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Nature Oct 2023Although haemoglobin is a known carrier of oxygen in erythrocytes that functions to transport oxygen over a long range, its physiological roles outside erythrocytes are...
Although haemoglobin is a known carrier of oxygen in erythrocytes that functions to transport oxygen over a long range, its physiological roles outside erythrocytes are largely elusive. Here we found that chondrocytes produced massive amounts of haemoglobin to form eosin-positive bodies in their cytoplasm. The haemoglobin body (Hedy) is a membraneless condensate characterized by phase separation. Production of haemoglobin in chondrocytes is controlled by hypoxia and is dependent on KLF1 rather than the HIF1/2α pathway. Deletion of haemoglobin in chondrocytes leads to Hedy loss along with severe hypoxia, enhanced glycolysis and extensive cell death in the centre of cartilaginous tissue, which is attributed to the loss of the Hedy-controlled oxygen supply under hypoxic conditions. These results demonstrate an extra-erythrocyte role of haemoglobin in chondrocytes, and uncover a heretofore unrecognized mechanism in which chondrocytes survive a hypoxic environment through Hedy.
Topics: Humans; Cartilage, Articular; Cell Death; Cell Hypoxia; Chondrocytes; Cytoplasm; Eosine Yellowish-(YS); Erythrocytes; Glycolysis; Hemoglobins; Oxygen; Adaptation, Physiological
PubMed: 37794190
DOI: 10.1038/s41586-023-06611-6 -
Cell Metabolism Jan 2024Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial... (Review)
Review
Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease.
Topics: Animals; Humans; Mitochondria; Cell Respiration; Fatty Acids; Thioctic Acid; Oxidative Stress; Mammals
PubMed: 38128528
DOI: 10.1016/j.cmet.2023.11.017 -
The Journal of Biological Chemistry Sep 2023Ferredoxins are a family of iron-sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes that are conserved through...
Ferredoxins are a family of iron-sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes that are conserved through evolution. The promiscuous nature of ferredoxins as electron donors enables them to participate in many metabolic processes including steroid, heme, vitamin D, and Fe-S cluster biosynthesis in different organisms. However, the unique natural function(s) of each of the two human ferredoxins (FDX1 and FDX2) are still poorly characterized. We recently reported that FDX1 is both a crucial regulator of copper ionophore-induced cell death and serves as an upstream regulator of cellular protein lipoylation, a mitochondrial lipid-based post-translational modification naturally occurring on four mitochondrial enzymes that are crucial for TCA cycle function. Here we show that FDX1 directly regulates protein lipoylation by binding the lipoyl synthase (LIAS) enzyme promoting its functional binding to the lipoyl carrier protein GCSH and not through indirect regulation of cellular Fe-S cluster biosynthesis. Metabolite profiling revealed that the predominant cellular metabolic outcome of FDX1 loss of function is manifested through the regulation of the four lipoylation-dependent enzymes ultimately resulting in loss of cellular respiration and sensitivity to mild glucose starvation. Transcriptional profiling established that FDX1 loss-of-function results in the induction of both compensatory metabolism-related genes and the integrated stress response, consistent with our findings that FDX1 loss-of-function is conditionally lethal. Together, our findings establish that FDX1 directly engages with LIAS, promoting its role in cellular protein lipoylation, a process essential in maintaining cell viability under low glucose conditions.
Topics: Humans; Ferredoxins; Lipoylation; Protein Binding; Cell Respiration; Cell Proliferation; Metabolome; Sulfurtransferases
PubMed: 37453661
DOI: 10.1016/j.jbc.2023.105046 -
Individualized Treatment Effects of Oxygen Targets in Mechanically Ventilated Critically Ill Adults.JAMA Apr 2024Among critically ill adults, randomized trials have not found oxygenation targets to affect outcomes overall. Whether the effects of oxygenation targets differ based on...
IMPORTANCE
Among critically ill adults, randomized trials have not found oxygenation targets to affect outcomes overall. Whether the effects of oxygenation targets differ based on an individual's characteristics is unknown.
