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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 -
Journal of Neurophysiology Nov 2022The moment-to-moment variation of neurovascular coupling in the brain was determined by computing the moment-to-moment turnover of the blood-oxygen-level-dependent...
The moment-to-moment variation of neurovascular coupling in the brain was determined by computing the moment-to-moment turnover of the blood-oxygen-level-dependent signal (TBOLD) at resting state. Here we show that ) TBOLD is heritable, ) its heritability estimates are highly correlated between left and right hemispheres, and ) the degree of its heritability is determined, in part, by the anatomical proximity of the brain areas involved. We also show that the regional distribution of TBOLD in the cortex is significantly associated with that of the vesicular acetylcholine transporter. These findings establish that TBOLD as a key heritable measure of local cortical brain function captured by neurovascular coupling. Here we show that the sample-to-sample turnover of the resting state fMRI blood-oxygen-level-dependent turnover (TBOLD) is heritable, the left and right hemisphere TBOLD heritabilities are highly correlated, and TBOLD heritability varies among cortical areas. Moreover, we documented that TBOLD is associated with the regional cortical distribution of the vesicular acetylcholine transporter.
Topics: Neurovascular Coupling; Vesicular Acetylcholine Transport Proteins; Brain; Magnetic Resonance Imaging; Brain Mapping; Oxygen
PubMed: 36259671
DOI: 10.1152/jn.00402.2022 -
American Journal of Physiology. Lung... Aug 2021COVID-19 hinders oxygen transport to the consuming tissues by at least two mechanisms: In the injured lung, saturation of hemoglobin is compromised, and in the tissues,... (Review)
Review
COVID-19 hinders oxygen transport to the consuming tissues by at least two mechanisms: In the injured lung, saturation of hemoglobin is compromised, and in the tissues, an associated anemia reduces the volume of delivered oxygen. For the first problem, increased hemoglobin oxygen affinity [left shift of the oxygen dissociation curve (ODC)] is of advantage, for the second, however, the contrary is the case. Indeed a right shift of the ODC has been found in former studies for anemia caused by reduced cell production or hemolysis. This resulted from increased 2,3-bisphosphoglycerate (2,3-BPG) concentration. In three investigations in COVID-19, however, no change of hemoglobin affinity was detected in spite of probably high [2,3-BPG]. The most plausible cause for this finding is formation of methemoglobin (MetHb), which increases the oxygen affinity and thus apparently compensates for the 2,3-BPG effect. However, this "useful effect" is cancelled by the concomitant reduction of functional hemoglobin. In the largest study on COVID-19, even a clear left shift of the ODC was detected when calculated from measurements in fresh blood rather than after equilibration with gases outside the body. This additional "in vivo" left shift possibly results from various factors, e.g., concentration changes of Cl, 2,3-BPG, ATP, lactate, nitrocompounds, glutathione, glutamate, because of time delay between blood sampling and end of equilibration, or enlarged distribution space including interstitial fluid and is useful for O uptake in the lungs. Under discussion for therapy are the affinity-increasing 5-hydroxymethyl-2-furfural (5-HMF), erythropoiesis-stimulating substances like erythropoietin, and methylene blue against MetHb formation.
Topics: Biological Transport; COVID-19; Hemoglobins; Humans; Oxygen; SARS-CoV-2
PubMed: 33978488
DOI: 10.1152/ajplung.00079.2021 -
Nature Communications Jul 2023Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cytc) are involved...
Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cytc) are involved in ischemia-reperfusion injury by regulating mitochondrial respiration and apoptosis. Here, we describe an acetylation site of Cytc, lysine 39 (K39), which was mapped in ischemic porcine skeletal muscle and removed by sirtuin5 in vitro. Using purified protein and cellular double knockout models, we show that K39 acetylation and acetylmimetic K39Q replacement increases cytochrome c oxidase (COX) activity and ROS scavenging while inhibiting apoptosis via decreased binding to Apaf-1, caspase cleavage and activity, and cardiolipin peroxidase activity. These results are discussed with X-ray crystallography structures of K39 acetylated (1.50 Å) and acetylmimetic K39Q Cytc (1.36 Å) and NMR dynamics. We propose that K39 acetylation is an adaptive response that controls electron transport chain flux, allowing skeletal muscle to meet heightened energy demand while simultaneously providing the tissue with robust resilience to ischemia-reperfusion injury.
