bims-mepmim 2023-10-01 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2023‒10‒01
25 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Inhibition of fatty acid oxidation enables heart regeneration in adult mice.
Calponin 2 regulates ketogenesis to mitigate acute kidney injury.
Low dietary fiber intake impairs small intestinal Th17 and intraepithelial T cell development over generations.
Microenvironmental stiffness induces metabolic reprogramming in glioblastoma.
ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control.
TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.
Iron drives anabolic metabolism through active histone demethylation and mTORC1.
A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators.
Regulated adipose tissue-specific expression of human AGPAT2 in lipodystrophic Agpat2-null mice results in regeneration of adipose tissue.
Coculturing Liver Cancer Cells and Monocytes in Spheroids Conditions Monocytes to Adopt Tumor-associated Macrophage Phenotypes that Favor Tumor Growth via Cholesterol Metabolism.
Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.
Differences in hepatocellular iron metabolism underlie sexual dimorphism in hepatocyte ferroptosis.
Functional screening and rational design of compounds targeting GPR132 to treat diabetes.
Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis.
Identifying G protein-coupled receptors involved in adipose tissue function using the innovative RNA-seq database FATTLAS.
Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models.
Iron Metabolism of the Skin: Recycling versus Release.
Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes.
Dehydroascorbic acid sensitizes cancer cells to system xc- inhibition-induced ferroptosis by promoting lipid droplet peroxidation.
Natural product P57 induces hypothermia through targeting pyridoxal kinase.
Proteome census upon nutrient stress reveals Golgiphagy membrane receptors.
The bisphosphonates alendronate and zoledronate induce adaptations of aerobic metabolism in permanent human endothelial cells.
GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway.
Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis.
Early fate decision for mitochondrially encoded proteins by a molecular triage.

Nature. 2023 Sep 27.

Inhibition of fatty acid oxidation enables heart regeneration in adult mice.

Xiang Li, Fan Wu, Stefan Günther, Mario Looso, Carsten Kuenne, Ting Zhang, Marion Wiesnet, Stephan Klatt, Sven Zukunft, Ingrid Fleming, Gernot Poschet, Astrid Wietelmann, Ann Atzberger, Michael Potente, Xuejun Yuan, Thomas Braun.

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 regeneration1,2. 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. 3). 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.

DOI: https://doi.org/10.1038/s41586-023-06585-5
JCI Insight. 2023 Sep 26. pii: e170521. [Epub ahead of print]

Calponin 2 regulates ketogenesis to mitigate acute kidney injury.

Yuan Gui, Zachary Palanza, Priya R Gupta, Hanwen Li, Yuchen Pan, Yuanyuan Wang, Geneva R Hargis, Donald L Kreutzer, Yanlin Wang, Sheldon I Bastacky, Yansheng Liu, Silvia Liu, Dong Zhou.

  Calponin 2 (CNN2) is a prominent actin stabilizer. It regulates fatty acid oxidation (FAO) by interacting with estrogen receptor 2 (ESR2) to determine kidney fibrosis. However, whether CNN2 is actively involved in acute kidney injury (AKI) remains unclear. Here, we report that CNN2 was induced in human and animal kidneys after AKI. Knockdown of CNN2 preserved kidney function, mitigated tubular cell death and inflammation, and promoted cell proliferation. Distinct from kidney fibrosis, proteomics showed that the key elements in the FAO pathway have few changes during AKI, but we identified that 3-hydroxymethylglutaryl-CoA synthase 2 (Hmgcs2), a rate-limiting enzyme of endogenous ketogenesis that promotes cell self-renewal, was markedly increased in CNN2 knockdown kidneys. The ketone bodies β-hydroxybutyrate and ATP production were increased in CNN2 knockdown mice. Mechanistically, CNN2 interacts with ESR2 to negatively regulate activities of mitochondrial sirtuin 5. Activated sirtuin 5 subsequently desuccinylates Hmgcs2 to produce energy for mitigating AKI. Understanding CNN2-mediated discrete fine-tuning of protein posttranslational modification is critical to optimize organ performance after AKI.

