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Cell Death & Disease Jan 2023The alteration of cellular energy metabolism is a hallmark of colorectal cancer (CRC). Accumulating evidence has suggested oxidative phosphorylation (OXPHOS) is...
The alteration of cellular energy metabolism is a hallmark of colorectal cancer (CRC). Accumulating evidence has suggested oxidative phosphorylation (OXPHOS) is upregulated to meet the demand for energy in tumor initiation and development. However, the role of OXPHOS and its regulatory mechanism in CRC tumorigenesis and progression remain unclear. Here, we reveal that Prohibitin 2 (PHB2) expression is elevated in precancerous adenomas and CRC, which promotes cell proliferation and tumorigenesis of CRC. Additionally, knockdown of PHB2 significantly reduces mitochondrial OXPHOS levels in CRC cells. Meanwhile, NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), as a PHB2 binding partner, is screened and identified by co-immunoprecipitation and mass spectrometry. Furthermore, PHB2 directly interacts with NDUFS1 and they co-localize in mitochondria, which facilitates NDUFS1 binding to NADH:ubiquinone oxidoreductase core subunit V1 (NDUFV1), regulating the activity of complex I. Consistently, partial inhibition of complex I activity also abrogates the increased cell proliferation induced by overexpression of PHB2 in normal human intestinal epithelial cells and CRC cells. Collectively, these results indicate that increased PHB2 directly interacts with NDUFS1 to stabilize mitochondrial complex I and enhance its activity, leading to upregulated OXPHOS levels, thereby promoting cell proliferation and tumorigenesis of CRC. Our findings provide a new perspective for understanding CRC energy metabolism, as well as novel intervention strategies for CRC therapeutics.
Topics: Humans; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms; NAD; NADH Dehydrogenase; Oxidative Phosphorylation; Oxidoreductases; Repressor Proteins; Ubiquinone; Prohibitins
PubMed: 36658121
DOI: 10.1038/s41419-023-05575-9 -
International Journal of Molecular... Mar 2023This Special Issue on lysyl oxidases, which are proteins derived from five related genes known as , and -, brings together articles that reflect some of the diverse...
This Special Issue on lysyl oxidases, which are proteins derived from five related genes known as , and -, brings together articles that reflect some of the diverse approaches and perspectives needed to better understand the biology of these multifunctional proteins [...].
Topics: Protein-Lysine 6-Oxidase; Amino Acid Oxidoreductases
PubMed: 37047014
DOI: 10.3390/ijms24076044 -
Cell Reports Jan 2023Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin...
Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria-ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induction of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1⍺ covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1⍺ interaction requires the C-terminal active site of ERO1⍺ and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1⍺ complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca flux to maintain bioenergetics in both organelles, while limiting oxidative stress. Therefore, the PERK-ERO1⍺ complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.
Topics: Oxidoreductases; Mitochondria; Endoplasmic Reticulum Stress; Endoplasmic Reticulum; Oxidative Stress
PubMed: 36586409
DOI: 10.1016/j.celrep.2022.111899 -
Brain, Behavior, and Immunity Nov 2022There is a need for early therapeutic interventions after traumatic brain injury (TBI) to prevent neurodegeneration. Microglia/macrophage (M/M) depletion and...
BACKGROUND
There is a need for early therapeutic interventions after traumatic brain injury (TBI) to prevent neurodegeneration. Microglia/macrophage (M/M) depletion and repopulation after treatment with colony stimulating factor 1 receptor (CSF1R) inhibitors reduces neurodegeneration. The present study investigates short- and long-term consequences after CSF1R inhibition during the early phase after TBI.
METHODS
Sex-matched mice were subjected to TBI and CSF1R inhibition by PLX3397 for 5 days and sacrificed at 5 or 30 days post injury (dpi). Neurological deficits were monitored and brain tissues were examined for histo- and molecular pathological markers. RNAseq was performed with 30 dpi TBI samples.
RESULTS
At 5 dpi, CSF1R inhibition attenuated the TBI-induced perilesional M/M increase and associated gene expressions by up to 50%. M/M attenuation did not affect structural brain damage at this time-point, impaired hematoma clearance, and had no effect on IL-1β expression. At 30 dpi, following drug discontinuation at 5 dpi and M/M repopulation, CSF1R inhibition attenuated brain tissue loss regardless of sex, as well as hippocampal atrophy and thalamic neuronal loss in male mice. Selected gene markers of brain inflammation and apoptosis were reduced in males but increased in females after early CSF1R inhibition as compared to corresponding TBI vehicle groups. Neurological outcome in behaving mice was almost not affected. RNAseq and gene set enrichment analysis (GSEA) of injured brains at 30 dpi revealed more genes associated with dendritic spines and synapse function after early CSF1R inhibition as compared to vehicle, suggesting improved neuronal maintenance and recovery. In TBI vehicle mice, GSEA showed high oxidative phosphorylation, oxidoreductase activity and ribosomal biogenesis suggesting oxidative stress and increased abundance of metabolically highly active cells. More genes associated with immune processes and phagocytosis in PLX3397 treated females vs males, suggesting sex-specific differences in response to early CSF1R inhibition after TBI.
