bims-mepmim 2023-10-15 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2023–10–15
thirty-one papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.
Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation.
Metabolic support by macrophages sustains colonic epithelial homeostasis.
Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism.
Arginine reprograms metabolism in liver cancer via RBM39.
ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia.
COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
Depletion of IQ motif-containing GTPase activating protein 2 (IQGAP2) reduces hepatic glycogen and impairs insulin signaling.
Upregulation of exosome secretion from tumor-associated macrophages plays a key role in the suppression of anti-tumor immunity.
PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.
FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.
Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction.
Synthesis and validation of click-modified NOD1/2 agonists.
Very-long-chain fatty acids are crucial to neuronal polarity by providing sphingolipids to lipid rafts.
Metabolic switch from glycogen to lipid in the liver maintains glucose homeostasis in neonatal mice.
Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.
Acidic extracellular pH drives accumulation of N1-acetylspermidine and recruitment of protumor neutrophils.
Human macrophages choreograph tissue development.
Intermittent fasting induced ketogenesis inhibits mouse epithelial ovarian cancer by promoting antitumor T cell response.
Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice.
Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.
WTAP boosts lipid oxidation and induces diabetic cardiac fibrosis by enhancing AR methylation.
CD38 regulates ovarian function and fecundity via NAD+ metabolism.
Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis.
The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.
Allosterically inhibited PFKL via prostaglandin E2 withholds glucose metabolism and ovarian cancer invasiveness.
Carnitine acetyltransferase deficiency mediates mitochondrial dysfunction-induced cellular senescence in dermal fibroblasts.
GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.
Myeloid PTP1B deficiency protects against atherosclerosis by improving cholesterol homeostasis through an AMPK-dependent mechanism.
Cardiolipin Regulates the Activity of the Mitochondrial ABC Transporter ABCB10.

Cell Death Dis. 2023 Oct 10. 14(10): 664

Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.

Sumati Hasani, Lyndsay E A Young, Warren Van Nort, Moumita Banerjee, Dylan R Rivas, Jinhwan Kim, Xiaopeng Xiong, Ramon C Sun, Matthew S Gentry, Hiromi Sesaki, Tianyan Gao.

Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA and promote glycogen storage. Using 3D organoids from Apcf/f/Villin-CreERT2 models, we show that glycogen levels are elevated in tumor organoids upon genetic deletion of Drp1. Similarly, increased GYS1 expression and glycogen accumulation are detected in xenograft tumors derived from Drp1 knockdown colon cancer cells. Functionally, increased glycogen storage provides survival advantage to Drp1 knockdown cells. Co-targeting glycogen phosphorylase-mediated glycogenolysis sensitizes Drp1 knockdown cells to chemotherapy drug treatment. Taken together, our results suggest that Drp1-loss activates glucose uptake and glycogenesis as compensative metabolic pathways to promote cell survival. Combined inhibition of glycogen metabolism may enhance the efficacy of chemotherapeutic agents for colon cancer treatment.

DOI: https://doi.org/10.1038/s41419-023-06202-3
J Clin Invest. 2023 Oct 12. pii: e173160. [Epub ahead of print]

Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation.

Boa Kim, Wencao Zhao, Soon Yew Tang, Michael G Levin, Ayon Ibrahim, Yifan Yang, Emilia M Roberts, Ling Lai, Jian Li, Richard K Assoian, Garret A FitzGerald, Zoltan Arany.

  The metabolic syndrome, today affecting more than 20% of the US population, is a group of five conditions that often co-exist and that strongly predispose to cardiovascular disease. How these conditions are linked mechanistically remains unclear, especially two of these: obesity and elevated blood pressure. Here we show that high fat consumption in mice leads to the accumulation of lipid droplets in endothelial cells throughout the organism, and that lipid droplet accumulation in endothelium suppresses endothelial nitric oxide synthase (eNOS), reduces NO production, elevates blood pressure, and accelerates atherosclerosis. Mechanistically, the accumulation of lipid droplets destabilizes eNOS mRNA and activates an endothelial inflammatory signaling cascade that suppresses eNOS and NO production. Pharmacological prevention of lipid droplet formation reverses the suppression of NO production in cell culture and in vivo, and blunts blood pressure elevation in response to high fat diet. These results highlight lipid droplets as a critical and unappreciated component of endothelial cell biology, explain how lipids increase blood pressure acutely, and provide a mechanistic account for the epidemiological link between obesity and elevated blood pressure.

Keywords:  Cardiology; Endothelial cells

DOI:  https://doi.org/10.1172/JCI173160
Cell Metab. 2023 Sep 29. pii: S1550-4131(23)00341-8. [Epub ahead of print]

Metabolic support by macrophages sustains colonic epithelial homeostasis.

Stephanie Deborah Fritsch, Nyamdelger Sukhbaatar, Karine Gonzales, Alishan Sahu, Loan Tran, Andrea Vogel, Mario Mazic, Jayne Louise Wilson, Stephan Forisch, Hannah Mayr, Raimund Oberle, Jakob Weiszmann, Martin Brenner, Roeland Vanhoutte, Melanie Hofmann, Sini Pirnes-Karhu, Christoph Magnes, Torben Kühnast, Wolfram Weckwerth, Christoph Bock, Kristaps Klavins, Markus Hengstschläger, Christine Moissl-Eichinger, Gernot Schabbauer, Gerda Egger, Eija Pirinen, Steven H L Verhelst, Thomas Weichhart.