Keywords:  Apoptosis; Mouse models; Nephrology; Pericytes

DOI:  https://doi.org/10.1172/jci.insight.170521
Cell Rep. 2023 Sep 27. pii: S2211-1247(23)01152-X. [Epub ahead of print]42(10): 113140

Low dietary fiber intake impairs small intestinal Th17 and intraepithelial T cell development over generations.

Charlotte J Royer, Naomi Rodriguez-Marino, Madelyn D Yaceczko, Dormarie E Rivera-Rodriguez, Thomas R Ziegler, Luisa Cervantes-Barragan.

  Dietary fiber strongly impacts the microbiota. Here, we show that a low-fiber diet changes the small intestinal (SI) microbiota and impairs SI Th17, TCRαβ+CD8αβ+ and TCRαβ+CD8αα+ intraepithelial T cell development. We restore T cell development with dietary fiber supplementation, but this defect becomes persistent over generations with constant low-fiber diets. Offspring of low-fiber diet-fed mice have reduced SI T cells even after receiving a fiber-rich diet due to loss of bacteria important for T cell development. In these mice, only a microbiota transplant from a fiber-rich diet-fed mouse and a fiber-rich diet can restore T cell development. Low-fiber diets reduce segmented filamentous bacteria (SFB) abundance, impairing its vertical transmission. SFB colonization and a fiber-rich diet partially restore T cell development. Finally, we observe that low-fiber diet-induced T cell defects render mice more susceptible to Citrobacter rodentium infection. Together, these results demonstrate the importance of fiber to microbiota vertical transmission and host immune system development.

Keywords:  CD8αβ(+) IEL; CP: Immunology; CP: Microbiology; IEL T cells; Th17; dietary fiber; interleukin 17; intraepithelial; microbiota; segmented filamentous bacteria

DOI:  https://doi.org/10.1016/j.celrep.2023.113140
Cell Rep. 2023 Sep 26. pii: S2211-1247(23)01187-7. [Epub ahead of print]42(10): 113175

Microenvironmental stiffness induces metabolic reprogramming in glioblastoma.

Alireza Sohrabi, Austin E Y T Lefebvre, Mollie J Harrison, Michael C Condro, Talia M Sanazzaro, Gevick Safarians, Itay Solomon, Soniya Bastola, Shadi Kordbacheh, Nadia Toh, Harley I Kornblum, Michelle A Digman, Stephanie K Seidlits.

  The mechanical properties of solid tumors influence tumor cell phenotype and the ability to invade surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state, which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peritumoral brain tissues, but tumor stiffness is heterogeneous where tumor edges are softer than the tumor core. We then developed 3D scaffolds with μ-compressive moduli resembling either stiffer tumor core or softer peritumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis, which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells.

Keywords:  CP: Cancer; CP: Metabolism; extracellular matrix; tissue mechanics

DOI:  https://doi.org/10.1016/j.celrep.2023.113175
Cell Rep. 2023 Sep 23. pii: S2211-1247(23)01175-0. [Epub ahead of print]42(10): 113163

ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control.

Yimeng Gao, Joshua T Zimmer, Radovan Vasic, Chengyang Liu, Rana Gbyli, Shu-Jian Zheng, Amisha Patel, Wei Liu, Zhihong Qi, Yaping Li, Raman Nelakanti, Yuanbin Song, Giulia Biancon, Andrew Z Xiao, Sarah Slavoff, Richard G Kibbey, Richard A Flavell, Matthew D Simon, Toma Tebaldi, Hua-Bing Li, Stephanie Halene.

