Innate Immune ◽  
Metabolic Reprogramming ◽  
Clinical Knowledge ◽  
Respiratory Dysfunction ◽  
Hypoxia Inducible Factor 1 ◽  
Microglia Polarization ◽  
The Warburg Effect

Despite the international scientific community’s commitment to improve clinical knowledge about coronavirus disease 2019 (COVID-19), knowledge regarding molecular details remains limited. In this review, we discuss hypoxia’s potential role in the pathogenesis of the maladaptive immune reaction against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The state of infection, with serious respiratory dysfunction, causes tissues to become hypoxic due to a discrepancy between cellular O2 uptake and consumption similar to that seen within tumor tissue during the progression of numerous solid cancers. In this context, the heterogeneous clinical behavior and the multiorgan deterioration of COVID-19 are discussed as a function of the upregulated expression of the hypoxia-inducible factor-1 (HIF-1) and of the metabolic reprogramming associated with HIF-1 and with a proinflammatory innate immune response activation, independent of the increase in the viral load of SARS-CoV-2. Possible pharmacological strategies targeting O2 aimed to improve prognosis are suggested.

scholarly journals Adaptive and Maladaptive Cardiorespiratory Responses to Continuous and Intermittent Hypoxia Mediated by Hypoxia-Inducible Factors 1 and 2

2012 ◽  
Vol 92 (3) ◽  
pp. 967-1003 ◽  
Author(s):  
Nanduri R. Prabhakar ◽  
Gregg L. Semenza
Keyword(s):  
Transcriptional Activation ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Homeostasis ◽  
Physiological Adaptations ◽  
Prolyl Hydroxylation ◽  
Insight Into ◽  
Subsequent Identification

Hypoxia is a fundamental stimulus that impacts cells, tissues, organs, and physiological systems. The discovery of hypoxia-inducible factor-1 (HIF-1) and subsequent identification of other members of the HIF family of transcriptional activators has provided insight into the molecular underpinnings of oxygen homeostasis. This review focuses on the mechanisms of HIF activation and their roles in physiological and pathophysiological responses to hypoxia, with an emphasis on the cardiorespiratory systems. HIFs are heterodimers comprised of an O2-regulated HIF-1α or HIF-2α subunit and a constitutively expressed HIF-1β subunit. Induction of HIF activity under conditions of reduced O2availability requires stabilization of HIF-1α and HIF-2α due to reduced prolyl hydroxylation, dimerization with HIF-1β, and interaction with coactivators due to decreased asparaginyl hydroxylation. Stimuli other than hypoxia, such as nitric oxide and reactive oxygen species, can also activate HIFs. HIF-1 and HIF-2 are essential for acute O2sensing by the carotid body, and their coordinated transcriptional activation is critical for physiological adaptations to chronic hypoxia including erythropoiesis, vascularization, metabolic reprogramming, and ventilatory acclimatization. In contrast, intermittent hypoxia, which occurs in association with sleep-disordered breathing, results in an imbalance between HIF-1α and HIF-2α that causes oxidative stress, leading to cardiorespiratory pathology.

scholarly journals Bartonella Adhesin A Mediates a Proangiogenic Host Cell Response

2004 ◽  
Vol 200 (10) ◽  
pp. 1267-1278 ◽  
Author(s):  
Tanja Riess ◽  
Siv G.E. Andersson ◽  
Andrei Lupas ◽  
Martin Schaller ◽  
Andrea Schäfer ◽  
...  
Keyword(s):  
Potential Role ◽  
Bartonella Henselae ◽  
Hypoxia Inducible Factor ◽  
Host Cells ◽  
Matrix Proteins ◽  
Vascular Endothelial ◽  
Host Cell Response ◽  
Hypoxia Inducible Factor 1 ◽  
In Trans ◽  
Endothelial Growth Factor

