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Science Advances Nov 2023Poor oxygenation (hypoxia) is a common spatially heterogeneous feature of human tumors. Biological responses to tumor hypoxia are orchestrated by the decreased activity... (Review)
Review
Poor oxygenation (hypoxia) is a common spatially heterogeneous feature of human tumors. Biological responses to tumor hypoxia are orchestrated by the decreased activity of oxygen-dependent enzymes. The affinity of these enzymes for oxygen positions them along a continuum of oxygen sensing that defines their roles in launching reactive and adaptive cellular responses. These responses encompass regulation of all steps in the central dogma, with rapid perturbation of the metabolome and proteome followed by more persistent reprogramming of the transcriptome and epigenome. Core hypoxia response genes and pathways are commonly regulated at multiple inflection points, fine-tuning the dependencies on oxygen concentration and hypoxia duration. Ultimately, shifts in the activity of oxygen-sensing enzymes directly or indirectly endow cells with intrinsic hypoxia tolerance and drive processes that are associated with aggressive phenotypes in cancer including angiogenesis, migration, invasion, immune evasion, epithelial mesenchymal transition, and stemness.
Topics: Humans; Tumor Hypoxia; Neoplasms; Hypoxia; Oxygen; Phenotype
PubMed: 37992163
DOI: 10.1126/sciadv.adj6409 -
Nature Communications Nov 2023Implantable cell therapies and tissue transplants require sufficient oxygen supply to function and are limited by a delay or lack of vascularization from the transplant...
Implantable cell therapies and tissue transplants require sufficient oxygen supply to function and are limited by a delay or lack of vascularization from the transplant host. Previous exogenous oxygenation strategies have been bulky and had limited oxygen production or regulation. Here, we show an electrocatalytic approach that enables bioelectronic control of oxygen generation in complex cellular environments to sustain engineered cell viability and therapy under hypoxic stress and at high cell densities. We find that nanostructured sputtered iridium oxide serves as an ideal catalyst for oxygen evolution reaction at neutral pH. We demonstrate that this approach exhibits a lower oxygenation onset and selective oxygen production without evolution of toxic byproducts. We show that this electrocatalytic on site oxygenator can sustain high cell loadings (>60k cells/mm) in hypoxic conditions in vitro and in vivo. Our results showcase that exogenous oxygen production devices can be readily integrated into bioelectronic platforms, enabling high cell loadings in smaller devices with broad applicability.
Topics: Humans; Oxygen; Hypoxia; Cell Hypoxia; Respiratory Physiological Phenomena
PubMed: 37945597
DOI: 10.1038/s41467-023-42697-2 -
Redox Biology May 2024Mitochondrial respiration extends beyond ATP generation, with the organelle participating in many cellular and physiological processes. Parallel changes in components of...
Mitochondrial respiration extends beyond ATP generation, with the organelle participating in many cellular and physiological processes. Parallel changes in components of the mitochondrial electron transfer system with respiration render it an appropriate hub for coordinating cellular adaption to changes in oxygen levels. How changes in respiration under functional hypoxia (i.e., when intracellular O levels limit mitochondrial respiration) are relayed by the electron transfer system to impact mitochondrial adaption and remodeling after hypoxic exposure remains poorly defined. This is largely due to challenges integrating findings under controlled and defined O levels in studies connecting functions of isolated mitochondria to humans during physical exercise. Here we present experiments under conditions of hypoxia in isolated mitochondria, myotubes and exercising humans. Performing steady-state respirometry with isolated mitochondria we found that oxygen limitation of respiration reduced electron flow and oxidative phosphorylation, lowered the mitochondrial membrane potential difference, and decreased mitochondrial calcium influx. Similarly, in myotubes under functional hypoxia mitochondrial calcium uptake decreased in response to sarcoplasmic reticulum calcium release for contraction. In both myotubes and human skeletal muscle this blunted mitochondrial adaptive responses and remodeling upon contractions. Our results suggest that by regulating calcium uptake the mitochondrial electron transfer system is a hub for coordinating cellular adaption under functional hypoxia.
Topics: Humans; Calcium; Oxygen Consumption; Cell Respiration; Hypoxia; Muscle, Skeletal; Oxygen
PubMed: 38401291
DOI: 10.1016/j.redox.2024.103037 -
Plant & Cell Physiology Nov 2021Oxygen is essential for multicellular aerobic life due to its central role in energy metabolism. The availability of oxygen can drop below the level to sustain oxidative... (Review)
Review
Oxygen is essential for multicellular aerobic life due to its central role in energy metabolism. The availability of oxygen can drop below the level to sustain oxidative phosphorylation when plants are flooded, posing a severe threat to survival. However, under non-stressful conditions, the internal oxygen concentration of most plant tissue is not in equilibrium with the environment, which is attributed to cellular respiration and diffusion constrains imposed by O2 barriers and bulky tissue. This is exemplified by the observations of steep oxygen gradients in roots, fruits, tubers, anthers and meristems. To adapt to a varying availability of oxygen, plants sense O2 via the conditional proteolysis of transcriptional regulators. This mechanism acts to switch oxidative metabolism to anaerobic fermentation, but it was also shown to play a role in plant development and pathogen defense. To investigate how dynamic and spatial distribution of O2 impacts on these processes, accurate mapping of its concentration in plants is essential. Physical oxygen sensors have been employed for decades to profile internal oxygen concentrations in plants, while genetically encoded oxygen biosensors have only recently started to see use. Driven by the critical role of hypoxia in human pathology and development, several novel oxygen-sensing devices have also been characterized in cell lines and animal model organisms. This review aims to provide an overview of available oxygen biosensors and to discuss their potential application to image oxygen levels in plants.