  N6-methyladenosine (m6A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m6A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m6A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and instability of oxoglutarate-dehydrogenase (Ogdh) messenger RNA and reduction of OGDH protein levels. Limited OGDH availability slows the tricarboxylic acid (TCA) cycle with accumulation of α-ketoglutarate (α-KG) and conversion of α-KG into L-2-hydroxyglutarate (L-2-HG). L-2-HG inhibits energy production in both murine and human hematopoietic cells in vitro. Impaired mitochondrial energy production confers competitive disadvantage to HSPCs and limits clonogenicity of Mll-AF9-induced leukemia. Our study uncovers a mechanism whereby the RNA m6A demethylase ALKBH5 regulates the stability of metabolic enzyme transcripts, thereby controlling energy metabolism in hematopoiesis and leukemia.

Keywords:  ALKBH5; ATP production; CP: Molecular biology; CP: Stem cell research; OXPHOS; RNA stability; energy metabolism; hematopoietic stem and progenitor cells; leukemia; m(6)A modification; oxidative phosphorylation; stress hematopoiesis

DOI:  https://doi.org/10.1016/j.celrep.2023.113163
Nat Commun. 2023 Sep 29. 14(1): 6099

TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.

Donghua Hu, Min Tan, Dongliang Lu, Brian Kleiboeker, Xuejing Liu, Hongsuk Park, Alexxai V Kravitz, Kooresh I Shoghi, Yu-Hua Tseng, Babak Razani, Akihiro Ikeda, Irfan J Lodhi.

Mitochondrial morphology, which is controlled by mitochondrial fission and fusion, is an important regulator of the thermogenic capacity of brown adipocytes. Adipose-specific peroxisome deficiency impairs thermogenesis by inhibiting cold-induced mitochondrial fission due to decreased mitochondrial membrane content of the peroxisome-derived lipids called plasmalogens. Here, we identify TMEM135 as a critical mediator of the peroxisomal regulation of mitochondrial fission and thermogenesis. Adipose-specific TMEM135 knockout in mice blocks mitochondrial fission, impairs thermogenesis, and increases diet-induced obesity and insulin resistance. Conversely, TMEM135 overexpression promotes mitochondrial division, counteracts obesity and insulin resistance, and rescues thermogenesis in peroxisome-deficient mice. Mechanistically, thermogenic stimuli promote association between peroxisomes and mitochondria and plasmalogen-dependent localization of TMEM135 in mitochondria, where it mediates PKA-dependent phosphorylation and mitochondrial retention of the fission factor Drp1. Together, these results reveal a previously unrecognized inter-organelle communication regulating mitochondrial fission and energy homeostasis and identify TMEM135 as a potential target for therapeutic activation of BAT.

DOI: https://doi.org/10.1038/s41467-023-41849-8
Nat Cell Biol. 2023 Sep 25.

Iron drives anabolic metabolism through active histone demethylation and mTORC1.

Jason S Shapiro, Hsiang-Chun Chang, Yuki Tatekoshi, Zibo Zhao, Zohra Sattar Waxali, Bong Jin Hong, Haimei Chen, Justin A Geier, Elizabeth T Bartom, Adam De Jesus, Farnaz K Nejad, Amir Mahmoodzadeh, Tatsuya Sato, Lucia Ramos-Alonso, Antonia Maria Romero, Maria Teresa Martinez-Pastor, Shang-Chuan Jiang, Shiv K Sah-Teli, Liming Li, David Bentrem, Gary Lopaschuk, Issam Ben-Sahra, Thomas V O'Halloran, Ali Shilatifard, Sergi Puig, Joy Bergelson, Peppi Koivunen, Hossein Ardehali.

All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.

DOI: https://doi.org/10.1038/s41556-023-01225-6
Nat Commun. 2023 Sep 25. 14(1): 5971

A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators.

Yi-Cheng Chang, Hsiao-Lin Lee, Wenjin Yang, Meng-Lun Hsieh, Cai-Cin Liu, Tung-Yuan Lee, Jing-Yong Huang, Jiun-Yi Nong, Fu-An Li, Hsiao-Li Chuang, Zhi-Zhong Ding, Wei-Lun Su, Li-Yun Chueh, Yi-Ting Tsai, Che-Hong Chen, Daria Mochly-Rosen, Lee-Ming Chuang.