Topics: Animals; Swine; Lysine; Cytochromes c; Phosphorylation; Acetylation; Protein Processing, Post-Translational; Apoptosis; Cell Respiration; Reperfusion Injury; Muscle, Skeletal
PubMed: 37443314
DOI: 10.1038/s41467-023-39820-8 -
The Journal of Physiology Mar 2021Timely delivery of oxygen (O ) to tissue mitochondria is so essential that elaborate circulatory systems have evolved to minimize diffusion distances within tissue. Yet,... (Review)
Review
Timely delivery of oxygen (O ) to tissue mitochondria is so essential that elaborate circulatory systems have evolved to minimize diffusion distances within tissue. Yet, knowledge is surprisingly limited regarding the diffusion pathway between blood capillaries and tissue mitochondria. An established and growing body of work examines the influence cellular and extracellular structures may have on subcellular oxygen availability. This brief review discusses the physiological and pathophysiological significance of oxygen availability, highlights recent computer modelling studies of transport at the cell-membrane level, and considers alternative diffusion pathways within tissue. Experimental and computer modelling studies suggest that oxygen diffusion may be accelerated by cellular lipids, relative to cytosolic and interstitial fluids. Such acceleration, or 'channelling', would occur due to greatly enhanced oxygen solubility in lipids, especially near the midplane of lipid bilayers. Rapid long-range movement would be promoted by anisotropically enhanced lateral diffusion of oxygen along the midplane and by junctions holding lipid structures in close proximity to one another throughout the tissue. Clarifying the biophysical mechanism of oxygen transport within tissue will shed light on limitations and opportunities in tumour radiotherapy and tissue engineering.
Topics: Capillaries; Cell Membrane Permeability; Diffusion; Mitochondria; Oxygen; Oxygen Consumption
PubMed: 33215707
DOI: 10.1113/JP278815 -
Molecular Cell Oct 2022Mitochondrial Ca uptake, mediated by the mitochondrial Ca uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca signaling. Previous studies...
Mitochondrial Ca uptake, mediated by the mitochondrial Ca uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer and that human/mouse cardiac uniporters are largely devoid of MICUs. Cells employ protein-importation machineries to fine-tune the relative abundance of MICU1 homo- and heterodimers and utilize a conserved MICU intersubunit disulfide to protect properly assembled dimers from proteolysis by YME1L1. Using the MICU1 homodimer or removing MICU1 allows mitochondria to more readily take up Ca so that cells can produce more ATP in response to intracellular Ca transients. However, the trade-off is elevated ROS, impaired basal metabolism, and higher susceptibility to death. These results provide mechanistic insights into how tissues can manipulate mitochondrial Ca uptake properties to support their unique physiological functions.
Topics: Adenosine Triphosphate; Animals; Calcium; Calcium Channels; Calcium-Binding Proteins; Cation Transport Proteins; Disulfides; Humans; Mice; Mitochondrial Membrane Transport Proteins; Reactive Oxygen Species
PubMed: 36206740
DOI: 10.1016/j.molcel.2022.09.006 -
The European Respiratory Journal Dec 2022The lack of knowledge about the effect of inspiratory hyperoxia on the lung-specific tumour microenvironment and progression of lung cancer has attracted considerable...
