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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 -
Science (New York, N.Y.) Sep 2023Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for...
Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.
Topics: Humans; Antigen Presentation; Antigens, Neoplasm; Electron Transport Complex I; Electron Transport Complex II; Electrons; Gene Knockout Techniques; Histones; HSP40 Heat-Shock Proteins; Melanoma; Methylation; Mitochondria; Neoplasms; Cell Line, Tumor
PubMed: 37733872
DOI: 10.1126/science.abq1053 -
Autophagy Aug 2023Copper is an essential trace element in biological systems, maintaining the activity of enzymes and the function of transcription factors. However, at high... (Review)
Review
Copper is an essential trace element in biological systems, maintaining the activity of enzymes and the function of transcription factors. However, at high concentrations, copper ions show increased toxicity by inducing regulated cell death, such as apoptosis, paraptosis, pyroptosis, ferroptosis, and cuproptosis. Furthermore, copper ions can trigger macroautophagy/autophagy, a lysosome-dependent degradation pathway that plays a dual role in regulating the survival or death fate of cells under various stress conditions. Pathologically, impaired copper metabolism due to environmental or genetic causes is implicated in a variety of human diseases, such as rare Wilson disease and common cancers. Therapeutically, copper-based compounds are potential chemotherapeutic agents that can be used alone or in combination with other drugs or approaches to treat cancer. Here, we review the progress made in understanding copper metabolic processes and their impact on the regulation of cell death and autophagy. This knowledge may help in the design of future clinical tools to improve cancer diagnosis and treatment. ACSL4, acyl-CoA synthetase long chain family member 4; AIFM1/AIF, apoptosis inducing factor mitochondria associated 1; AIFM2, apoptosis inducing factor mitochondria associated 2; ALDH, aldehyde dehydrogenase; ALOX, arachidonate lipoxygenase; AMPK, AMP-activated protein kinase; APAF1, apoptotic peptidase activating factor 1; ATF4, activating transcription factor 4; ATG, autophagy related; ATG13, autophagy related 13; ATG5, autophagy related 5; ATOX1, antioxidant 1 copper chaperone; ATP, adenosine triphosphate; ATP7A, ATPase copper transporting alpha; ATP7B, ATPase copper transporting beta; BAK1, BCL2 antagonist/killer 1; BAX, BCL2 associated X apoptosis regulator; BBC3/PUMA, BCL2 binding component 3; BCS, bathocuproinedisulfonic acid; BECN1, beclin 1; BID, BH3 interacting domain death agonist; BRCA1, BRCA1 DNA repair associated; BSO, buthionine sulphoximine; CASP1, caspase 1; CASP3, caspase 3; CASP4/CASP11, caspase 4; CASP5, caspase 5; CASP8, caspase 8; CASP9, caspase 9; CCS, copper chaperone for superoxide dismutase; CD274/PD-L1, CD274 molecule; CDH2, cadherin 2; CDKN1A/p21, cyclin dependent kinase inhibitor 1A; CDKN1B/p27, cyclin-dependent kinase inhibitor 1B; COMMD10, COMM domain containing 10; CoQ10, coenzyme Q 10; CoQ10H2, reduced coenzyme Q 10; COX11, cytochrome c oxidase copper chaperone COX11; COX17, cytochrome c oxidase copper chaperone COX17; CP, ceruloplasmin; CYCS, cytochrome c, somatic; DBH, dopamine beta-hydroxylase; DDIT3/CHOP, DNA damage inducible transcript 3; DLAT, dihydrolipoamide S-acetyltransferase; DTC, diethyldithiocarbamate; EIF2A, eukaryotic translation initiation factor 2A; EIF2AK3/PERK, eukaryotic translation initiation factor 2 alpha kinase 3; ER, endoplasmic reticulum; ESCRT-III, endosomal sorting complex required for transport-III; ETC, electron transport chain; FABP3, fatty acid binding protein 3; FABP7, fatty acid binding protein 7; FADD, Fas associated via death domain; FAS, Fas cell surface death receptor; FASL, Fas ligand; FDX1, ferredoxin 1; GNAQ/11, G protein subunit alpha q/11; GPX4, glutathione peroxidase 4; GSDMD, gasdermin D; GSH, glutathione; HDAC, histone deacetylase; HIF1, hypoxia inducible factor 1; HIF1A, hypoxia inducible factor 1 subunit alpha; HMGB1, high mobility group box 1; IL1B, interleukin 1 beta; IL17, interleukin 17; KRAS, KRAS proto-oncogene, GTPase; LOX, lysyl oxidase; LPCAT3, lysophosphatidylcholine acyltransferase 3; MAP1LC3, microtubule associated protein 1 light chain 3; MAP2K1, mitogen-activated protein kinase kinase 1; MAP2K2, mitogen-activated protein kinase kinase 2; MAPK, mitogen-activated protein kinases; MAPK14/p38, mitogen-activated protein kinase 14; MEMO1, mediator of cell motility 1; MT-CO1/COX1, mitochondrially encoded cytochrome c oxidase I; MT-CO2/COX2, mitochondrially encoded cytochrome c oxidase II; MTOR, mechanistic target of rapamycin kinase; MTs, metallothioneins; NAC, N-acetylcysteine; NFKB/NF-Κb, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; NPLOC4/NPL4, NPL4 homolog ubiquitin recognition factor; PDE3B, phosphodiesterase 3B; PDK1, phosphoinositide dependent protein kinase 1; PHD, prolyl-4-hydroxylase domain; PIK3C3/VPS34, phosphatidylinositol 3-kinase catalytic subunit type 3; PMAIP1/NOXA, phorbol-12-myristate-13-acetate-induced protein 1; POR, cytochrome P450 oxidoreductase; PUFA-PL, PUFA of phospholipids; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; SCO1, synthesis of cytochrome C oxidase 1; SCO2, synthesis of cytochrome C oxidase 2; SLC7A11, solute carrier family 7 member 11; SLC11A2/DMT1, solute carrier family 11 member 2; SLC31A1/CTR1, solute carrier family 31 member 1; SLC47A1, solute carrier family 47 member 1; SOD1, superoxide dismutase; SP1, Sp1 transcription factor; SQSTM1/p62, sequestosome 1; STEAP4, STEAP4 metalloreductase; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TFEB, transcription factor EB; TM, tetrathiomolybdate; TP53/p53, tumor protein p53; TXNRD1, thioredoxin reductase 1; UCHL5, ubiquitin C-terminal hydrolase L5; ULK1, Unc-51 like autophagy activating kinase 1; ULK1, unc-51 like autophagy activating kinase 1; ULK2, unc-51 like autophagy activating kinase 2; USP14, ubiquitin specific peptidase 14; VEGF, vascular endothelial gro wth factor; XIAP, X-linked inhibitor of apoptosis.