Bartonella henselae causes vasculoproliferative disorders in humans. We identified a nonfimbrial adhesin of B. henselae designated as Bartonella adhesin A (BadA). BadA is a 340-kD outer membrane protein encoded by the 9.3-kb badA gene. It has a modular structure and contains domains homologous to the Yersinia enterocolitica nonfimbrial adhesin (Yersinia adhesin A). Expression of BadA was restored in a BadA-deficient transposon mutant by complementation in trans. BadA mediates the binding of B. henselae to extracellular matrix proteins and to endothelial cells, possibly via β1 integrins, but prevents phagocytosis. Expression of BadA is crucial for activation of hypoxia-inducible factor 1 in host cells by B. henselae and secretion of proangiogenic cytokines (e.g., vascular endothelial growth factor). BadA is immunodominant in B. henselae–infected patients and rodents, indicating that it is expressed during Bartonella infections. Our results suggest that BadA, the largest characterized bacterial protein thus far, is a major pathogenicity factor of B. henselae with a potential role in the induction of vasculoproliferative disorders.

Regulation of Oxygen Homeostasis by Hypoxia-Inducible Factor 1

Physiology ◽  
2009 ◽  
Vol 24 (2) ◽  
pp. 97-106 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Systemic Hypertension ◽  
Adaptive Responses ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Homeostasis ◽  
Genes Encoding

Metazoan organisms are dependent on a continuous supply of O2 for survival. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in development, physiology, and disease. HIF-1 activity is induced in response to continuous hypoxia, intermittent hypoxia, growth factor stimulation, and Ca2+ signaling. HIF-1 mediates adaptive responses to hypoxia, including erythropoiesis, angiogenesis, and metabolic reprogramming. In each case, HIF-1 regulates the expression of multiple genes encoding key components of the response pathway. HIF-1 also mediates maladaptive responses to chronic continuous and intermittent hypoxia, which underlie the development of pulmonary and systemic hypertension, respectively.

scholarly journals Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

2015 ◽  
Vol 35 (9) ◽  
pp. 1491-1505 ◽  
Author(s):  
M. Christiane Brahimi-Horn ◽  
Sandra Lacas-Gervais ◽  
Ricardo Adaixo ◽  
Karine Ilc ◽  
Matthieu Rouleau ◽  
...  
Keyword(s):  
Cell Survival ◽  
Hypoxia Inducible Factor ◽  
Anion Channel ◽  
Metabolic Reprogramming ◽  
Hypoxic Cell ◽  
Voltage Dependent Anion Channel ◽  
Drug Induced ◽  
Hypoxia Inducible Factor 1 ◽  
Voltage Dependent ◽  
Induced Apoptosis

The oxygen-limiting (hypoxic) microenvironment of tumors induces metabolic reprogramming and cell survival, but the underlying mechanisms involving mitochondria remain poorly understood. We previously demonstrated that hypoxia-inducible factor 1 mediates the hyperfusion of mitochondria by inducing Bcl-2/adenovirus E1B 19-kDa interacting protein 3 and posttranslational truncation of the mitochondrial ATP transporter outer membrane voltage-dependent anion channel 1 in hypoxic cells. In addition, we showed that truncation is associated with increased resistance to drug-induced apoptosis and is indicative of increased patient chemoresistance. We now show that silencing of the tumor suppressor TP53 decreases truncation and increases drug-induced apoptosis. We also show that TP53 regulates truncation through induction of the mitochondrial protein Mieap. While we found that truncation was independent of mitophagy, we observed local microfusion between mitochondria and endolysosomes in hypoxic cells in culture and in patients' tumor tissues. Since we found that the endolysosomal asparagine endopeptidase was responsible for truncation, we propose that it is a readout of mitochondrial-endolysosomal microfusion in hypoxia. These novel findings provide the framework for a better understanding of hypoxic cell metabolism and cell survival through mitochondrial-endolysosomal microfusion regulated by hypoxia-inducible factor 1 and TP53.

Hypoxia Inducible Factor-1: Its Potential Role In Cerebral Ischemia

2012 ◽  
Vol 32 (4) ◽  
pp. 491-507 ◽  
Author(s):  
Neetu Singh ◽  
Gaurav Sharma ◽  
Vikas Mishra ◽  
Ram Raghubir
Keyword(s):  
Cerebral Ischemia ◽  
Potential Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1
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