CONCLUSIONS
M/M attenuation after CSF1R inhibition via PLX3397 during the early phase of TBI reduces long-term brain tissue loss, improves neuronal maintenance and fosters synapse recovery. Overall effects were not sex-specific but there is evidence that male mice benefit more than female mice.
Topics: Aminopyridines; Animals; Brain Injuries, Traumatic; Disease Models, Animal; Female; Inflammation; Macrophage Colony-Stimulating Factor; Male; Mice; Mice, Inbred C57BL; Microglia; Oxidoreductases; Pyrroles; Receptors, Colony-Stimulating Factor; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
PubMed: 35933030
DOI: 10.1016/j.bbi.2022.07.164 -
International Journal of Molecular... Apr 2023Ovarian cancer is one of the most dangerous gynecologic malignancies showing a high fatality rate because of late diagnosis and relapse occurrence due to chemoresistance... (Review)
Review
Ovarian cancer is one of the most dangerous gynecologic malignancies showing a high fatality rate because of late diagnosis and relapse occurrence due to chemoresistance onset. Several researchers reported that oxidative stress plays a key role in ovarian cancer occurrence, growth and development. The NAD(P)H:quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme that, using NADH or NADPH as substrates to reduce quinones to hydroquinones, avoids the formation of the highly reactive semiquinones, then protecting cells against oxidative stress. In this review, we report evidence from the literature describing the effect of NQO1 on ovarian cancer onset and progression.
Topics: Female; Humans; NAD(P)H Dehydrogenase (Quinone); Neoplasm Recurrence, Local; Antioxidants; NADH, NADPH Oxidoreductases; Quinones; Ovarian Neoplasms
PubMed: 37175546
DOI: 10.3390/ijms24097839 -
Current Opinion in Biotechnology Feb 2022Enzymatic biofuel cells utilize oxidoreductases as highly specific and highly active electrocatalysts to convert a fuel and an oxidant even in complex biological... (Review)
Review
Enzymatic biofuel cells utilize oxidoreductases as highly specific and highly active electrocatalysts to convert a fuel and an oxidant even in complex biological matrices like hydrolysates or physiological fluids into electric energy. The hemoflavoenzyme cellobiose dehydrogenase is investigated as a versatile bioelectrocatalyst for the anode reaction of biofuel cells, because it is robust, converts a range of different carbohydrates, and can transfer electrons to the anode by direct electron transfer or via redox mediators. The versatility of cellobiose dehydrogenase has led to the development of various electrode modifications to create biofuel cells and biosupercapacitors that are capable to power small electronic devices like biosensors and connect them wireless to a receiver.
Topics: Bioelectric Energy Sources; Carbohydrate Dehydrogenases; Electrodes; Electron Transport
PubMed: 34482156
DOI: 10.1016/j.copbio.2021.08.013 -
Current Opinion in Chemical Biology Apr 2017Imine reductases (IREDs) have emerged as a valuable new set of biocatalysts for the asymmetric synthesis of optically active amines. The development of bioinformatics... (Review)
Review
Imine reductases (IREDs) have emerged as a valuable new set of biocatalysts for the asymmetric synthesis of optically active amines. The development of bioinformatics tools and searchable databases has led to the identification of a diverse range of new IRED biocatalysts that have been characterised and employed in different synthetic processes. This review describes the latest developments in the structural and mechanistic aspects of IREDs, together with synthetic applications of these enzymes, and identifies ongoing and future challenges in the field.
Topics: Amination; Biocatalysis; Imines; Oxidation-Reduction; Oxidoreductases
PubMed: 28038349
DOI: 10.1016/j.cbpa.2016.11.022 -
Applied and Environmental Microbiology Apr 2022The phylum " Omnitrophica" (candidate division OP3) is ubiquitous in anaerobic habitats but is currently characterized only by draft genomes from metagenomes and single...