Obesity and type 2 diabetes have reached pandemic proportion. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal. A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We find that male Aldh2 knock-in mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver due to reduced adaptive thermogenesis and energy expenditure. We find reduced activity of ALDH2 of the brown adipose tissue from the male Aldh2 homozygous knock-in mice. Proteomic analyses of the brown adipose tissue from the male Aldh2 knock-in mice identifies increased 4-hydroxynonenal-adducted proteins involved in mitochondrial fatty acid oxidation and electron transport chain, leading to markedly decreased fatty acid oxidation rate and mitochondrial respiration of brown adipose tissue, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble, potent, and highly selective ALDH2 activator. AD-9308 treatment ameliorates diet-induced obesity and fatty liver, and improves glucose homeostasis in both male Aldh2 wild-type and knock-in mice. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for metabolic diseases.

DOI: https://doi.org/10.1038/s41467-023-41570-6
iScience. 2023 Oct 20. 26(10): 107806

Regulated adipose tissue-specific expression of human AGPAT2 in lipodystrophic Agpat2-null mice results in regeneration of adipose tissue.

Anil K Agarwal, Katie Tunison, Goncalo Vale, Jeffrey G McDonald, Xilong Li, Philipp E Scherer, Jay D Horton, Abhimanyu Garg.

  Genetic loss of Agpat2 in humans and mice results in congenital generalized lipodystrophy with near-total loss of adipose tissue and predisposition to develop insulin resistance, diabetes mellitus, hepatic steatosis, and hypertriglyceridemia. The mechanism by which Agpat2 deficiency results in loss of adipose tissue remains unknown. We studied this by re-expressing human AGPAT2 (hAGPAT2) in Agpat2-null mice, regulated by doxycycline. In both sexes of Agpat2-null mice, adipose-tissue-specific re-expression of hAGPAT2 resulted in partial regeneration of both white and brown adipose tissue (but only 30%-50% compared with wild-type mice), which had molecular signatures of adipocytes, including leptin secretion. Furthermore, the stromal vascular fraction cells of regenerated adipose depots differentiated ex vivo only with doxycycline, suggesting the essential role of Agpat2 in adipocyte differentiation. Turning off expression of hAGPAT2 in vivo resulted in total loss of regenerated adipose tissue, clear evidence that Agpat2 is essential for adipocyte differentiation in vivo.

Keywords:  cell biology; cellular physiology; physiology

DOI:  https://doi.org/10.1016/j.isci.2023.107806
J Leukoc Biol. 2023 Sep 23. pii: qiad114. [Epub ahead of print]

Coculturing Liver Cancer Cells and Monocytes in Spheroids Conditions Monocytes to Adopt Tumor-associated Macrophage Phenotypes that Favor Tumor Growth via Cholesterol Metabolism.

Pornlapat Keawvilai, Patipark Kueanjinda, Jeerameth Klomsing, Tanapat Palaga.