Topics: Biosensing Techniques; Cell Respiration; Intravital Microscopy; Oxygen; Plant Cells
PubMed: 33725087
DOI: 10.1093/pcp/pcab039 -
Plant Physiology Apr 2023Plant respiration is a foundational biological process with the potential to be optimized to improve crop yield. To understand and manipulate the outputs of respiration,... (Review)
Review
Plant respiration is a foundational biological process with the potential to be optimized to improve crop yield. To understand and manipulate the outputs of respiration, the inputs of respiration-respiratory substrates-need to be probed in detail. Mitochondria house substrate catabolic pathways and respiratory machinery, so transport into and out of these organelles plays an important role in committing substrates to respiration. The large number of mitochondrial carriers and catabolic pathways that remain unidentified hinder this process and lead to confusion about the identity of direct and indirect respiratory substrates in plants. The sources and usage of respiratory substrates vary and are increasing found to be highly regulated based on cellular processes and environmental factors. This review covers the use of direct respiratory substrates following transport through mitochondrial carriers and catabolism under normal and stressed conditions. We suggest the introduction of enzymes not currently found in plant mitochondria to enable serine and acetate to be direct respiratory substrates in plants. We also compare respiratory substrates by assessing energetic yields, availability in cells, and their full or partial oxidation during cell catabolism. This information can assist in decisions to use synthetic biology approaches to alter the range of respiratory substrates in plants. As a result, respiration could be optimized by introducing, improving, or controlling specific mitochondrial transporters and mitochondrial catabolic pathways.
Topics: Mitochondria; Cell Respiration; Oxidation-Reduction; Energy Metabolism; Plants; Respiration
PubMed: 36573332
DOI: 10.1093/plphys/kiac599 -
Seminars in Cancer Biology May 2024Mitochondria are the major sink for oxygen in the cell, consuming it during ATP production. Therefore, when environmental oxygen levels drop in the tumor, significant... (Review)
Review
Mitochondria are the major sink for oxygen in the cell, consuming it during ATP production. Therefore, when environmental oxygen levels drop in the tumor, significant adaptation is required. Mitochondrial activity is also a major producer of biosynthetic precursors and a regulator of cellular oxidative and reductive balance. Because of the complex biochemistry, mitochondrial adaptation to hypoxia occurs through multiple mechanisms and has significant impact on other cellular processes such as macromolecule synthesis and gene regulation. In tumor hypoxia, mitochondria shift their location in the cell and accelerate the fission and quality control pathways. Hypoxic mitochondria also undergo significant changes to fundamental metabolic pathways of carbon metabolism and electron transport. These metabolic changes further impact the nuclear epigenome because mitochondrial metabolites are used as enzymatic substrates for modifying chromatin. This coordinated response delivers physiological flexibility and increased tumor cell robustness during the environmental stress of low oxygen.
Topics: Humans; Mitochondria; Hypoxia; Oxygen; Cell Hypoxia; Stress, Physiological; Adaptation, Physiological
PubMed: 38556040
DOI: 10.1016/j.semcancer.2024.03.004 -
International Journal of Molecular... Aug 2019Neutrophils have been well-characterized for their role in the host anti-microbial response. However, it is now appreciated that neutrophils have a critical role in... (Review)
Review
Neutrophils have been well-characterized for their role in the host anti-microbial response. However, it is now appreciated that neutrophils have a critical role in tumorigenesis and tumor progression in the majority of solid tumors. Recent studies have indicated a critical role for hypoxia in regulating neutrophil function in tumors. Furthermore, neutrophil-specific expression of hypoxia-inducible transcription factors may represent a novel therapeutic target for human cancer. In this review, we highlight the function of neutrophils in cancer and the role of the neutrophil hypoxic response in regulating the neoplastic progression of cancer.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Hypoxia; Humans; Neoplasms; Neutrophils; Oxygen; Tumor Microenvironment
PubMed: 31461847
DOI: 10.3390/ijms20174189 -
International Journal of Molecular... May 2022Marginal liver grafts, such as steatotic livers and those from cardiac death donors, are highly vulnerable to ischemia-reperfusion injury that occurs in the complex... (Review)
Review
Marginal liver grafts, such as steatotic livers and those from cardiac death donors, are highly vulnerable to ischemia-reperfusion injury that occurs in the complex route of the graft from "harvest to revascularization". Recently, several preservation methods have been developed to preserve liver grafts based on hypothermic static preservation and hypothermic oxygenated perfusion (HOPE) strategies, either combined or alone. However, their effects on mitochondrial functions and their relevance have not yet been fully investigated, especially if different preservation solutions/effluents are used. Ischemic liver graft damage is caused by oxygen deprivation conditions during cold storage that provoke alterations in mitochondrial integrity and function and energy metabolism breakdown. This review deals with the relevance of mitochondrial machinery in cold static preservation and how the mitochondrial respiration function through the accumulation of succinate at the end of cold ischemia is modulated by different preservation solutions such as IGL-2, HTK, and UW (gold-standard reference). IGL-2 increases mitochondrial integrity and function (ALDH2) when compared to UW and HTK. This mitochondrial protection by IGL-2 also extends to protective HOPE strategies when used as an effluent instead of Belzer MP. The transient oxygenation in HOPE sustains the mitochondrial machinery at basal levels and prevents, in part, the accumulation of energy metabolites such as succinate in contrast to those that occur in cold static preservation conditions. Additionally, several additives for combating oxygen deprivation and graft energy metabolism breakdown during hypothermic static preservation such as oxygen carriers, ozone, AMPK inducers, and mitochondrial UCP2 inhibitors, and whether they are or not to be combined with HOPE, are presented and discussed. Finally, we affirm that IGL-2 solution is suitable for protecting graft mitochondrial machinery and simplifying the complex logistics in clinical transplantation where traditional (static preservation) and innovative (HOPE) strategies may be combined. New mitochondrial markers are presented and discussed. The final goal is to take advantage of marginal livers to increase the pool of suitable organs and thereby shorten patient waiting lists at transplantation clinics.