  The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently characterized signals from the microenvironment. Here, we showed that colonic macrophages were located directly adjacent to epithelial crypt cells in mice, where they metabolically supported epithelial cell proliferation in an mTORC1-dependent manner. Specifically, deletion of tuberous sclerosis complex 2 (Tsc2) in macrophages activated mTORC1 signaling that protected against colitis-induced intestinal damage and induced the synthesis of the polyamines spermidine and spermine. Epithelial cells ingested these polyamines and rewired their cellular metabolism to optimize proliferation and defense. Notably, spermine directly stimulated proliferation of colon epithelial cells and colon organoids. Genetic interference with polyamine production in macrophages altered global polyamine levels in the colon and modified epithelial cell proliferation. Our results suggest that macrophages act as "commensals" that provide metabolic support to promote efficient self-renewal of the colon epithelium.

Keywords:  arginase-1; homeostasis; immunometabolism; intestine; mTOR; mTORC1; macrophages; polyamines; spermine

DOI:  https://doi.org/10.1016/j.cmet.2023.09.010
J Biol Chem. 2023 Oct 10. pii: S0021-9258(23)02361-X. [Epub ahead of print] 105333

Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism.

Nicholas L Arp, Gretchen L Seim, James A Votava, Jordyn Josephson, Jing Fan.

  Branched chain α-ketoacid dehydrogenase complex (BCKDC) is the rate-limiting enzyme in branched chain amino acid (BCAA) catabolism, a metabolic pathway with great importance for human health. BCKDC belongs to the mitochondrial α-ketoacid dehydrogenase complex family, which also includes pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC). Here we revealed that BCKDC can be substantially inhibited by reactive nitrogen species (RNS) via a mechanism similar to what we recently discovered with PDHC and OGDC - RNS can cause inactivating covalent modifications of the lipoic arm on its E2 subunit. In addition, we showed that such reaction between RNS and the lipoic arm of the E2 subunit can further promote inhibition of the E3 subunits of α-ketoacid dehydrogenase complexes. We examined the impacts of this RNS-mediated BCKDC inhibition in muscle cells, an important site of BCAA metabolism, and demonstrated that the nitric oxide production induced by cytokine stimulation leads to a strong inhibition of BCKDC activity and BCAA oxidation in myotubes and myoblasts. More broadly, nitric oxide production reduced the level of functional lipoic arms across the multiple α-ketoacid dehydrogenases and led to intracellular accumulation of their substrates (α-ketoacids), decrease of their products (acyl-CoAs), and a lower cellular energy charge. In sum, this work revealed a new mechanism for BCKDC regulation, demonstrated that RNS can generally inhibit all α-ketoacid dehydrogenases, which has broad physiological implications across multiple cell types, and elucidated the mechanistic connection between RNS-driven inhibitory modifications on the E2 and E3 subunits of α-ketoacid dehydrogenases.

Keywords:  branched chain amino acid; metabolic regulation; mitochondria metabolism; nitric oxide; α-ketoacid dehydrogenase

DOI:  https://doi.org/10.1016/j.jbc.2023.105333
Cell. 2023 Sep 26. pii: S0092-8674(23)01032-2. [Epub ahead of print]

Arginine reprograms metabolism in liver cancer via RBM39.

Dirk Mossmann, Christoph Müller, Sujin Park, Brendan Ryback, Marco Colombi, Nathalie Ritter, Diana Weißenberger, Eva Dazert, Mairene Coto-Llerena, Sandro Nuciforo, Lauriane Blukacz, Caner Ercan, Veronica Jimenez, Salvatore Piscuoglio, Fatima Bosch, Luigi M Terracciano, Uwe Sauer, Markus H Heim, Michael N Hall.

  Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.

Keywords:  AGMAT; ARG1; ASNS; RBM39; arginine; hepatocellular carcinoma; indisulam; metabolism

DOI:  https://doi.org/10.1016/j.cell.2023.09.011
Cell Rep. 2023 Oct 11. pii: S2211-1247(23)01218-4. [Epub ahead of print]42(10): 113206

ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia.

Tuan Anh Phu, Ngan K Vu, Martin Ng, Alex S Gao, Joshua S Stoolman, Navdeep S Chandel, Robert L Raffai.

  Apolipoprotein E (ApoE) is recognized for its pleiotropic properties that suppress inflammation. We report that ApoE serves as a metabolic rheostat that regulates microRNA control of glycolytic and mitochondrial activity in myeloid cells and hematopoietic stem and progenitor cells (HSPCs). ApoE expression in myeloid cells increases microRNA-146a, which reduces nuclear factor κB (NF-κB)-driven GLUT1 expression and glycolytic activity. In contrast, ApoE expression reduces microRNA-142a, which increases carnitine palmitoyltransferase 1a (CPT1A) expression, fatty acid oxidation, and oxidative phosphorylation. Improved mitochondrial metabolism by ApoE expression causes an enrichment of tricarboxylic acid (TCA) cycle metabolites and nicotinamide adenine dinucleotide (NAD+) in macrophages. The study of mice with conditional ApoE expression supports the capacity of ApoE to foster microRNA-controlled immunometabolism. Modulation of microRNA-146a and -142a in the hematopoietic system of hyperlipidemic mice using RNA mimics and antagonists, respectively, improves mitochondrial metabolism, which suppresses inflammation and hematopoiesis. Our findings unveil microRNA regulatory circuits, controlled by ApoE, that exert metabolic control over hematopoiesis and inflammation in hyperlipidemia.

Keywords:  ApoE; CP: Metabolism; CPT1A; Glut1; fatty acid oxidation; hematopoiesis; inflammation; macrophage; microRNA-142a; microRNA-146a; mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.113206
Nat Metab. 2023 Oct 09.

COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.

