scholarly journals Specific cyprinid HIF isoforms contribute to cellular mitochondrial regulation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jing Chen ◽  
Lihong Guan ◽  
Ming Zou ◽  
Shunping He ◽  
Dapeng Li ◽  
...  
Keyword(s):  
Cellular Response ◽  
Genome Duplication ◽  
Citrate Synthase ◽  
Tricarboxylic Acid Cycle ◽  
Hypoxia Inducible Factor ◽  
Cyprinid Fish ◽  
Hypoxia Tolerance ◽  
Mitochondrial Mass ◽  
Mitochondrial Regulation ◽  
Hypoxia Inducible Factor 1

Abstract Hypoxia-inducible factor 1 (HIF-1) functions as a master regulator of the cellular response to hypoxic stress. Two HIF-1α paralogs, HIF-1αA and HIF-1αB, were generated in euteleosts by the specific, third round of genome duplication, but one paralog was later lost in most families with the exception of cyprinid fish. How these duplicates function in mitochondrial regulation and whether their preservation contributes to the hypoxia tolerance demonstrated by cyprinid fish in freshwater environments is not clear. Here we demonstrated the divergent function of these two zebrafish Hif-1a paralogs through cellular approaches. The results showed that Hif-1aa played a role in tricarboxylic acid cycle by increasing the expression of Citrate synthase and the activity of mitochondrial complex II, and it also enhanced mitochondrial membrane potential and ROS production by reducing free Ca2+ in the cytosol. Hif-1ab promoted intracellular ATP content by up-regulating the activity of mitochondrial complexes I, III and IV and the expression of related genes. Furthermore, both the two zebrafish Hif-1a paralogs promoted mitochondrial mass and the expression level of mtDNA, contributing to mitochondrial biogenesis. Our study reveals the divergent functions of Hif-1aa and Hif-1ab in cellular mitochondrial regulation.

scholarly journals Hypoxia-inducible factor-1 mediates adaptive developmental plasticity of hypoxia tolerance in zebrafish, Danio rerio

2014 ◽  
Vol 281 (1786) ◽  
pp. 20140637 ◽  
Author(s):  
Cayleih E. Robertson ◽  
Patricia A. Wright ◽  
Louise Köblitz ◽  
Nicholas J. Bernier
Keyword(s):  
Danio Rerio ◽  
Cellular Response ◽  
Developmental Plasticity ◽  
Developmental Stages ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Anthropogenic Factors ◽  
Critical Window ◽  
Hypoxia Inducible Factor 1

In recent years, natural and anthropogenic factors have increased aquatic hypoxia the world over. In most organisms, the cellular response to hypoxia is mediated by the master regulator hypoxia-inducible factor-1 (HIF-1). HIF-1 also plays a critical role in the normal development of the cardiovascular system of vertebrates. We tested the hypothesis that hypoxia exposures which resulted in HIF-1 induction during embryogenesis would be associated with enhanced hypoxia tolerance in subsequent developmental stages. We exposed zebrafish ( Danio rerio ) embryos to just 4 h of severe hypoxia or total anoxia at 18, 24 and 36 h post-fertilization (hpf). Of these, exposure to hypoxia at 24 and 36 hpf as well as anoxia at 36 hpf activated the HIF-1 cellular pathway. Zebrafish embryos that acutely upregulated the HIF-1 pathway had an increased hypoxia tolerance as larvae. The critical window for hypoxia sensitivity and HIF-1 signalling was 24 hpf. Adult male fish had a lower critical oxygen tension ( P crit ) compared with females. Early induction of HIF-1 correlated directly with an increased proportion of males in the population. We conclude that mounting a HIF-1 response during embryogenesis is associated with long-term impacts on the phenotype of later stages which could influence both individual hypoxia tolerance and population dynamics.