OBJECTIVE
To determine whether an individual's characteristics modify the effect of lower vs higher peripheral oxygenation-saturation (Spo2) targets on mortality.
DESIGN, SETTING, AND PARTICIPANTS
A machine learning model to predict the effect of treatment with a lower vs higher Spo2 target on mortality for individual patients was derived in the Pragmatic Investigation of Optimal Oxygen Targets (PILOT) trial and externally validated in the Intensive Care Unit Randomized Trial Comparing Two Approaches to Oxygen Therapy (ICU-ROX) trial. Critically ill adults received invasive mechanical ventilation in an intensive care unit (ICU) in the United States between July 2018 and August 2021 for PILOT (n = 1682) and in 21 ICUs in Australia and New Zealand between September 2015 and May 2018 for ICU-ROX (n = 965).
EXPOSURES
Randomization to a lower vs higher Spo2 target group.
MAIN OUTCOME AND MEASURE
28-Day mortality.
RESULTS
In the ICU-ROX validation cohort, the predicted effect of treatment with a lower vs higher Spo2 target for individual patients ranged from a 27.2% absolute reduction to a 34.4% absolute increase in 28-day mortality. For example, patients predicted to benefit from a lower Spo2 target had a higher prevalence of acute brain injury, whereas patients predicted to benefit from a higher Spo2 target had a higher prevalence of sepsis and abnormally elevated vital signs. Patients predicted to benefit from a lower Spo2 target experienced lower mortality when randomized to the lower Spo2 group, whereas patients predicted to benefit from a higher Spo2 target experienced lower mortality when randomized to the higher Spo2 group (likelihood ratio test for effect modification P = .02). The use of a Spo2 target predicted to be best for each patient, instead of the randomized Spo2 target, would have reduced the absolute overall mortality by 6.4% (95% CI, 1.9%-10.9%).
CONCLUSION AND RELEVANCE
Oxygenation targets that are individualized using machine learning analyses of randomized trials may reduce mortality for critically ill adults. A prospective trial evaluating the use of individualized oxygenation targets is needed.
Topics: Adult; Humans; Oxygen; Critical Illness; Respiration, Artificial; Prospective Studies; Oxygen Inhalation Therapy; Intensive Care Units
PubMed: 38501205
DOI: 10.1001/jama.2024.2933 -
Current Opinion in Microbiology Apr 2024Cyanobacteria evolved the oxygenic photosynthesis to generate organic matter from CO and sunlight, and they were responsible for the production of oxygen in the Earth's... (Review)
Review
Cyanobacteria evolved the oxygenic photosynthesis to generate organic matter from CO and sunlight, and they were responsible for the production of oxygen in the Earth's atmosphere. This made them a model for photosynthetic organisms, since they are easier to study than higher plants. Early studies suggested that only a minority among cyanobacteria might assimilate organic compounds, being considered mostly autotrophic for decades. However, compelling evidence from marine and freshwater cyanobacteria, including toxic strains, in the laboratory and in the field, has been obtained in the last decades: by using physiological and omics approaches, mixotrophy has been found to be a more widespread feature than initially believed. Furthermore, dominant clades of marine cyanobacteria can take up organic compounds, and mixotrophy is critical for their survival in deep waters with very low light. Hence, mixotrophy seems to be an essential trait in the metabolism of most cyanobacteria, which can be exploited for biotechnological purposes.
Topics: Cyanobacteria; Photosynthesis; Atmosphere; Oxygen
PubMed: 38325247
DOI: 10.1016/j.mib.2024.102432 -
Pneumologie (Stuttgart, Germany) Jul 2023
Topics: Humans; Oxygen
PubMed: 37442145
DOI: 10.1055/a-2022-4044 -
Seminars in Respiratory and Critical... Oct 2023Gas exchange in the lung depends on tidal breathing, which brings new oxygen to and removes carbon dioxide from alveolar gas. This maintains alveolar partial pressures... (Review)
Review
Gas exchange in the lung depends on tidal breathing, which brings new oxygen to and removes carbon dioxide from alveolar gas. This maintains alveolar partial pressures that promote passive diffusion to add oxygen and remove carbon dioxide from blood in alveolar capillaries. In a lung model without ventilation and perfusion (V̇Q̇) mismatch, alveolar partial pressures of oxygen and carbon dioxide are primarily determined by inspiratory pressures and alveolar ventilation. Regions with shunt or low ratios worsen arterial oxygenation while alveolar dead space and high lung units lessen CO elimination efficiency. Although less common, diffusion limitation might cause hypoxemia in some situations. This review covers the principles of lung gas exchange and therefore mechanisms of hypoxemia or hypercapnia. In addition, we discuss different metrics that quantify the deviation from ideal gas exchange.