Sukanya Guhathakurta, Niyazi Umut Erdogdu, Juliane J Hoffmann, Iga Grzadzielewska, Alexander Schendzielorz, Janine Seyfferth, Christoph U Mårtensson, Mauro Corrado, Adam Karoutas, Bettina Warscheid, Nikolaus Pfanner, Thomas Becker, Asifa Akhtar.

Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members leads to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain complex IV integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a complex IV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopies the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains complex IV activity even in the absence of MOF, suggesting an activatory role of mitochondrial electron transport chain protein acetylation. Fibroblasts from patients with MOF syndrome who have intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.

DOI: https://doi.org/10.1038/s42255-023-00904-w
J Biol Chem. 2023 Oct 05. pii: S0021-9258(23)02350-5. [Epub ahead of print] 105322

Depletion of IQ motif-containing GTPase activating protein 2 (IQGAP2) reduces hepatic glycogen and impairs insulin signaling.

Anushna Sen, Sara Youssef, Karen Wendt, Sayeepriyadarshini Anakk.

  The liver is critical in maintaining metabolic homeostasis, regulating both anabolic and catabolic processes. Scaffold protein IQGAP2 is highly expressed in the liver and implicated in fatty acid uptake. However, its role in coordinating either fed or fasted responses is not well understood. Here we report that IQGAP2 is widely expressed in the liver that is pronounced in the pericentral region. Although control and IQGAP2 knockout (Iqgap2-/-) mouse model showed comparable hepatic gene expression in the fasted state, we found significant defects in fed state responses. Glycogen levels were reduced in the periportal region when IQGAP2 was deleted. Consistently, we observed a decrease in phosphorylated glycogen synthase kinase 3α (GSK3α) and total glycogen synthase (GYS2) protein in the fed Iqgap2-/- mice which suggest inadequate glycogen synthesis. Moreover, immunoprecipitation of IQGAP2 revealed its interaction with GSK3 and GYS. Furthermore, our study demonstrated that knocking down IQGAP2 in vitro significantly decreased the phosphorylation of AKT and FOXO3 proteins downstream of insulin signaling. These findings suggest that IQGAP2 contributes to liver fed-state metabolism by interacting with glycogen synthesis regulators and affecting the phosphorylation of insulin pathway components. Our results suggest that IQGAP2 plays a role in regulating fed-state metabolism.

Keywords:  and insulin signaling; carbohydrate; glycogen synthase (GYS2); glycogen synthase kinase 3 (GSK‐3); liver; protein kinase B (PKB/AKT); scaffold protein

DOI:  https://doi.org/10.1016/j.jbc.2023.105322
Cell Rep. 2023 Oct 07. pii: S2211-1247(23)01236-6. [Epub ahead of print]42(10): 113224

Upregulation of exosome secretion from tumor-associated macrophages plays a key role in the suppression of anti-tumor immunity.

Wenqun Zhong, Youtao Lu, Xuexiang Han, Jingbo Yang, Zhiyuan Qin, Wei Zhang, Ziyan Yu, Bin Wu, Shujing Liu, Wei Xu, Cathy Zheng, Lynn M Schuchter, Giorgos C Karakousis, Tara C Mitchell, Ravi Amaravadi, Ahron J Flowers, Phyllis A Gimotty, Min Xiao, Gordon Mills, Meenhard Herlyn, Haidong Dong, Michael J Mitchell, Junhyong Kim, Xiaowei Xu, Wei Guo.

  Macrophages play a pivotal role in tumor immunity. We report that reprogramming of macrophages to tumor-associated macrophages (TAMs) promotes the secretion of exosomes. Mechanistically, increased exosome secretion is driven by MADD, which is phosphorylated by Akt upon TAM induction and activates Rab27a. TAM exosomes carry high levels of programmed death-ligand 1 (PD-L1) and potently suppress the proliferation and function of CD8+ T cells. Analysis of patient melanoma tissues indicates that TAM exosomes contribute significantly to CD8+ T cell suppression. Single-cell RNA sequencing analysis showed that exosome-related genes are highly expressed in macrophages in melanoma; TAM-specific RAB27A expression inversely correlates with CD8+ T cell infiltration. In a murine melanoma model, lipid nanoparticle delivery of small interfering RNAs (siRNAs) targeting macrophage RAB27A led to better T cell activation and sensitized tumors to anti-programmed cell death protein 1 (PD-1) treatment. Our study demonstrates tumors use TAM exosomes to combat CD8 T cells and suggests targeting TAM exosomes as a potential strategy to improve immunotherapies.

Keywords:  CP: Cancer; CP: Immunology; exosome; immunotherapy; programmed cell death ligand 1; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.celrep.2023.113224
Nat Commun. 2023 Oct 13. 14(1): 6431

PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.

Natalie M Niemi, Lia R Serrano, Laura K Muehlbauer, Catherine E Balnis, Lianjie Wei, Andrew J Smith, Keri-Lyn Kozul, Merima Forny, Olivia M Connor, Edrees H Rashan, Evgenia Shishkova, Kathryn L Schueler, Mark P Keller, Alan D Attie, Jonathan R Friedman, Julia K Pagan, Joshua J Coon, David J Pagliarini.

PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7-/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.

DOI: https://doi.org/10.1038/s41467-023-42069-w
Cell Rep. 2023 Oct 10. pii: S2211-1247(23)01253-6. [Epub ahead of print]42(10): 113241

Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.

Makayla S Lancaster, Byungwook Kim, Emma H Doud, Mason D Tate, Ahmad D Sharify, Hongyu Gao, Duojiao Chen, Ed Simpson, Patrick Gillespie, Xiaona Chu, Marcus J Miller, Yue Wang, Yunlong Liu, Amber L Mosley, Jungsu Kim, Brett H Graham.

  Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency.

Keywords:  ATAC sequencing; CP: Metabolism; CP: Neuroscience; RNA sequencing; chromatin; electron transport chain; mass spectrometry; metabolism; neurons; post-translational modification; succinyl-CoA synthetase; succinylation

DOI:  https://doi.org/10.1016/j.celrep.2023.113241
Nat Commun. 2023 10 10. 14(1): 6344

FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.

Jiamin Qiu, Feng Yue, Peipei Zhu, Jingjuan Chen, Fan Xu, Lijia Zhang, Kun Ho Kim, Madigan M Snyder, Nanjian Luo, Hao-Wei Xu, Fang Huang, W Andy Tao, Shihuan Kuang.

Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a (Fam210aAKO) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210aAKO mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210aiAKO) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.

DOI: https://doi.org/10.1038/s41467-023-41988-y
Nat Commun. 2023 Oct 13. 14(1): 6454

Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction.

Angélica María Sabogal-Guáqueta, Alejandro Marmolejo-Garza, Marina Trombetta-Lima, Asmaa Oun, Jasmijn Hunneman, Tingting Chen, Jari Koistinaho, Sarka Lehtonen, Arjan Kortholt, Justina C Wolters, Barbara M Bakker, Bart J L Eggen, Erik Boddeke, Amalia Dolga.

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.

DOI: https://doi.org/10.1038/s41467-023-42096-7
Innate Immun. 2023 Oct 13. 17534259231207198

Synthesis and validation of click-modified NOD1/2 agonists.

Ravi Bharadwaj, Madison V Anonick, Swati Jaiswal, Siavash Mashayekh, Ashley Brown, Kimberly A Wodzanowski, Kendi Okuda, Neal Silverman, Catherine L Grimes.

  NOD1 and NOD2 sense small bacterial peptidoglycan fragments, often called muropeptides, that access the cytosol. These muropeptides include iE-DAP and MDP, the minimal agonists for NOD1 and NOD2, respectively. Here, we synthesized and validated alkyne-modified muropeptides, iE-DAP-Alk and MDP-Alk, for use in click-chemistry reactions. While it has long been known that many cell types respond to extracellular exposure to muropeptides, it is unclear how these innate immune activators access their cytosolic innate immune receptors, NOD1 and NOD2. The subcellular trafficking and transport mechanisms by which muropeptides access these cytosolic innate immune receptors are a major gap in our understanding of these critical host responses. The click-chemistry-enabled agonists developed here will be particularly powerful to decipher the underlying cell biology and biochemistry of NOD1 and NOD2 innate immune sensing.

Keywords:  Click-chemistry; MDP; NOD1; alkyne-modification; and NOD2; iE-DAP; muropeptide

DOI:  https://doi.org/10.1177/17534259231207198
Cell Rep. 2023 Oct 02. pii: S2211-1247(23)01207-X. [Epub ahead of print] 113195

Very-long-chain fatty acids are crucial to neuronal polarity by providing sphingolipids to lipid rafts.

Atsuko Honda, Motohiro Nozumi, Yasuyuki Ito, Rie Natsume, Asami Kawasaki, Fubito Nakatsu, Manabu Abe, Haruki Uchino, Natsuki Matsushita, Kazutaka Ikeda, Makoto Arita, Kenji Sakimura, Michihiro Igarashi.

  Fatty acids have long been considered essential to brain development; however, the involvement of their synthesis in nervous system formation is unclear. We generate mice with knockout of GPSN2, an enzyme for synthesis of very-long-chain fatty acids (VLCFAs) and investigate the effects. Both GPSN2-/- and GPSN2+/- mice show abnormal neuronal networks as a result of impaired neuronal polarity determination. Lipidomics of GPSN2-/- embryos reveal that ceramide synthesis is specifically inhibited depending on FA length; namely, VLCFA-containing ceramide is reduced. We demonstrate that lipid rafts are highly enriched in growth cones and that GPSN2+/- neurons lose gangliosides in their membranes. Application of C24:0 ceramide, but not C16:0 ceramide or C24:0 phosphatidylcholine, to GPSN2+/- neurons rescues both neuronal polarity determination and lipid-raft density in the growth cone. Taken together, our results indicate that VLCFA synthesis contributes to physiological neuronal development in brain network formation, in particular neuronal polarity determination through the formation of lipid rafts.

Keywords:  CP: Cell biology; CP: Neuroscience

DOI:  https://doi.org/10.1016/j.celrep.2023.113195
J Lipid Res. 2023 Oct 10. pii: S0022-2275(23)00113-X. [Epub ahead of print]64(10): 100440

Metabolic switch from glycogen to lipid in the liver maintains glucose homeostasis in neonatal mice.

Liangkui Li, Haoyu Zhou, Jinhui Wang, Jiaxin Li, Xuchao Lyu, Wenshan Wang, Chengting Luo, He Huang, Dawang Zhou, Xiaowei Chen, Li Xu, Peng Li.

