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Brain Research Bulletin Jul 2023Impairments in systematic and regional glucose metabolism exist in patients with Parkinson's disease (PD) at every stage of the disease course, and such impairments are... (Review)
Review
Impairments in systematic and regional glucose metabolism exist in patients with Parkinson's disease (PD) at every stage of the disease course, and such impairments are associated with the incidence, progression, and special phenotypes of PD, which affect each physiological process of glucose metabolism including glucose uptake, glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and pentose phosphate shunt pathway. These impairments may be attributed to various mechanisms, such as insulin resistance, oxidative stress, abnormal glycated modification, blood-brain-barrier dysfunction, and hyperglycemia-induced damages. These mechanisms could subsequently cause excessive methylglyoxal and reactive oxygen species production, neuroinflammation, abnormal aggregation of protein, mitochondrial dysfunction, and decreased dopamine, and finally result in energy supply insufficiency, neurotransmitter dysregulation, aggregation and phosphorylation of α-synuclein, and dopaminergic neuron loss. This review discusses the glucose metabolism impairment in PD and its pathophysiological mechanisms, and briefly summarized the currently-available therapies targeting glucose metabolism impairment in PD, including glucagon-likepeptide-1 (GLP-1) receptor agonists and dual GLP-1/gastric inhibitory peptide receptor agonists, metformin, and thiazoledinediones.
Topics: Humans; Parkinson Disease; Hyperglycemia; Glycolysis; Dopamine; Glucose; Glucagon-Like Peptide 1; Dopaminergic Neurons
PubMed: 37210012
DOI: 10.1016/j.brainresbull.2023.110672 -
Cell Research Jan 2024Oxidative phosphorylation (OXPHOS) consumes oxygen to produce ATP. However, the mechanism that balances OXPHOS activity and intracellular oxygen availability remains...
Oxidative phosphorylation (OXPHOS) consumes oxygen to produce ATP. However, the mechanism that balances OXPHOS activity and intracellular oxygen availability remains elusive. Here, we report that mitochondrial protein lactylation is induced by intracellular hypoxia to constrain OXPHOS. We show that mitochondrial alanyl-tRNA synthetase (AARS2) is a protein lysine lactyltransferase, whose proteasomal degradation is enhanced by proline 377 hydroxylation catalyzed by the oxygen-sensing hydroxylase PHD2. Hypoxia induces AARS2 accumulation to lactylate PDHA1 lysine 336 in the pyruvate dehydrogenase complex and carnitine palmitoyltransferase 2 (CPT2) lysine 457/8, inactivating both enzymes and inhibiting OXPHOS by limiting acetyl-CoA influx from pyruvate and fatty acid oxidation, respectively. PDHA1 and CPT2 lactylation can be reversed by SIRT3 to activate OXPHOS. In mouse muscle cells, lactylation is induced by lactate oxidation-induced intracellular hypoxia during exercise to constrain high-intensity endurance running exhaustion time, which can be increased or decreased by decreasing or increasing lactylation levels, respectively. Our results reveal that mitochondrial protein lactylation integrates intracellular hypoxia and lactate signals to regulate OXPHOS.
Topics: Mice; Animals; Oxidative Phosphorylation; Mitochondrial Proteins; Lysine; Hypoxia; Oxygen; Lactates
PubMed: 38163844
DOI: 10.1038/s41422-023-00864-6 -
Frontiers in Immunology 2023Cellular metabolism plays a critical role in determining the fate and function of cells. Metabolic reprogramming and its byproducts have a complex impact on cellular... (Review)
Review
Cellular metabolism plays a critical role in determining the fate and function of cells. Metabolic reprogramming and its byproducts have a complex impact on cellular activities. In quiescent T cells, oxidative phosphorylation (OXPHOS) is the primary pathway for survival. However, upon antigen activation, T cells undergo rapid metabolic reprogramming, characterized by an elevation in both glycolysis and OXPHOS. While both pathways are induced, the balance predominantly shifts towards glycolysis, enabling T cells to rapidly proliferate and enhance their functionality, representing the most distinctive signature during activation. Metabolic processes generate various small molecules resulting from enzyme-catalyzed reactions, which also modulate protein function and exert regulatory control. Notably, recent studies have revealed the direct modification of histones, known as lactylation, by lactate derived from glycolysis. This lactylation process influences gene transcription and adds a novel variable to the regulation of gene expression. Protein lactylation has been identified as an essential mechanism by which lactate exerts its diverse functions, contributing to crucial biological processes such as uterine remodeling, tumor proliferation, neural system regulation, and metabolic regulation. This review focuses on the metabolic reprogramming of T cells, explores the interplay between lactate and the immune system, highlights the impact of lactylation on cellular function, and elucidates the intersection of metabolic reprogramming and epigenetics.