  Tumor-infiltrating immune cells and their crosstalk with cancer cells in the tumor microenvironment (TME) play a crucial role in shaping tumor progression and response to therapy. We utilized three-dimension (3D) liver cancer spheroids incorporating human primary monocytes to investigate the crosstalk between tumor-associated macrophages (TAMs) and Hepatocellular carcinoma (HCC) cells, HepG2 and PLC/PRF5. Using multiplexed gene expression panels, the critical pathways involved in shaping primary human monocytes to adopt TAMs phenotypes were identified. Specific inhibitor for identified pathway was used to explore its involvement in polarization of TAMs. In the cocultured spheroids comprised of the human HCC cell lines, the infiltrating monocytes resembled protumor M2-like macrophage phenotypes. Gene expression panels of the infiltrating monocytes demonstrated that the upregulated genes were enriched in the cholesterol metabolism pathway. Cholesterol metabolism-related genes were upregulated together with the nuclear receptors, PPARG and LXR. When lysosomal acid lipase (LAL), the key enzyme necessary for the hydrolysis of lipoprotein, was inhibited, infiltrating monocytes in 3D spheroid coculture showed significantly decreased M2 marker and lipid uptake receptor expression as well as increased cellular lipid content, which indicated that cholesterol metabolism was important for conditioning the TAMs. Moreover, LAL inhibition reduced the spheroid growth and invasiveness of HCC cell lines. siRNA-mediated LAL silencing in monocytes yielded similar results upon spheroid coculture. These data indicated that liver cancer cells and infiltrating monocytes participate in crosstalk via cholesterol metabolism to condition monocytes toward TAMs, which favors tumor growth and survival, thereby promoting liver cancer progression.

Keywords:  cholesterol metabolism; liver cancer; monocytes; tumor-associated macrophages

DOI:  https://doi.org/10.1093/jleuko/qiad114
Nat Cancer. 2023 Sep 25.

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

Jacqueline Taylor, Leonie Uhl, Iris Moll, Sana Safatul Hasan, Lena Wiedmann, Jakob Morgenstern, Benedetto Daniele Giaimo, Tobias Friedrich, Elisenda Alsina-Sanchis, Francesca De Angelis Rigotti, Ronja Mülfarth, Sarah Kaltenbach, Darius Schenk, Felix Nickel, Thomas Fleming, David Sprinzak, Carolin Mogler, Thomas Korff, Adrian T Billeter, Beat P Müller-Stich, Mauricio Berriel Diaz, Tilman Borggrefe, Stephan Herzig, Maria Rohm, Juan Rodriguez-Vita, Andreas Fischer.

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.

DOI: https://doi.org/10.1038/s43018-023-00622-y
Redox Biol. 2023 Sep 17. pii: S2213-2317(23)00293-8. [Epub ahead of print]67 102892

Differences in hepatocellular iron metabolism underlie sexual dimorphism in hepatocyte ferroptosis.

Hui Tao, Hamid Y Dar, Cheng Tian, Somesh Banerjee, Evan S Glazer, Shanthi Srinivasan, Liqin Zhu, Roberto Pacifici, Peijian He.

  Males show higher incidence and severity than females in hepatic injury and many liver diseases, but the mechanisms are not well understood. Ferroptosis, an iron-mediated lipid peroxidation-dependent death, plays an important role in the pathogenesis of liver diseases. We determined whether hepatocyte ferroptosis displays gender difference, accounting for sexual dimorphism in liver diseases. Compared to female hepatocytes, male hepatocytes were much more vulnerable to ferroptosis by iron and pharmacological inducers including RSL3 and iFSP1. Male but not female hepatocytes exhibited significant increases in mitochondrial Fe2+ and mitochondrial ROS (mtROS) contents. Female hepatocytes showed a lower expression of iron importer transferrin receptor 1 (TfR1) and mitochondrial iron importer mitoferrin 1 (Mfrn1), but a higher expression of iron storage protein ferritin heavy chain 1 (FTH1). It is well known that TfR1 expression is positively correlated with ferroptosis. Herein, we showed that silencing FTH1 enhanced while knockdown of Mfrn1 decreased ferroptosis in HepG2 cells. Removing female hormones by ovariectomy (OVX) did not dampen but rather enhanced hepatocyte resistance to ferroptosis. Mechanistically, OVX potentiated the decrease in TfR1 and increase in FTH1 expression. OVX also increased FSP1 expression in ERK-dependent manner. Elevation in FSP1 suppressed mitochondrial Fe2+ accumulation and mtROS production, constituting a novel mechanism of FSP1-mediated inhibition of ferroptosis. In conclusion, differences in hepatocellular iron handling between male and female account, at least in part, for sexual dimorphism in induced ferroptosis of the hepatocytes.