  Neonates strive to acquire energy when the continuous transplacental nutrient supply ceases at birth, whereas milk consumption takes hours to start. Using murine models, we report the metabolic switches in the first days of life, with an unexpected discovery of glucose as the universal fuel essential for neonatal life. Blood glucose quickly drops as soon as birth, but immediately rebounds even before suckling and maintains stable afterward. Meanwhile, neonatal liver undergoes drastic metabolic changes, from extensive glycogenolysis before suckling to dramatically induced fatty acid oxidation (FAO) and gluconeogenesis after milk suckling. Unexpectedly, blocking hepatic glycogenolysis only caused a transient hypoglycemia before milk suckling without causing lethality. Limiting lipid supply in milk (low-fat milk, [LFM]) using Cidea-/- mice, however, led to a chronic and severe hypoglycemia and consequently claimed neonatal lives. While fat replenishment rescued LFM-caused neonatal lethality, the rescue effects were abolished by blocking FAO or gluconeogenesis, pointing to a funneling of lipids and downstream metabolites into glucose as the essential fuel. Finally, glucose administration also rescued LFM-caused neonatal lethality, independent on FAO or gluconeogenesis. Therefore, our results show that the liver works as an energy conversion center to maintain blood glucose homeostasis in neonates, providing theoretical basis for managing infant hypoglycemia.

Keywords:  Physiology; biological sciences; gluconeogenesis; glucose homeostasis; glycogen; lipids; neonates

DOI:  https://doi.org/10.1016/j.jlr.2023.100440
Nat Commun. 2023 Oct 10. 14(1): 6328

Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.

Tomas Venit, Oscar Sapkota, Wael Said Abdrabou, Palanikumar Loganathan, Renu Pasricha, Syed Raza Mahmood, Nadine Hosny El Said, Shimaa Sherif, Sneha Thomas, Salah Abdelrazig, Shady Amin, Davide Bedognetti, Youssef Idaghdour, Mazin Magzoub, Piergiorgio Percipalle.

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Here, we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. NM1 directly affects mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial transcription factors TFAM and PGC1α, and its deletion leads to underdeveloped mitochondria inner cristae and mitochondrial redistribution within the cell. These changes are associated with reduced OXPHOS gene expression, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics, which lead to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis.This, in turn, is associated with a metabolomic profile typical for cancer cells, namely increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. NM1 KO cells form solid tumors in a mouse model, suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient carcinogenic signal. We suggest that NM1 plays a role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the onset of tumorigenesis.

DOI: https://doi.org/10.1038/s41467-023-42093-w
PNAS Nexus. 2023 Oct;2(10): pgad306

Acidic extracellular pH drives accumulation of N1-acetylspermidine and recruitment of protumor neutrophils.

Miki Kato, Keisuke Maeda, Ryuichi Nakahara, Haruka Hirose, Ayano Kondo, Sho Aki, Maki Sugaya, Sana Hibino, Miyuki Nishida, Manami Hasegawa, Hinano Morita, Ritsuko Ando, Rika Tsuchida, Minoru Yoshida, Tatsuhiko Kodama, Hideyuki Yanai, Teppei Shimamura, Tsuyoshi Osawa.

  An acidic tumor microenvironment plays a critical role in tumor progression. However, understanding of metabolic reprogramming of tumors in response to acidic extracellular pH has remained elusive. Using comprehensive metabolomic analyses, we demonstrated that acidic extracellular pH (pH 6.8) leads to the accumulation of N1-acetylspermidine, a protumor metabolite, through up-regulation of the expression of spermidine/spermine acetyltransferase 1 (SAT1). Inhibition of SAT1 expression suppressed the accumulation of intra- and extracellular N1-acetylspermidine at acidic pH. Conversely, overexpression of SAT1 increased intra- and extracellular N1-acetylspermidine levels, supporting the proposal that SAT1 is responsible for accumulation of N1-acetylspermidine. While inhibition of SAT1 expression only had a minor effect on cancer cell growth in vitro, SAT1 knockdown significantly decreased tumor growth in vivo, supporting a contribution of the SAT1-N1-acetylspermidine axis to protumor immunity. Immune cell profiling revealed that inhibition of SAT1 expression decreased neutrophil recruitment to the tumor, resulting in impaired angiogenesis and tumor growth. We showed that antineutrophil-neutralizing antibodies suppressed growth in control tumors to a similar extent to that seen in SAT1 knockdown tumors in vivo. Further, a SAT1 signature was found to be correlated with poor patient prognosis. Our findings demonstrate that extracellular acidity stimulates recruitment of protumor neutrophils via the SAT1-N1-acetylspermidine axis, which may represent a metabolic target for antitumor immune therapy.

Keywords:  N1-acetylspermidine; SAT1; acidic extracellular pH; cancer metabolism; neutrophils

DOI:  https://doi.org/10.1093/pnasnexus/pgad306
Trends Immunol. 2023 Oct 11. pii: S1471-4906(23)00206-5. [Epub ahead of print]

Human macrophages choreograph tissue development.

Elvira Mass.

Yolk sac-derived macrophages have been described to promote organogenesis and tissue function in animal models, but the relevance of these studies for humans has been debated. Wang et al. reveal that human macrophage development follows similar developmental trajectories with functionally distinct macrophage populations across tissues as observed in mice.

DOI: https://doi.org/10.1016/j.it.2023.09.010
iScience. 2023 Oct 20. 26(10): 107839

Intermittent fasting induced ketogenesis inhibits mouse epithelial ovarian cancer by promoting antitumor T cell response.

Mary Priyanka Udumula, Harshit Singh, Faraz Rashid, Laila Poisson, Nivedita Tiwari, Irina Dimitrova, Miriana Hijaz, Radhika Gogoi, Margaret Swenor, Adnan Munkarah, Shailendra Giri, Ramandeep Rattan.