Topics: Glycolysis; Histones; Oxidative Phosphorylation; Lactates; Protein Processing, Post-Translational
PubMed: 37457701
DOI: 10.3389/fimmu.2023.1211221 -
BioRxiv : the Preprint Server For... Aug 2023Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and...
Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.
PubMed: 37577602
DOI: 10.1101/2023.08.02.551712 -
Genes & Diseases Jan 2024Ferroptosis is a novel form of regulated cell death characterized by iron-dependent excessive lipid peroxidation. The core organelle involved in ferroptosis is... (Review)
Review
Ferroptosis is a novel form of regulated cell death characterized by iron-dependent excessive lipid peroxidation. The core organelle involved in ferroptosis is mitochondria. Mitochondria undergoing ferroptosis are distinct from normal mitochondria in terms of morphology, biochemistry, gene expression, and energy metabolism. An increasing number of studies have shown that mitochondria and their associated metabolic pathways mediate ferroptosis in the development and progression of breast cancer. In this review, we discuss the relevant research about ferroptosis in breast cancer and provide a comprehensive summary of mitochondrial regulation in ferroptosis from the perspective of lipid metabolism, oxidative phosphorylation, ion metabolism, glycometabolism, and nucleotide metabolism. We also summarize the application of mitochondrial metabolism-related pathways as ferroptosis treatment targets. Here we provide new insights into the relationship between mitochondria, ferroptosis, and breast cancer treatment.
PubMed: 37588231
DOI: 10.1016/j.gendis.2023.03.019 -
Nature Communications Jul 2023Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers...
Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic and metabolomics analyses of patients' tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients.
Topics: Animals; Humans; Female; Breast Neoplasms; Oxidative Phosphorylation; Cell Line, Tumor; Drug Resistance, Neoplasm; Receptors, Estrogen; Disease Models, Animal
PubMed: 37452026
DOI: 10.1038/s41467-023-40022-5 -
Cell Reports. Medicine Dec 2023Bile acids are altered and associated with prognosis in patients with acute pancreatitis (AP). Here, we conduct targeted metabolomic analyses to detect bile acids...
Bile acids are altered and associated with prognosis in patients with acute pancreatitis (AP). Here, we conduct targeted metabolomic analyses to detect bile acids changes in patients during the acute (n = 326) and the recovery (n = 133) phases of AP, as well as in healthy controls (n = 60). Chenodeoxycholic acid (CDCA) decreases in the acute phase, increases in the recovery phase, and is associated with pancreatic necrosis. CDCA and its derivative obeticholic acid exhibit a protective effect against acinar cell injury in vitro and pancreatic necrosis in murine models, and RNA sequencing reveals that the oxidative phosphorylation pathway is mainly involved. Moreover, we find that overexpression of farnesoid X receptor (FXR, CDCA receptor) inhibits pancreatic necrosis, and interfering expression of FXR exhibits an opposite phenotype in mice. Our results possibly suggest that targeting CDCA is a potential strategy for the treatment of acinar cell necrosis in AP, but further verification is needed.
Topics: Humans; Mice; Animals; Bile Acids and Salts; Pancreatitis, Acute Necrotizing; Acute Disease; Receptors, Cytoplasmic and Nuclear; Chenodeoxycholic Acid
PubMed: 38035885
DOI: 10.1016/j.xcrm.2023.101304 -
Nature Communications Oct 2023Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation...
Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation (OXPHOS) to glycolysis or alterations in other metabolic pathways. However, most of the experimental findings have been acquired in murine immune cells, and little is known about the metabolic reprogramming of human microglia. In this study, we investigate the transcriptomic, proteomic, and metabolic profiles of mouse and iPSC-derived human microglia challenged with the TLR4 agonist LPS. We demonstrate that both species display a metabolic shift and an overall increased glycolytic gene signature in response to LPS treatment. The metabolic reprogramming is characterized by the upregulation of hexokinases in mouse microglia and phosphofructokinases in human microglia. This study provides a direct comparison of metabolism between mouse and human microglia, highlighting the species-specific pathways involved in immunometabolism and the importance of considering these differences in translational research.