Topics: Humans; Autophagy; Tumor Suppressor Protein p53; Apoptosis Inducing Factor; Copper; Ubiquinone; Electron Transport Complex IV; Autophagy-Related Protein-1 Homolog; Proto-Oncogene Proteins p21(ras); Apoptosis; Caspases; Hypoxia-Inducible Factor 1; Superoxide Dismutase; Neoplasms; Ions; Proto-Oncogene Proteins c-bcl-2
PubMed: 37055935
DOI: 10.1080/15548627.2023.2200554 -
Nature Apr 2024Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct...
Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system.
Topics: Animals; Female; Humans; Male; Mice; Central Nervous System; Disease Models, Animal; Electron Transport; Electron Transport Complex I; Inflammation; Microglia; Mitochondria; Multiomics; Myeloid Cells; Neuroinflammatory Diseases; Reactive Oxygen Species
PubMed: 38480879
DOI: 10.1038/s41586-024-07167-9 -
Redox Biology Nov 2023Mitochondria are a main source of cellular energy. Oxidative phosphorylation (OXPHOS) is the major process of aerobic respiration. Enzyme complexes of the electron... (Review)
Review
Mitochondria are a main source of cellular energy. Oxidative phosphorylation (OXPHOS) is the major process of aerobic respiration. Enzyme complexes of the electron transport chain (ETC) pump protons to generate a protonmotive force (Δp) that drives OXPHOS. Complex I is an electron entry point into the ETC. Complex I oxidizes nicotinamide adenine dinucleotide (NADH) and transfers electrons to ubiquinone in a reaction coupled with proton pumping. Complex I also produces reactive oxygen species (ROS) under various conditions. The enzymatic activities of complex I can be regulated by metabolic conditions and serves as a regulatory node of the ETC. Complex I ROS plays diverse roles in cell metabolism ranging from physiologic to pathologic conditions. Progress in our understanding indicates that ROS release from complex I serves important signaling functions. Increasing evidence suggests that complex I ROS is important in signaling a mismatch in energy production and demand. In this article, we review the role of ROS from complex I in sensing acute hypoxia.
Topics: Humans; Reactive Oxygen Species; Oxidation-Reduction; Mitochondria; Electron Transport Complex I; Hypoxia
PubMed: 37871533
DOI: 10.1016/j.redox.2023.102926 -
Advanced Science (Weinheim,... Nov 2023Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti-tumor effects of deubiquitylating enzymes (DUB) inhibitors...
Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti-tumor effects of deubiquitylating enzymes (DUB) inhibitors in HCC. It is found that the inhibitor of ubiquitin specific peptidase 8 (USP8) and DUB-IN-3 shows the most effective anti-cancer responses. Targeting USP8 inhibits the proliferation of HCC and induces cell ferroptosis. In vivo xenograft and metastasis experiments indicate that inhibition of USP8 suppresses tumor growth and lung metastasis. DUB-IN-3 treatment or USP8 depletion decrease intracellular cystine levels and glutathione biosynthesis while increasing the accumulation of reactive oxygen species (ROS). Mechanistical studies reveal that USP8 stabilizes O-GlcNAc transferase (OGT) via inhibiting K48-specific poly-ubiquitination process on OGT protein at K117 site, and STE20-like kinase (SLK)-mediated S716 phosphorylation of USP8 is required for the interaction with OGT. Most importantly, OGT O-GlcNAcylates solute carrier family 7, member 11 (SLC7A11) at Ser26 in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. Collectively, this study demonstrates that pharmacological inhibition or knockout of USP8 can inhibit the progression of HCC and induce ferroptosis via decreasing the stability of OGT, which imposes a great challenge that targeting of USP8 is a potential approach for HCC treatment.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Ferroptosis; Cystine; Endopeptidases; Ubiquitin Thiolesterase; Endosomal Sorting Complexes Required for Transport; Amino Acid Transport System y+
PubMed: 37867237
DOI: 10.1002/advs.202302953 -
Cell Reports Aug 2023Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we...
Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors.
Topics: Animals; Mice; Cell Hypoxia; Cell Line, Tumor; Ferroptosis; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lactic Acid; Neoplasms; Tumor Microenvironment; Excitatory Amino Acid Transporter 3
PubMed: 37542723
DOI: 10.1016/j.celrep.2023.112945