  In various cancer models, dietary interventions have been shown to inhibit tumor growth, improve anticancer drug efficacy, and enhance immunity, but no such evidence exists for epithelial ovarian cancer (EOC), the most lethal gynecologic cancer. The anticancer immune responses induced by 16-h intermittent fasting (IF) were studied in mice with EOC. IF consistently reduced metabolic growth factors and cytokines that stimulate tumor growth, creating a tumor-hostile environment. Immune profiling showed that IF dramatically alters anti-cancer immunity by increasing CD4+ and CD8+ cells, Th1 and cytotoxic responses, and metabolic fitness. β-hydroxy butyrate (BHB), a bioactive metabolite produced by IF, partially imitates its anticancer effects by inducing CD8+ effector function. In a direct comparison, IF outperformed exogenous BHB treatment in survival and anti-tumor immune response, probably due to increased ketogenesis. Thus, IF and one of its metabolic mediators BHB suppress EOC growth and sustain a potent anti-tumor T cell response.

Keywords:  Biological sciences; Cancer; Immunology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2023.107839
Nat Commun. 2023 10 10. 14(1): 6330

Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice.

Stacy K Thomas, Max M Wattenberg, Shaanti Choi-Bose, Mark Uhlik, Ben Harrison, Heather Coho, Christopher R Cassella, Meredith L Stone, Dhruv Patel, Kelly Markowitz, Devora Delman, Michael Chisamore, Jeremy Drees, Nandita Bose, Gregory L Beatty.

Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to β-glucan (odetiglucan) treatment by inhibiting liver metastasis. β-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of β-glucan, which also required T cells. Furthermore, β-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver.

DOI: https://doi.org/10.1038/s41467-023-41771-z
Elife. 2023 Oct 12. pii: RP88084. [Epub ahead of print]12

Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.

Michele Brischigliaro, Alfredo Cabrera-Orefice, Susanne Arnold, Carlo Viscomi, Massimo Zeviani, Erika Fernández-Vizarra.

  Mammalian mitochondrial respiratory chain (MRC) complexes are able to associate into quaternary structures named supercomplexes (SCs), which normally coexist with non-bound individual complexes. The functional significance of SCs has not been fully clarified and the debate has been centered on whether or not they confer catalytic advantages compared with the non-bound individual complexes. Mitochondrial respiratory chain organization does not seem to be conserved in all organisms. In fact, and differently from mammalian species, mitochondria from Drosophila melanogaster tissues are characterized by low amounts of SCs, despite the high metabolic demands and MRC activity shown by these mitochondria. Here, we show that attenuating the biogenesis of individual respiratory chain complexes was accompanied by increased formation of stable SCs, which are missing in Drosophila melanogaster in physiological conditions. This phenomenon was not accompanied by an increase in mitochondrial respiratory activity. Therefore, we conclude that SC formation is necessary to stabilize the complexes in suboptimal biogenesis conditions, but not for the enhancement of respiratory chain catalysis.

Keywords:  D. melanogaster; Drosophila; Mitochondria; OXPHOS; biochemistry; chemical biology; supercomplexes

DOI:  https://doi.org/10.7554/eLife.88084
iScience. 2023 Oct 20. 26(10): 107931

WTAP boosts lipid oxidation and induces diabetic cardiac fibrosis by enhancing AR methylation.

Kai Song, He Sun, Bin Tu, Yang Zhou, Li-Chan Lin, Zhi-Yan Liu, Rui Li, Jing-Jing Yang, Ye Zhang, Jian-Yuan Zhao, Hui Tao.

  Dysregulated lipid metabolism occurs in pathological processes characterized by cell proliferation and migration. Nonetheless, the mechanism of increased mitochondrial lipid oxidation is poorly appreciated in diabetic cardiac fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. Herein, increased WTAP expression promotes cardiac fibroblast proliferation and migration, contributing to diabetic cardiac fibrosis. Knockdown of WTAP suppresses mitochondrial lipid oxidation, fibroblast proliferation and migration to ameliorate diabetic cardiac fibrosis. Mechanistically, WTAP-mediated m6A methylation of AR induced its degradation, dependent on YTHDF2. Additionally, AR directly interacts with mitochondrial lipid oxidation enzyme Decr1; overexpression of AR-suppressed Decr1-mediates mitochondrial lipid oxidation, inhibiting cardiac fibroblast proliferation and migration. Knockdown of AR produced the opposite effect. Clinically, increased WTAP and YTHDF2 levels correlate with decreased AR expression in human DCM heart tissue. We describe a mechanism wherein WTAP boosts higher mitochondrial lipid oxidation, cardiac fibroblast proliferation, and migration by enhancing AR methylation in a YTHDF2-dependent manner.

Keywords:  Biological sciences; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.107931
iScience. 2023 Oct 20. 26(10): 107949

CD38 regulates ovarian function and fecundity via NAD+ metabolism.

Rosalba Perrone, Prasanna Vadhana Ashok Kumaar, Lauren Haky, Cosmo Hahn, Rebeccah Riley, Julia Balough, Giuliana Zaza, Bikem Soygur, Kaitlyn Hung, Leandro Prado, Herbert G Kasler, Ritesh Tiwari, Hiroyuki Matsui, Genesis Vega Hormazabal, Indra Heckenbach, Morten Scheibye-Knudsen, Francesca E Duncan, Eric Verdin.

  Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD+ levels. However, the mechanisms underlying this loss of ovarian NAD+ are unclear. Here, we show that CD38, an NAD+ consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD+ levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD+ metabolism and establishing the ovarian reserve, a critical process that dictates a female's reproductive lifespan.

Keywords:  Biochemistry; Biological sciences; Physiology

DOI:  https://doi.org/10.1016/j.isci.2023.107949
Nat Commun. 2023 Oct 09. 14(1): 6304

Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis.