Topics: Animals; Mice; Humans; Microglia; Lipopolysaccharides; Proteomics; Oxidative Phosphorylation; Glycolysis
PubMed: 37833292
DOI: 10.1038/s41467-023-42096-7 -
Human Reproduction (Oxford, England) Nov 2023Are human ovarian aging and the age-related female fertility decline caused by oxidative stress and mitochondrial dysfunction in oocytes?
STUDY QUESTION
Are human ovarian aging and the age-related female fertility decline caused by oxidative stress and mitochondrial dysfunction in oocytes?
SUMMARY ANSWER
We found oxidative damage in oocytes of advanced maternal age, even at the primordial follicle stage, and confirmed mitochondrial dysfunction in such oocytes, which likely resulted in the use of alternative energy sources.
WHAT IS KNOWN ALREADY
Signs of reactive oxygen species-induced damage and mitochondrial dysfunction have been observed in maturing follicles, and even in early stages of embryogenesis. However, although recent evidence indicates that also primordial follicles have metabolically active mitochondria, it is still often assumed that these follicles avoid oxidative phosphorylation to prevent oxidative damage in dictyate arrested oocytes. Data on the influence of ovarian aging on oocyte metabolism and mitochondrial function are still limited.
STUDY DESIGN, SIZE, DURATION
A set of 39 formalin-fixed and paraffin-embedded ovarian tissue biopsies were divided into different age groups and used for immunofluorescence analysis of oxidative phosphorylation activity and oxidative damage to proteins, lipids, and DNA. Additionally, 150 immature oocytes (90 germinal vesicle oocytes and 60 metaphase I oocytes) and 15 cumulus cell samples were divided into different age groups and used for targeted metabolomics and lipidomics analysis.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Ovarian tissues used for immunofluorescence microscopy were collected through PALGA, the nationwide network, and registry of histo- and cytopathology in The Netherlands. Comprehensive metabolomics and lipidomics were performed by liquid-liquid extraction and full-scan mass spectrometry, using oocytes and cumulus cells of women undergoing ICSI treatment based on male or tubal factor infertility, or fertility preservation for non-medical reasons.
MAIN RESULTS AND THE ROLE OF CHANCE
Immunofluorescence imaging on human ovarian tissue indicated oxidative damage by protein and lipid (per)oxidation already at the primordial follicle stage. Metabolomics and lipidomics analysis of oocytes and cumulus cells in advanced maternal-age groups demonstrated a shift in the glutathione-to-oxiglutathione ratio and depletion of phospholipids. Age-related changes in polar metabolites suggested a decrease in mitochondrial function, as demonstrated by NAD+, purine, and pyrimidine depletion, while glycolysis substrates and glutamine accumulated, with age. Oocytes from women of advanced maternal age appeared to use alternative energy sources like glycolysis and the adenosine salvage pathway, and possibly ATP which showed increased production in cumulus cells.
LIMITATIONS, REASONS FOR CAUTION
The immature oocytes used in this study were all subjected to ovarian stimulation with high doses of follicle-stimulating hormones, which might have concealed some age-related differences.
WIDER IMPLICATIONS OF THE FINDINGS
Further studies on how to improve mitochondrial function, or lower oxidative damage, in oocytes from women of advanced maternal age, for instance by supplementation of NAD+ precursors to promote mitochondrial biogenesis, are warranted. In addition, supplementing the embryo medium of advanced maternal-age embryos with such compounds could be a treatment option worth exploring.
STUDY FUNDING/COMPETING INTEREST(S)
The study was funded by the Amsterdam UMC. The authors declare to have no competing interests.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Humans; Female; Male; NAD; Oocytes; Oxidative Stress; Mitochondria; Aging
PubMed: 37671592
DOI: 10.1093/humrep/dead177 -
Cell Reports Oct 2023Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant...
Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.
Topics: Humans; Apolipoprotein E4; Astrocytes; Oxidative Phosphorylation; Cells, Cultured; Induced Pluripotent Stem Cells; Apolipoprotein E3; Cholesterol; Alzheimer Disease; Apolipoproteins E
PubMed: 37777962
DOI: 10.1016/j.celrep.2023.113183