scholarly journals Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

2014 ◽  
Vol 37 (6) ◽  
pp. E8 ◽  
Author(s):  
Matthew Womeldorff ◽  
David Gillespie ◽  
Randy L. Jensen
Keyword(s):  
Cellular Response ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Poor Patient ◽  
Growth Development ◽  
The Relationship ◽  
Insight Into ◽  
Upstream Regulators

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

scholarly journals Cavefish cope with environmental hypoxia by developing more erythrocytes and overexpression of hypoxia inducible genes

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Corine M van der Weele ◽  
William R Jeffery
Keyword(s):  
Normal Development ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Astyanax Mexicanus ◽  
Hypoxia Inducible Factor 1 ◽  
Primitive Hematopoiesis ◽  
Cave Environment ◽  
Surface Dwelling ◽  
Inducible Genes ◽  
Lateral Mesoderm

Dark caves lacking primary productivity can expose subterranean animals to hypoxia. We used the surface-dwelling (surface fish) and cave-dwelling (cavefish) morphs of Astyanax mexicanus as a model for understanding the mechanisms of hypoxia tolerance in the cave environment. Primitive hematopoiesis, which is restricted to the posterior lateral mesoderm in other teleosts, also occurs in the anterior lateral mesoderm in Astyanax, potentially pre-adapting surface fish for hypoxic cave colonization. Cavefish have enlarged both hematopoietic domains and develop more erythrocytes than surface fish, which are required for normal development in both morphs. Laboratory induced hypoxia suppresses growth in surface fish but not in cavefish. Both morphs respond to hypoxia by overexpressing hypoxia-inducible factor 1 (hif1) pathway genes, and some hif1 genes are constitutively upregulated in normoxic cavefish to similar levels as in hypoxic surface fish. We conclude that cavefish cope with hypoxia by increasing erythrocyte development and constitutive hif1 gene overexpression.

scholarly journals Hypoxia-Inducible Factor-1 as a Therapeutic Target in Endometrial Cancer Management

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Laura M. S. Seeber ◽  
Ronald P. Zweemer ◽  
René H. M. Verheijen ◽  
Paul J. van Diest
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Therapeutic Target ◽  
Topoisomerase I ◽  
Cellular Response ◽  
Hypoxia Inducible Factor ◽  
Female Genital Tract ◽  
Angiogenesis Inhibitor ◽  
Hypoxia Inducible Factor 1 ◽  
Cancer Management

In the Western world, endometrial cancer (EC) is the most common malignant tumor of the female genital tract. Solid tumors like EC outgrow their vasculature resulting in hypoxia. Tumor hypoxia is important because it renders an aggressive phenotype and leads to radio- and chemo-therapy resistance. Hypoxia-inducible factor-1 (HIF-1) plays an essential role in the adaptive cellular response to hypoxia and is associated with poor clinical outcome in EC. Therefore, HIF-1 could be an attractive therapeutic target. Selective HIF-1 inhibitors have not been identified. A number of nonselective inhibitors which target signaling pathways upstream or downstream HIF-1 are known to decrease HIF-1 protein levels. In clinical trials for the treatment of advanced and/or recurrent EC are the topoisomerase I inhibitor Topotecan, mTOR-inhibitor Rapamycin, and angiogenesis inhibitor Bevacizumab. Preliminary data shows encouraging results for these agents. Further work is needed to identify selective HIF-1 inhibitors and to translate these into clinical trials.

Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1

2007 ◽  
Vol 405 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Mitochondrial Respiration ◽  
Mammalian Cells ◽  
Tricarboxylic Acid Cycle ◽  
Hypoxia Inducible Factor ◽  
Mitochondrial Respiratory Chain ◽  
Pyruvate Dehydrogenase Kinase ◽  
Complex Iii ◽  
Metabolic Adaptation ◽  
Acetyl Coa ◽  
Hypoxia Inducible Factor 1

The survival of metazoan organisms is dependent upon the utilization of O2 as a substrate for COX (cytochrome c oxidase), which constitutes Complex IV of the mitochondrial respiratory chain. Premature transfer of electrons, either at Complex I or at Complex III, results in the increased generation of ROS (reactive oxygen species). Recent studies have identified two critical adaptations that may function to prevent excessive ROS production in hypoxic cells. First, expression of PDK1 [PDH (pyruvate dehydrogenase) kinase 1] is induced. PDK1 phosphorylates and inactivates PDH, the mitochondrial enzyme that converts pyruvate into acetyl-CoA. In combination with the hypoxia-induced expression of LDHA (lactate dehydrogenase A), which converts pyruvate into lactate, PDK1 reduces the delivery of acetyl-CoA to the tricarboxylic acid cycle, thus reducing the levels of NADH and FADH2 delivered to the electron-transport chain. Secondly, the subunit composition of COX is altered in hypoxic cells by increased expression of the COX4-2 subunit, which optimizes COX activity under hypoxic conditions, and increased degradation of the COX4-1 subunit, which optimizes COX activity under aerobic conditions. Hypoxia-inducible factor 1 controls the metabolic adaptation of mammalian cells to hypoxia by activating transcription of the genes encoding PDK1, LDHA, COX4-2 and LON, a mitochondrial protease that is required for the degradation of COX4-1. COX subunit switching occurs in yeast, but by a completely different regulatory mechanism, suggesting that selection for O2-dependent homoeostatic regulation of mitochondrial respiration is ancient and likely to be shared by all eukaryotic organisms.

scholarly journals Oxygen versus Reactive Oxygen in the Regulation of HIF-1α: The Balance Tips

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Thilo Hagen
Keyword(s):  
Cellular Response ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Thioredoxin Reductase ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Prolyl Hydroxylases ◽  
Hypoxia Inducible Factor 1 ◽  
Transport Chain ◽  
Cellular Oxygen

Hypoxia inducible factor (HIF) is known as the master regulator of the cellular response to hypoxia and is of pivotal importance during development as well as in human disease, particularly in cancer. It is composed of a constitutively expressedβsubunit (HIF-1β) and an oxygen-regulatedαsubunit (HIF-1αand HIF-2α), whose stability is tightly controlled by a family of oxygen- and iron-dependent prolyl hydroxylase enzymes. Whether or not mitochondria-derived reactive oxygen species (ROS) are involved in the regulation of Hypoxia Inducible Factor-1αhas been a matter of contention for the last 10 years, with equally compelling evidence in favor and against their contribution. A number of recent papers appear to tip the balance against a role for ROS. Thus, it has been demonstrated that HIF prolyl hydroxylases are unlikely to be physiological targets of ROS and that the increase in ROS that is associated with downregulation of Thioredoxin Reductase in hypoxia does not affect HIF-1αstabilization. Finally, the protein CHCHD4, which modulates cellular HIF-1αconcentrations by promoting mitochondrial electron transport chain activity, has been proposed to exert its regulatory effect by affecting cellular oxygen availability. These reports are consistent with the hypothesis that mitochondria play a critical role in the regulation of HIF-1αby controlling intracellular oxygen concentrations.

scholarly journals HIF-1 regulation of miR-29c impairs SERCA2 expression and cardiac contractility

2019 ◽  
Vol 316 (3) ◽  
pp. H554-H565 ◽  
Author(s):  
Allison Lesher Williams ◽  
Chad B. Walton ◽  
Keith A. MacCannell ◽  
Abigail Avelar ◽  
Ralph V. Shohet
Keyword(s):  
Heart Failure ◽  
Cellular Response ◽  
Cardiac Contractility ◽  
Hypoxia Inducible Factor ◽  
Stable Form ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1 ◽  
Heart Size ◽  
Overexpression System ◽  
Pathological Environment