Yuichi Tsuchiya, Takao Seki, Kenta Kobayashi, Sachiko Komazawa-Sakon, Shigeyuki Shichino, Takashi Nishina, Kyoko Fukuhara, Kenichi Ikejima, Hidenari Nagai, Yoshinori Igarashi, Satoshi Ueha, Akira Oikawa, Shinya Tsurusaki, Soh Yamazaki, Chiharu Nishiyama, Tetuo Mikami, Hideo Yagita, Ko Okumura, Taketomo Kido, Atsushi Miyajima, Kouji Matsushima, Mai Imasaka, Kimi Araki, Toru Imamura, Masaki Ohmuraya, Minoru Tanaka, Hiroyasu Nakano.

Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that the expression of fibroblast growth factor 18 (Fgf18) is elevated in mouse livers following the induction of chronic liver fibrosis models. Deletion of Fgf18 in hepatocytes attenuates liver fibrosis; conversely, overexpression of Fgf18 promotes liver fibrosis. Single-cell RNA sequencing reveals that overexpression of Fgf18 in hepatocytes results in an increase in the number of Lrat+ hepatic stellate cells (HSCs), thereby inducing fibrosis. Mechanistically, FGF18 stimulates the proliferation of HSCs by inducing the expression of Ccnd1. Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2, in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis.

DOI: https://doi.org/10.1038/s41467-023-42058-z
Nat Immunol. 2023 Oct 09.

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

Nina Weisshaar, Sicong Ma, Yanan Ming, Alaa Madi, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Kerstin Mohr, Nora Ten Bosch, Diana Stichling, Michael Buettner, Gernot Poschet, Glynis Klinke, Michael Schulz, Nina Kunze-Rohrbach, Carolin Kerber, Isabel Madeleine Klein, Jingxia Wu, Xi Wang, Guoliang Cui.

The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.

DOI: https://doi.org/10.1038/s41590-023-01636-5
Cell Rep. 2023 Oct 12. pii: S2211-1247(23)01258-5. [Epub ahead of print]42(10): 113246

Allosterically inhibited PFKL via prostaglandin E2 withholds glucose metabolism and ovarian cancer invasiveness.

Shengmiao Chen, Yiran Wu, Yang Gao, Chenxu Wu, Yuetong Wang, Chun Hou, Miao Ren, Shuyuan Zhang, Qi Zhu, Jiali Zhang, Yufeng Yao, Mei Huang, Yingchuan B Qi, Xue-Song Liu, Tiffany Horng, Haopeng Wang, Dan Ye, Zhengjiang Zhu, Suwen Zhao, Gaofeng Fan.

  Metastasis is the leading cause of high ovarian-cancer-related mortality worldwide. Three major processes constitute the whole metastatic cascade: invasion, intravasation, and extravasation. Tumor cells often reprogram their metabolism to gain advantages in proliferation and survival. However, whether and how those metabolic alterations contribute to the invasiveness of tumor cells has yet to be fully understood. Here we performed a genome-wide CRISPR-Cas9 screening to identify genes participating in tumor cell dissemination and revealed that PTGES3 acts as an invasion suppressor in ovarian cancer. Mechanistically, PTGES3 binds to phosphofructokinase, liver type (PFKL) and generates a local source of prostaglandin E2 (PGE2) to allosterically inhibit the enzymatic activity of PFKL. Repressed PFKL leads to downgraded glycolysis and the subsequent TCA cycle for glucose metabolism. However, ovarian cancer suppresses the expression of PTGES3 and disrupts the PTGES3-PGE2-PFKL inhibitory axis, leading to hyperactivation of glucose oxidation, eventually facilitating ovarian cancer cell motility and invasiveness.

Keywords:  CP: Cancer; CP: Metabolism; CRISPR-Cas9 screening; EMT; PFKL; PGE2; PTGES3; TET2; fumarate; invasion; metastasis; ovarian cancer

DOI:  https://doi.org/10.1016/j.celrep.2023.113246
Aging Cell. 2023 Oct 13. e14000

Carnitine acetyltransferase deficiency mediates mitochondrial dysfunction-induced cellular senescence in dermal fibroblasts.

Min Ji Song, Chi-Hyun Park, Haesoo Kim, Sangbum Han, Si Hyung Lee, Dong Hun Lee, Jin Ho Chung.

  Aging is accompanied by impaired mitochondrial function and accumulation of senescent cells. Mitochondrial dysfunction contributes to senescence by increasing the levels of reactive oxygen species and compromising energy metabolism. Senescent cells secrete a senescence-associated secretory phenotype (SASP) and stimulate chronic low-grade inflammation, ultimately inducing inflammaging. Mitochondrial dysfunction and cellular senescence are two closely related hallmarks of aging; however, the key driver genes that link mitochondrial dysfunction and cellular senescence remain unclear. Here, we aimed to elucidate a novel role of carnitine acetyltransferase (CRAT) in the development of mitochondrial dysfunction and cellular senescence in dermal fibroblasts. Transcriptomic analysis of skin tissues from young and aged participants showed significantly decreased CRAT expression in intrinsically aged skin. CRAT downregulation in human dermal fibroblasts recapitulated mitochondrial changes in senescent cells and induced SASP secretion. Specifically, CRAT knockdown caused mitochondrial dysfunction, as indicated by increased oxidative stress, disruption of mitochondrial morphology, and a metabolic shift from oxidative phosphorylation to glycolysis. Mitochondrial damage induced the release of mitochondrial DNA into the cytosol, which activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NF-ĸB pathways to induce SASPs. Consistently, fibroblast-specific CRAT-knockout mice showed increased skin aging phenotypes in vivo, including decreased cell proliferation, increased SASP expression, increased inflammation, and decreased collagen density. Our results suggest that CRAT deficiency contributes to aging by mediating mitochondrial dysfunction-induced senescence.