Keywords:  Antioxidant defense; FSP1; FTH1; Mfrn1; Mitochondrial ROS; Ovariectomy

DOI:  https://doi.org/10.1016/j.redox.2023.102892
Nat Metab. 2023 Sep 28.

Functional screening and rational design of compounds targeting GPR132 to treat diabetes.

Jia-Le Wang, Xiao-Dong Dou, Jie Cheng, Ming-Xin Gao, Guo-Feng Xu, Wei Ding, Jin-Hui Ding, Yu Li, Si-Han Wang, Zhao-Wei Ji, Xin-Yi Zhao, Tong-Yu Huo, Cai-Fang Zhang, Ya-Meng Liu, Xue-Ying Sha, Jia-Rui Gao, Wen-Hui Zhang, Yong Hao, Cheng Zhang, Jin-Peng Sun, Ning Jiao, Xiao Yu.

Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes.

DOI: https://doi.org/10.1038/s42255-023-00899-4
Nat Commun. 2023 Sep 28. 14(1): 6047

Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis.

Shanshan Guo, Yonghao Feng, Xiaopeng Zhu, Xinyi Zhang, Hui Wang, Ruwen Wang, Qiongyue Zhang, Yiming Li, Yan Ren, Xin Gao, Hua Bian, Tiemin Liu, Huanqing Gao, Xingxing Kong.

Inter-organ crosstalk has gained increasing attention in recent times; however, the underlying mechanisms remain unclear. In this study, we elucidate an endocrine pathway that is regulated by skeletal muscle interferon regulatory factor (IRF) 4, which manipulates liver pathology. Skeletal muscle specific IRF4 knockout (F4MKO) mice exhibited ameliorated hepatic steatosis, inflammation, and fibrosis, without changes in body weight, when put on a nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis results suggested that follistatin-like protein 1 (FSTL1) may constitute a link between muscles and the liver. Dual luciferase assays showed that IRF4 can transcriptionally regulate FSTL1. Further, inducing FSTL1 expression in the muscles of F4MKO mice is sufficient to restore liver pathology. In addition, co-culture experiments confirmed that FSTL1 plays a distinct role in various liver cell types via different receptors. Finally, we observed that the serum FSTL1 level is positively correlated with NASH progression in humans. These data indicate a signaling pathway involving IRF4-FSTL1-DIP2A/CD14, that links skeletal muscle cells to the liver in the pathogenesis of NASH.

DOI: https://doi.org/10.1038/s41467-023-41832-3
iScience. 2023 Oct 20. 26(10): 107841

Identifying G protein-coupled receptors involved in adipose tissue function using the innovative RNA-seq database FATTLAS.

Isabell Kaczmarek, Isabel Wower, Katja Ettig, Christina Katharina Kuhn, Robert Kraft, Kathrin Landgraf, Antje Körner, Torsten Schöneberg, Susanne Horn, Doreen Thor.

  G protein-coupled receptors (GPCRs) modulate the function of adipose tissue (AT) in general and of adipocytes, specifically. Although it is well-established that GPCRs are widely expressed in AT, their repertoire as well as their regulation and function in (patho)physiological conditions (e.g., obesity) is not fully resolved. Here, we established FATTLAS, an interactive public database, for improved access and analysis of RNA-seq data of mouse and human AT. After extracting the GPCRome of non-obese and obese individuals, highly expressed and differentially regulated GPCRs were identified. Exemplarily, we describe four receptors (GPR146, MRGPRF, FZD5, PTGER2) and analyzed their functions in a (pre)adipocyte cell model. Besides all receptors being involved in adipogenesis, MRGPRF is essential for adipocyte viability and regulates cAMP levels, while GPR146 modulates adipocyte lipolysis via constitutive activation of Gi proteins. Taken together, by implementing and using FATTLAS we describe four hitherto unrecognized GPCRs associated with AT function and adipogenesis.

