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Nature Oct 2023Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell...
Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration. Here, to explore whether metabolic reprogramming can overcome this barrier and enable heart regeneration, we abrogate fatty acid oxidation in cardiomyocytes by inactivation of Cpt1b. We find that disablement of fatty acid oxidation in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischaemia-reperfusion injury. Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5 (ref. ). Activated KDM5 demethylates broad H3K4me3 domains in genes that drive cardiomyocyte maturation, lowering their transcription levels and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.
Topics: Animals; Mice; Carnitine O-Palmitoyltransferase; Cell Hypoxia; Cell Proliferation; Cellular Reprogramming; Energy Metabolism; Enzyme Activation; Epigenesis, Genetic; Fatty Acids; Heart; Histone Demethylases; Ketoglutaric Acids; Mutation; Myocardium; Myocytes, Cardiac; Oxidation-Reduction; Regeneration; Reperfusion Injury; Transcription, Genetic
PubMed: 37758950
DOI: 10.1038/s41586-023-06585-5 -
Cell Death and Differentiation Feb 2024Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis...
Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis and metabolism, but how it modulates myocardial infarction remains unclear. In this study, we showed that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Using RNA-seq, protein and molecular docking, and Targeted Metabolomics (LC-MS), our data demonstrated that macrophages expressing TREM2 exhibited decreased SLC25A53 transcription through the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD transport into mitochondria, downregulated SLC25A53 thereby causing the breakpoint in the TCA cycle and subsequently increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2 macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages could improve cardiac function. In summary, our study reveals a novel role for macrophage-specific TREM2 in MI, connecting efferocytosis to immune metabolism during cardiac repair.
Topics: Animals; Mice; Macrophages; Mice, Inbred C57BL; Molecular Docking Simulation; Myocardial Infarction; Succinates; Humans
PubMed: 38182899
DOI: 10.1038/s41418-023-01252-8 -
The Malaysian Journal of Pathology Dec 2023Urolithiasis is defined as a disease diagnosed by the presence of one or more stones in the urinary tract. It is one of the oldest and most widespread diseases known to... (Review)
Review
Urolithiasis is defined as a disease diagnosed by the presence of one or more stones in the urinary tract. It is one of the oldest and most widespread diseases known to man, their discovery and characterisation chronology began with the civilisation's history. This pathology has a multifactorial aetiology, very frequent worldwide with geographic and racial variation, their prevalence is increasing in lockstep with socioeconomic development. In fact, this disorder affects between 2 and 20% of the population, with an approximate recurrence rate of 30% to 50% in 5 years. Furthermore, calciumtype stones, which are composed of calcium oxalate (CaOx) alone or a mixture of CaOx and calcium phosphate are the most common, accounting for more than 80% of cases. The medical management of urolithiasis is done by medical treatments and/or by surgical intervention for the stones extraction by the techniques such as extracorporeal shock wave lithotripsy (ESWL), ureteroscopy (URS), percutaneous nephrolithotomy (PCNL) and open surgery. However, various therapies, including thiazide diuretics and alkaline citrate, are used in an attempt to prevent stones recurrence induced by hypercalciuria and hyperoxaluria, but the scientific evidence for their effectiveness is less convincing. On the other hand, endoscopic and ESWL methods have revolutionised the treatment of urinary lithiasis, but these costly methods, can cause acute kidney injury and decreased renal function, in addition, do not prevent the probability of new stone formation. The deepening of our knowledge on all points relating to this disease is a priority for specialists in order to find adequate solutions for this disease. This review provides an overview of urolithiasis, its history, epidemiology, clinical manifestation, diagnosis and treatment methods.
Topics: Male; Humans; Kidney Calculi; Calcium Oxalate; Urolithiasis; Ureteroscopy; Lithotripsy; Treatment Outcome
PubMed: 38155376
DOI: No ID Found -
Advanced Science (Weinheim,... Oct 2023Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for...
Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for adipocyte thermogenesis. How brown adipocytes keep mitochondrial fitness upon a challenge of cold-induced oxidative stress has not been well characterized. This manuscript shows that IFI27 plays an important role in cristae morphogenesis, keeping intact succinate dehydrogenase (SDH) function and active fatty acid oxidation to sustain thermogenesis in brown adipocytes. IFI27 protein interaction map identifies SDHB and HADHA as its binding partners. IFI27 physically links SDHB to chaperone TNF receptor associated protein 1 (TRAP1), which shields SDHB from oxidative damage-triggered degradation. Moreover, IFI27 increases hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) catalytic activity in β-oxidation pathway. The reduced SDH level and fatty acid oxidation in Ifi27-knockout brown fat results in impaired oxygen consumption and defective thermogenesis. Thus, IFI27 is a novel regulator of mitochondrial metabolism and thermogenesis.