The lack of knowledge about the effect of inspiratory hyperoxia on the lung-specific tumour microenvironment and progression of lung cancer has attracted considerable attention. This study proposes that inspiratory hyperoxia has special significance for the malignant phenotype of lung cancer cells. The effects of different oxygenation parameters on the proliferation, apoptosis, invasion and migration of lung cancer cells were systematically evaluated and Our results reveal that inspiratory hyperoxia treatment (60% oxygen, 6 h·day) not only has no tumour progression-promoting effects, but also suppresses lung cancer metastasis and promotes long-term survival. In addition, we combined transcriptome, proteome and metabolome analysis and found that hyperoxia treatment induced significant intracellular metabolic changes in lung cancer cells. Overall, we established that MYC/SLC1A5-induced metabolic reprogramming and glutamine addiction is a new mechanism that drives lung cancer metastasis, which can be significantly suppressed by inspiratory hyperoxia treatment. These findings are relevant to the debate on the perils, promises and antitumour effect of inspiratory hyperoxia, especially for patients with lung cancer.
Topics: Humans; Amino Acid Transport System ASC; Apoptosis; Cell Line, Tumor; Cell Proliferation; Hyperoxia; Lung Neoplasms; Metabolic Networks and Pathways; Minor Histocompatibility Antigens; Oxygen; Tumor Microenvironment
PubMed: 35680143
DOI: 10.1183/13993003.00062-2022 -
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 -
Current Opinion in Cell Biology Aug 2019Copper is an essential micronutrient required for oxygen-dependent enzymes, yet excess of the metal is a toxicant. The tug-of-war between these copper activities is... (Review)
Review
Copper is an essential micronutrient required for oxygen-dependent enzymes, yet excess of the metal is a toxicant. The tug-of-war between these copper activities is balanced by chaperones and membrane transporters, which control copper distribution and availability. The P-type ATPase transporters, ATP7A and ATP7B, regulate cytoplasmic copper by pumping copper out of cells or into the endomembrane system. Mutations in ATP7A and ATP7B cause diseases that share neuropsychiatric phenotypes, which are similar to phenotypes observed in mutations affecting cytoplasmic trafficking complexes required for ATP7A/B dynamics. Here, we discuss evidence indicating that phenotypes associated to genetic defects in trafficking complexes, such as retromer and the adaptor complex AP-1, result in part from copper dyshomeostasis due to mislocalized ATP7A and ATP7B.
Topics: Animals; Copper Transport Proteins; Copper-Transporting ATPases; Humans; Mitochondria; Mutation; Parkinson Disease; Protein Transport
PubMed: 30928671
DOI: 10.1016/j.ceb.2019.02.009 -
Cell Death & Disease Aug 2023Ferroptosis, a form of programed cell death, can be promoted by inhibitors of the xCT transporter (erastin) or GPX4 (RSL3). We found that GPX4, but not the xCT...
Ferroptosis, a form of programed cell death, can be promoted by inhibitors of the xCT transporter (erastin) or GPX4 (RSL3). We found that GPX4, but not the xCT transporter, is selectively elevated in luminal breast cancer. Consistent with this observation, the majority of luminal breast cancer cell lines are exquisitely sensitive to RSL3 with limited sensitivity to erastin. In RSL3-resistant, but not sensitive, luminal breast cancer cell lines, RSL3 induces HER2 pathway activation. Irreversible HER2 inhibitors including neratinib reversed RSL3 resistance in constitutively RSL3-resistant cell lines. Combination treatment with RSL3 and neratinib increases ferroptosis through mitochondrial iron-dependent reactive oxygen species production and lipid peroxidation. RSL3 also activated replication stress and concomitant S phase and G2/M blockade leading to sensitivity to targeting the DNA damage checkpoint. Together, our data support the exploration of RSL3 combined with irreversible HER2 inhibitors in clinical trials.
Topics: Humans; Ferroptosis; Apoptosis; Lipid Peroxidation; Iron; MCF-7 Cells; Membrane Transport Proteins; Neoplasms
PubMed: 37596261
DOI: 10.1038/s41419-023-06042-1