Keywords:  carnitine acetyltransferase; cellular senescence; mitochondrial dysfunction; oxidative stress; skin aging

DOI:  https://doi.org/10.1111/acel.14000
Elife. 2023 Oct 11. pii: e86452. [Epub ahead of print]12

GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.

Jayashree Jena, Luis Miguel García-Peña, Eric T Weatherford, Alex Marti, Sarah H Bjorkman, Kevin Kato, Jivan Koneru, Jason H Chen, Randy J Seeley, E Dale Abel, Renata O Pereira.

  We previously reported that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) display induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates under baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice (Pereira et al., 2021). To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15), along with increased protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) levels in BAT. To investigate whether ATF4 induction was mediated by PERK and evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice with reduced OPA1 and PERK levels in BAT had preserved ISR activation. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to DIO and abrogated the improvements in glucose tolerance. Furthermore, GDF15 was required to improve cold-induced thermogenesis in OPA1 BKO mice. Taken together, our data indicate that PERK is dispensable to induce the ISR, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice by increasing energy expenditure.

Keywords:  GDF15; PERK; biochemistry; brown adipose tissue; chemical biology; integrated stress response; mitochondrial stress; mouse

DOI:  https://doi.org/10.7554/eLife.86452
J Transl Med. 2023 Oct 12. 21(1): 715

Myeloid PTP1B deficiency protects against atherosclerosis by improving cholesterol homeostasis through an AMPK-dependent mechanism.

Helk Oliver, Dekeryte Ruta, Dawn Thompson, Sarah Kamli-Salino, Sam Philip, Heather M Wilson, Nimesh Mody, Mirela Delibegovic.

   OBJECTIVE: Atherosclerosis is a chronic inflammatory process induced by the influx and entrapment of excess lipoproteins into the intima media of arteries. Previously, our lab demonstrated that systemic PTP1B inhibition protects against atherosclerosis in preclinical LDLR-/- models. Similarly, it was shown that myeloid-specific PTP1B ablation decreases plaque formation and ameliorates dyslipidaemia in the ApoE-/- model of atherosclerosis. We hypothesized that the relevant improvements in dyslipidaemia following modification of PTP1B activation may either result from changes in hepatic cholesterol biosynthesis and/or increased uptake and degradation by liver-resident macrophages. We examined this in animal models and patients with coronary artery disease.
METHODS: In this study, we determined the cholesterol-lowering effect of myeloid-PTP1B deletion in mice fed a high-fat high-cholesterol diet and examined effects on total cholesterol levels and lipoprotein profiles. We also determined the effects of PTP1B inhibition to oxLDL-C challenge on foam cell formation and cholesterol efflux in human monocytes/macrophages.
RESULTS: We present evidence that myeloid-PTP1B deficiency significantly increases the affinity of Kupffer cells for ApoB containing lipoproteins, in an IL10-dependent manner. We also demonstrate that PTP1B inhibitor, MSI-1436, treatment decreased foam cell formation in Thp1-derived macrophages and increased macrophage cholesterol efflux to HDL in an AMPK-dependent manner. We present evidence of three novel and distinct mechanisms regulated by PTP1B: an increase in cholesterol efflux from foam cells, decreased uptake of lipoproteins into intra-lesion macrophages in vitro and a decrease of circulating LDL-C and VLDL-C in vivo.
CONCLUSIONS: Overall, these results suggest that myeloid-PTP1B inhibition has atheroprotective effects through improved cholesterol handling in atherosclerotic lesions, as well as increased reverse cholesterol transport. Trial registration Research registry, researchregistry 3235. Registered 07 November 2017, https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5a01d0fce7e1904e93e0aac5/ .

Keywords:  Atherosclerosis; Cholesterol metabolism; Myeloid cells; PTP1B

DOI:  https://doi.org/10.1186/s12967-023-04598-2
Biochemistry. 2023 Oct 09.

Cardiolipin Regulates the Activity of the Mitochondrial ABC Transporter ABCB10.

Tianqi Zhang, Jixing Lyu, Yun Zhu, Arthur Laganowsky.

The ATP-binding cassette (ABC) transporter ABCB10 resides in the inner membrane of mitochondria and is implicated in erythropoiesis. Mitochondria from different cell types share some specific characteristics, one of which is the high abundance of cardiolipin. Although previous studies have provided insight into ABCB10, the affinity and selectivity of this transporter toward lipids, particularly those found in the mitochondria, remain poorly understood. Here, native mass spectrometry is used to directly monitor the binding events of lipids to human ABCB10. The results reveal that ABCB10 binds avidly to cardiolipin with an affinity significantly higher than that of other phospholipids. The first three binding events of cardiolipin display positive cooperativity, which is suggestive of specific cardiolipin-binding sites on ABCB10. Phosphatidic acid is the second-best binder of the lipids investigated. The bulk lipids, phosphatidylcholine and phosphatidylethanolamine, display the weakest binding affinity for ABCB10. Other lipids bind ABCB10 with a similar affinity. Functional assays show that cardiolipin regulates the ATPase activity of ABCB10 in a dose-dependent fashion. ATPase activity of ABCB10 was also impacted in the presence of other lipids but to a lesser extent than cardiolipin. Taken together, ABCB10 has a high binding affinity for cardiolipin, and this lipid also regulates the ATPase activity of the transporter.

DOI: https://doi.org/10.1021/acs.biochem.3c00417