The phylum " Omnitrophica" (candidate division OP3) is ubiquitous in anaerobic habitats but is currently characterized only by draft genomes from metagenomes and single cells. We had visualized cells of the phylotype OP3 LiM in methanogenic cultures on limonene as small epibiotic cells. In this study, we enriched OP3 cells by double density gradient centrifugation and obtained the first closed genome of an apparently clonal OP3 cell population by applying metagenomics and PCR for gap closure. Filaments of acetoclastic , the largest morphotype in the culture community, contained empty cells, cells devoid of rRNA or of both rRNA and DNA, and dead cells according to transmission electron microscopy (TEM), thin-section TEM, scanning electron microscopy (SEM), catalyzed reporter deposition-fluorescence hybridization (CARD-FISH), and LIVE/DEAD imaging. OP3 LiM cells were ultramicrobacteria (200 to 300 nm in diameter) and showed two physiological stages in CARD-FISH fluorescence signals: strong signals of OP3 LiM cells attached to and to indicated many rRNA molecules and an active metabolism, whereas free-living OP3 cells had weak signals. Metaproteomics revealed that OP3 LiM lives with highly expressed secreted proteins involved in depolymerization and uptake of macromolecules and an active glycolysis and energy conservation by the utilization of pyruvate via a pyruvate:ferredoxin oxidoreductase and an Rnf complex (ferredoxin:NAD oxidoreductase). Besides sugar fermentation, a nucleotidyl transferase may contribute to energy conservation by phosphorolysis, the phosphate-dependent depolymerization of nucleic acids. Thin-section TEM showed distinctive structures of predation. Our study demonstrated a predatory metabolism for OP3 LiM cells, and therefore, we propose the name " Velamenicoccus archaeovorus" gen. nov., sp. nov., for OP3 LiM. Epibiotic bacteria are known to live on and off bacterial cells. Here, we describe the ultramicrobacterial anaerobic epibiont OP3 LiM living on and . We detected sick and dead cells of the filamentous archaeon in slowly growing methanogenic cultures. OP3 LiM lives as a sugar fermenter, likely on polysaccharides from outer membranes, and has the genomic potential to live as a syntroph. The predatory lifestyle of OP3 LiM was supported by its genome, the first closed genome for the phylum " Omnitrophica," and by images of cell-to-cell contact with prey cells. We propose naming OP3 LiM " Velamenicoccus archaeovorus." Its metabolic versatility explains the ubiquitous presence of " Omnitrophica" 3 in anoxic habitats and gives ultramicrobacterial epibionts an important role in the recycling and remineralization of microbial biomass. The removal of polysaccharides from outer membranes by ultramicrobacteria may also influence biological interactions between pro- and eukaryotes.
Topics: Archaea; Bacteria; Ferredoxins; In Situ Hybridization, Fluorescence; Methanosarcinaceae; Oxidoreductases; Phylogeny; Pyruvic Acid; RNA, Ribosomal, 16S; Sugars
PubMed: 35311510
DOI: 10.1128/aem.02407-21 -
Antioxidants & Redox Signaling Nov 2021Protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductase 1 (ERO1) are crucial for oxidative protein folding in the endoplasmic reticulum (ER). These... (Review)
Review
Protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductase 1 (ERO1) are crucial for oxidative protein folding in the endoplasmic reticulum (ER). These enzymes are frequently overexpressed and secreted, and they contribute to the pathology of neurodegenerative, cardiovascular, and metabolic diseases. Tissue-specific knockout mouse models and pharmacologic inhibitors have been developed to advance our understanding of the cell-specific functions of PDI and ERO1. In addition to their roles in protecting cells from the unfolded protein response and oxidative stress, recent studies have revealed that PDI and ERO1 also function outside of the cells. Despite the well-known contributions of PDI and ERO1 to specific disease pathology, the detailed molecular and cellular mechanisms underlying these activities remain to be elucidated. Further, although PDI and ERO1 inhibitors have been identified, the results from previous studies require careful evaluation, as many of these agents are not selective and may have significant cytotoxicity. The functions of PDI and ERO1 in the ER have been extensively studied. Additional studies will be required to define their functions outside the ER.
Topics: Animals; Cardiovascular Diseases; Humans; Membrane Glycoproteins; Metabolic Diseases; Neurodegenerative Diseases; Oxidoreductases; Protein Disulfide-Isomerases; Signal Transduction
PubMed: 34074138
DOI: 10.1089/ars.2021.0018 -
Cells Sep 2020N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place... (Review)
Review
N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place in the endoplasmic reticulum (ER). They are essential modifications that are required for membrane and secretory proteins to achieve their correct folding and native structure. Several oxidoreductases responsible for disulfide bond formation, isomerization, and reduction have been shown to form stable, functional complexes with enzymes and chaperones that are involved in the initial addition of an N-glycan and in folding and quality control of the glycoproteins. Some of these oxidoreductases are selenoproteins. Recent studies also implicate glycan machinery-oxidoreductase complexes in the recognition and processing of misfolded glycoproteins and their reduction and targeting to ER-associated degradation. This review focuses on the intriguing cooperation between the glycoprotein-specific cell machineries and ER oxidoreductases, and highlights open questions regarding the functions of many members of this large family.
Topics: Calnexin; Disulfides; Endoplasmic Reticulum; Endoplasmic Reticulum-Associated Degradation; Eukaryotic Cells; Glycosylation; Humans; Mannosidases; Molecular Chaperones; Oxidation-Reduction; Oxidoreductases; Polysaccharides; Protein Folding; Protein Processing, Post-Translational; Selenoproteins
PubMed: 32971745
DOI: 10.3390/cells9092138