Topics: Succinic Acid; Adipocytes, Brown; Adipose Tissue, Brown; Fatty Acids; Thermogenesis
PubMed: 37544897
DOI: 10.1002/advs.202301855 -
Nature Metabolism Oct 2023T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in...
T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8 T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound is correlated with increased levels of both peripheral and intratumoural cytotoxic CD8 T cells. These results demonstrate that glutarate is an important regulator of T cell metabolism and differentiation with a potential role in the improvement of T cell immunotherapy.
Topics: CD8-Positive T-Lymphocytes; Glutarates; Biochemical Phenomena
PubMed: 37605057
DOI: 10.1038/s42255-023-00855-2 -
Circulation Research Dec 2023
Topics: Succinic Acid; Succinates; Heart
PubMed: 38112098
DOI: 10.1161/CIRCRESAHA.123.323651 -
Metabolism: Clinical and Experimental Aug 2023Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond...
OBJECTIVE
Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes.
METHODS
We studied the phenotype of wild-type and Sucnr1 mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages.
RESULTS
Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm.
CONCLUSIONS
We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.
Topics: Animals; Humans; Mice; Disease Models, Animal; Fibrosis; Glucose; Glycogen; Hepatocytes; Liver; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Succinates
PubMed: 37315889
DOI: 10.1016/j.metabol.2023.155630 -
Cell Reports Sep 2023The cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in defending foreign pathogens...
The cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in defending foreign pathogens and maintaining immune homeostasis. While substantial advances have been made in understanding the metabolic changes that occur during macrophage activation, little is known about how these metabolic changes affect the cGAS-STING axis. In this study, we identify that 4-octyl itaconate (4-OI), a derivative of itaconate, inhibits the activation of cGAS-STING. Furthermore, we show that 4-OI inhibits cGAS-STING-related antiviral immune responses and autoimmune inflammation. However, we find that endogenous itaconate does not affect cGAS-STING activation, indicating that 4-OI and itaconate function differently. Mechanistically, we find that 4-OI directly alkylates STING at Cys91, blocking STING palmitoylation and oligomerization. The alkylation of STING by 4-OI represents another type of post-translational modifications (PTMs) of STING. Our findings reveal a mechanism by which cGAS-STING function is regulated through 4-OI alkylation and provide insights into the crosstalk between different kinds of PTMs.
Topics: Lipoylation; Nucleotidyltransferases; Succinates
PubMed: 37624697
DOI: 10.1016/j.celrep.2023.113040 -
Current Opinion in Biotechnology Oct 20232-hydroxyglutarate (2HG) is a biproduct of the Krebs cycle, which exists in a D- and L- enantiomer and is structurally similar to α-ketoglutarate. Both 2HG enantiomers... (Review)
Review
2-hydroxyglutarate (2HG) is a biproduct of the Krebs cycle, which exists in a D- and L- enantiomer and is structurally similar to α-ketoglutarate. Both 2HG enantiomers have been described to accumulate in diverse cancer and immune cells and can influence cell fate and function. While D-2HG was originally considered as an 'oncometabolite' that aberrantly builds up in certain cancers, it is becoming clear that it also physiologically accumulates in immune cells and regulates immune function. Conversely, L-2HG is considered as an 'immunometabolite' due to its induction and regulatory function in T cells, but it can also be induced in certain cancers. Here, the authors review the effects of both 2HG enantiomers on immune cells within the tumor microenvironment.
Topics: Humans; Neoplasms; Glutarates; Ketoglutaric Acids; Stereoisomerism; Mutation; Tumor Microenvironment
PubMed: 37515937
DOI: 10.1016/j.copbio.2023.102976 -
Drugs Dec 2023Nedosiran (RIVFLOZA™), a once-monthly subcutaneous small interfering RNA (siRNA) therapy, is being developed by Dicerna Pharmaceuticals, a Novo Nordisk company, for... (Review)
Review
Nedosiran (RIVFLOZA™), a once-monthly subcutaneous small interfering RNA (siRNA) therapy, is being developed by Dicerna Pharmaceuticals, a Novo Nordisk company, for the treatment of primary hyperoxaluria (PH). It reduces oxalate overproduction by inhibiting the expression of the hepatic lactate dehydrogenase (LDH) enzyme. Nedosiran received its first approval on 29 September 2023 in the USA to lower urinary oxalate levels in children aged ≥ 9 years and adults with PH type 1 (PH1) and relatively preserved kidney function [e.g. estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m]. This article summarizes the milestones in the development of nedosiran leading to this first approval for PH1.
Topics: Child; Adult; Humans; Hyperoxaluria, Primary; Oxalates; Lactate Dehydrogenases; RNA, Small Interfering
PubMed: 38060091
DOI: 10.1007/s40265-023-01976-4