Keywords:  Bioinformatics; Biological sciences; Molecular biology; Natural sciences; Physiology

DOI:  https://doi.org/10.1016/j.isci.2023.107841
Nat Commun. 2023 Sep 26. 14(1): 5989

Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models.

Emily Howard, Benjamin P Hurrell, Doumet Georges Helou, Pedram Shafiei-Jahani, Spyridon Hasiakos, Jacob Painter, Sonal Srikanth, Yousang Gwack, Omid Akbari.

Ca2+ entry via Ca2+ release-activated Ca2+ (CRAC) channels is a predominant mechanism of intracellular Ca2+ elevation in immune cells. Here we show the immunoregulatory role of CRAC channel components Orai1 and Orai2 in Group 2 innate lymphoid cells (ILC2s), that play crucial roles in the induction of type 2 inflammation. We find that blocking or genetic ablation of Orai1 and Orai2 downregulates ILC2 effector function and cytokine production, consequently ameliorating the development of ILC2-mediated airway inflammation in multiple murine models. Mechanistically, ILC2 metabolic and mitochondrial homeostasis are inhibited and lead to the upregulation of reactive oxygen species production. We confirm our findings in human ILC2s, as blocking Orai1 and Orai2 prevents the development of airway hyperreactivity in humanized mice. Our findings have a broad impact on the basic understanding of Ca2+ signaling in ILC2 biology, providing potential insights into the development of therapies for the treatment of allergic and atopic inflammatory diseases.

DOI: https://doi.org/10.1038/s41467-023-41065-4
Metabolites. 2023 Sep 12. pii: 1005. [Epub ahead of print]13(9):

Iron Metabolism of the Skin: Recycling versus Release.

Marta Surbek, Supawadee Sukseree, Leopold Eckhart.

  The skin protects the body against exogenous stressors. Its function is partially achieved by the permanent regeneration of the epidermis, which requires high metabolic activity and the shedding of superficial cells, leading to the loss of metabolites. Iron is involved in a plethora of important epidermal processes, including cellular respiration and detoxification of xenobiotics. Likewise, microorganisms on the surface of the skin depend on iron, which is supplied by the turnover of epithelial cells. Here, we review the metabolism of iron in the skin with a particular focus on the fate of iron in epidermal keratinocytes. The iron metabolism of the epidermis is controlled by genes that are differentially expressed in the inner and outer layers of the epidermis, establishing a system that supports the recycling of iron and counteracts the release of iron from the skin surface. Heme oxygenase-1 (HMOX1), ferroportin (SLC40A1) and hephaestin-like 1 (HEPHL1) are constitutively expressed in terminally differentiated keratinocytes and allow the recycling of iron from heme prior to the cornification of keratinocytes. We discuss the evidence for changes in the epidermal iron metabolism in diseases and explore promising topics of future studies of iron-dependent processes in the skin.

Keywords:  epidermis; epithelium; ferroportin; ferroptosis; hair; heme oxygenase; hephaestin; keratinocytes; microbiome; oxidative stress

DOI:  https://doi.org/10.3390/metabo13091005
Redox Rep. 2023 Dec;28(1): 2260646

Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes.

Yifan Liu, Kaimin Wu, Yinkun Fu, Wenyan Li, Xu-Yun Zhao.