The principal regulator of cellular response to low oxygen is hypoxia-inducible factor (HIF)-1, which is stabilized in several forms of heart failure. Our laboratory developed a mouse strain in which a stable form of HIF-1 can be inducibly expressed in cardiomyocytes. Strikingly, these mice show a rapid decrease in cardiac contractility and a rapid loss of SERCA2 protein, which is also seen in heart failure. Interestingly, while the SERCA2 transcript decreased, it did not fully account for the observed decrease in protein. We therefore investigated whether HIF-1-regulated microRNA could impair SERCA translation. Multiple screening analyses identified the microRNA miR-29c to be substantially upregulated upon HIF-1 induction and to have complementarity to SERCA, and therefore be a potential regulator of SERCA2 expression in hypoxia. Subsequent evaluation confirmed that miR-29c reduced SERCA2 expression and Ca2+ reuptake. Additionally, administration of an antagonist sequence (antimir) improved cardiac contractility and SERCA2 expression in HIF transgenic mice. To extend the significance of these findings, we examined miR-29c expression in physiological hypoxia. Surprisingly, miR-29c decreased in these settings. We also treated mice with antimir before infarction to see if further suppression of miR-29c could improve cardiac function. While no improvement in contractility or SERCA2 was observed, reduction of heart size after infarction indicated that the antimir could modulate cardiac physiology. These results demonstrate that while a HIF-1-regulated microRNA, miR-29c, can reduce SERCA2 expression and contractility, additional factors in the ischemic milieu may limit these effects. Efforts to develop miRNA-based therapies will need to explore and account for these additional countervailing effects. NEW & NOTEWORTHY Our study demonstrated hypoxia-inducible factor-1-dependent upregulation of miR-29c, which, in turn, inhibited SERCA2 expression and reduced cardiac contractility in a transgenic overexpression system. Interestingly, these results were not recapitulated in a murine myocardial infarction model. These results underscore the complexity of the pathological environment and highlight the need for therapeutic target validation in physiologically relevant models. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/hif1-regulates-mir-29c-and-serca2/ .

scholarly journals Hypoxia inducible factor-1 α knockout does not impair acute thermal tolerance or heat hardening in zebrafish

2020 ◽  
Vol 16 (7) ◽  
pp. 20200292
Author(s):  
William Joyce ◽  
Steve F. Perry
Keyword(s):  
High Temperature ◽  
Thermal Tolerance ◽  
Hypoxia Inducible Factor ◽  
Extreme Environments ◽  
Hypoxia Tolerance ◽  
Similar Degree ◽  
Wild Type ◽  
Double Knockout ◽  
Hypoxia Inducible Factor 1 ◽  
Heat Hardening

The rapid increase in critical thermal maximum (CT max ) in fish (or other animals) previously exposed to critically high temperature is termed ‘heat hardening’, which likely represents a key strategy to cope with increasingly extreme environments. The physiological mechanisms that determine acute thermal tolerance, and the underlying pathways facilitating heat hardening, remain debated. It has been posited, however, that exposure to high temperature is associated with tissue hypoxia and may be associated with the increased expression of hypoxia-inducible factor-1 (Hif-1). We studied acute thermal tolerance in zebrafish ( Danio rerio ) lacking functional Hif-1 α paralogs (Hif-1aa and Hif-1ab double knockout; Hif-1 α −/− ), which are known to exhibit markedly reduced hypoxia tolerance. We hypothesized that Hif-1 α −/− zebrafish would suffer reduced acute thermal tolerance relative to wild type and that the heat hardening ability would be lost. However, on the contrary, we observed that Hif-1 α −/− and wild-type fish did not differ in CT max , and both genotypes exhibited heat hardening of a similar degree when CT max was re-tested 48 h later. Despite exhibiting impaired hypoxia tolerance, Hif-1 α −/− zebrafish display unaltered thermal tolerance, suggesting that these traits are not necessarily functionally associated. Hif-1 α is accordingly not required for short-term acclimation in the form of heat hardening.

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