Topics: Humans; Carbon Dioxide; Lung; Pulmonary Gas Exchange; Oxygen; Hypoxia
PubMed: 37816345
DOI: 10.1055/s-0043-1770060 -
Free Radical Biology & Medicine Sep 2023Reduced oxygen availability (hypoxia) can lead to cell and organ damage. Therefore, aerobic species depend on efficient mechanisms to counteract detrimental consequences... (Review)
Review
Reduced oxygen availability (hypoxia) can lead to cell and organ damage. Therefore, aerobic species depend on efficient mechanisms to counteract detrimental consequences of hypoxia. Hypoxia inducible factors (HIFs) and mitochondria are integral components of the cellular response to hypoxia and coordinate both distinct and highly intertwined adaptations. This leads to reduced dependence on oxygen, improved oxygen supply, maintained energy provision by metabolic remodeling and tapping into alternative pathways and increased resilience to hypoxic injuries. On one hand, many pathologies are associated with hypoxia and hypoxia can drive disease progression, for example in many cancer and neurological diseases. But on the other hand, controlled induction of hypoxia responses via HIFs and mitochondria can elicit profound health benefits and increase resilience. To tackle pathological hypoxia conditions or to apply health-promoting hypoxia exposures efficiently, cellular and systemic responses to hypoxia need to be well understood. Here we first summarize the well-established link between HIFs and mitochondria in orchestrating hypoxia-induced adaptations and then outline major environmental and behavioral modulators of their interaction that remain poorly understood.
Topics: Basic Helix-Loop-Helix Transcription Factors; Mitochondria; Cell Respiration; Humans; Animals; Temperature; Protein Stability; Altitude Sickness; Hypoxia; Diet; Oxygen; Environment
PubMed: 37385566
DOI: 10.1016/j.freeradbiomed.2023.06.015 -
NeuroImage Aug 2023This article provides an overview of MRI methods exploiting magnetic susceptibility properties of blood to assess cerebral oxygen metabolism, including the tissue oxygen... (Review)
Review
This article provides an overview of MRI methods exploiting magnetic susceptibility properties of blood to assess cerebral oxygen metabolism, including the tissue oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO). The first section is devoted to describing blood magnetic susceptibility and its effect on the MRI signal. Blood circulating in the vasculature can have diamagnetic (oxyhemoglobin) or paramagnetic properties (deoxyhemoglobin). The overall balance between oxygenated and deoxygenated hemoglobin determines the induced magnetic field which, in turn, modulates the transverse relaxation decay of the MRI signal via additional phase accumulation. The following sections of this review then illustrate the principles underpinning susceptibility-based techniques for quantifying OEF and CMRO. Here, it is detailed whether these techniques provide global (OxFlow) or local (Quantitative Susceptibility Mapping - QSM, calibrated BOLD - cBOLD, quantitative BOLD - qBOLD, QSM+qBOLD) measurements of OEF or CMRO, and what signal components (magnitude or phase) and tissue pools they consider (intravascular or extravascular). Validations studies and potential limitations of each method are also described. The latter include (but are not limited to) challenges in the experimental setup, the accuracy of signal modeling, and assumptions on the measured signal. The last section outlines the clinical uses of these techniques in healthy aging and neurodegenerative diseases and contextualizes these reports relative to results from gold-standard PET.
Topics: Humans; Brain; Magnetic Resonance Imaging; Oxygen; Oxygen Consumption; Cerebrovascular Circulation
PubMed: 37230206
DOI: 10.1016/j.neuroimage.2023.120189