Topics: Aldehyde Dehydrogenase, Mitochondrial; Humans; Liver; Liver Transplantation; Organ Preservation; Oxygen; Perfusion; Succinates; Transplants
PubMed: 35628554
DOI: 10.3390/ijms23105742 -
ASAIO Journal (American Society For... Oct 2022Extracorporeal membrane oxygenation (ECMO) has been advancing rapidly due to a combination of rising rates of acute and chronic lung diseases as well as significant...
Extracorporeal membrane oxygenation (ECMO) has been advancing rapidly due to a combination of rising rates of acute and chronic lung diseases as well as significant improvements in the safety and efficacy of this therapeutic modality. However, the complexity of the ECMO blood circuit, and challenges with regard to clotting and bleeding, remain as barriers to further expansion of the technology. Recent advances in microfluidic fabrication techniques, devices, and systems present an opportunity to develop new solutions stemming from the ability to precisely maintain critical dimensions such as gas transfer membrane thickness and blood channel geometries, and to control levels of fluid shear within narrow ranges throughout the cartridge. Here, we present a physiologically inspired multilayer microfluidic oxygenator device that mimics physiologic blood flow patterns not only within individual layers but throughout a stacked device. Multiple layers of this microchannel device are integrated with a three-dimensional physiologically inspired distribution manifold that ensures smooth flow throughout the entire stacked device, including the critical entry and exit regions. We then demonstrate blood flows up to 200 ml/min in a multilayer device, with oxygen transfer rates capable of saturating venous blood, the highest of any microfluidic oxygenator, and a maximum blood flow rate of 480 ml/min in an eight-layer device, higher than any yet reported in a microfluidic device. Hemocompatibility and large animal studies utilizing these prototype devices are planned. Supplemental Visual Abstract, http://links.lww.com/ASAIO/A769.
Topics: Animals; Biomimetics; Equipment Design; Microfluidics; Oxygen; Oxygenators
PubMed: 36194101
DOI: 10.1097/MAT.0000000000001647 -
Scientific Reports Aug 2020Acidosis of the tumor microenvironment leads to cancer invasion, progression and resistance to therapies. We present a biophysical model that describes how tumor cells...
Acidosis of the tumor microenvironment leads to cancer invasion, progression and resistance to therapies. We present a biophysical model that describes how tumor cells regulate intracellular and extracellular acidity while they grow in a microenvironment characterized by increasing acidity and hypoxia. The model takes into account the dynamic interplay between glucose and [Formula: see text] consumption with lactate and [Formula: see text] production and connects these processes to [Formula: see text] and [Formula: see text] fluxes inside and outside cells. We have validated the model with independent experimental data and used it to investigate how and to which extent tumor cells can survive in adverse micro-environments characterized by acidity and hypoxia. The simulations show a dominance of the [Formula: see text] exchanges in well-oxygenated regions, and of [Formula: see text] exchanges in the inner hypoxic regions where tumor cells are known to acquire malignant phenotypes. The model also includes the activity of the enzyme Carbonic Anhydrase 9 (CA9), a known marker of tumor aggressiveness, and the simulations demonstrate that CA9 acts as a nonlinear [Formula: see text] equalizer at any [Formula: see text] level in cells that grow in acidic extracellular environments.
Topics: Antigens, Neoplasm; Bile Duct Neoplasms; Carbon Dioxide; Carbonic Anhydrase IX; Cell Hypoxia; Cell Line, Tumor; Cholangiocarcinoma; Glucose; Humans; Hydrogen-Ion Concentration; Lactic Acid; Models, Biological; Oxygen; Tumor Microenvironment
PubMed: 32788634
DOI: 10.1038/s41598-020-70396-1