  Primary hepatocytes are widely used as a tool for studying metabolic function and regulation in the liver. However, the metabolic properties of primary hepatocytes are gradually lost after isolation. Here, we illustrated that fatty acid metabolism is the major compromised metabolic process in isolated primary hepatocytes, along with drastically decreased GSH and ROS content, while lipid peroxidation is increased. Gain- and loss-of-function studies revealed that Slc7a11 expression is critical in maintaining fatty acid metabolism and facilitating hormone-induced fatty acid metabolic events, which is synergistic with dexamethasone treatment. Intriguingly, Slc7a11 expression and dexamethasone treatment cooperatively upregulated AKT and AMPK signaling and mitochondrial complex expression in primary hepatocytes. Furthermore, direct treatment with reduced GSH or inhibition of ferroptosis is sufficient to drive protective effects on fatty acid metabolism in primary hepatocytes. Our results demonstrate that Slc7a11 expression in isolated primary hepatocytes induces GSH production, which protects against ferroptosis, to increase fatty acid metabolic gene expression, AKT and AMPK signaling and mitochondrial function in synergy with dexamethasone treatment, thereby efficiently preserving primary hepatocyte metabolic signatures, thus providing a promising approach to better reserve primary hepatocyte metabolic activities after isolation to potentially improve the understanding of liver biological functions from studies using primary hepatocytes.

Keywords:  AKT/AMPK signaling‌; GSH; Slc7a11; dexamethasone; fatty acid metabolism; ferroptosis; mitochondrial homeostasis; primary hepatocytes

DOI:  https://doi.org/10.1080/13510002.2023.2260646
Cell Death Dis. 2023 Sep 27. 14(9): 637

Dehydroascorbic acid sensitizes cancer cells to system xc- inhibition-induced ferroptosis by promoting lipid droplet peroxidation.

Luciano Ferrada, María José Barahona, Matías Vera, Brent R Stockwell, Francisco Nualart.

Since the discovery of ferroptosis, it has been postulated that this type of cell death could be utilized in treatments for cancer. Unfortunately, several highly aggressive tumor models are resistant to the pharmacological induction of ferroptosis. However, with the use of combined therapies, it is possible to recover sensitivity to ferroptosis in certain cellular models. Here, we discovered that co-treatment with the metabolically stable ferroptosis inducer imidazole ketone erastin (IKE) and the oxidized form of vitamin C, dehydroascorbic acid (DHAA), is a powerful therapy that induces ferroptosis in tumor cells previously resistant to IKE-induced ferroptosis. We determined that DHAA and IKE + DHAA delocalize and deplete GPX4 in tumor cells, specifically inducing lipid droplet peroxidation, which leads to ferroptosis. Moreover, in vivo, IKE + DHAA has high efficacy with regard to the eradication of highly aggressive tumors such as glioblastomas. Thus, the use of IKE + DHAA could be an effective and safe therapy for the eradication of difficult-to-treat cancers.

DOI: https://doi.org/10.1038/s41419-023-06153-9
Nat Commun. 2023 Sep 26. 14(1): 5984

Natural product P57 induces hypothermia through targeting pyridoxal kinase.

Ruina Wang, Lei Xiao, Jianbo Pan, Guangsen Bao, Yunmei Zhu, Di Zhu, Jun Wang, Chengfeng Pei, Qinfeng Ma, Xian Fu, Ziruoyu Wang, Mengdi Zhu, Guoxiang Wang, Ling Gong, Qiuping Tong, Min Jiang, Junchi Hu, Miao He, Yun Wang, Tiejun Li, Chunmin Liang, Wei Li, Chunmei Xia, Zengxia Li, Dengke K Ma, Minjia Tan, Jun Yan Liu, Wei Jiang, Cheng Luo, Biao Yu, Yongjun Dang.

Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.

DOI: https://doi.org/10.1038/s41467-023-41435-y
Nature. 2023 Sep 27.

Proteome census upon nutrient stress reveals Golgiphagy membrane receptors.

Kelsey L Hickey, Sharan Swarup, Ian R Smith, Julia C Paoli, Enya Miguel Whelan, Joao A Paulo, J Wade Harper.

During nutrient stress, macroautophagy degrades cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodeling the proteome1,2. While machinery responsible for initiation of macroautophagy is well characterized3,4, our understanding of the extent to which individual proteins, protein complexes and organelles are selected for autophagic degradation, and the underlying targeting mechanisms is limited. Here, we use orthogonal proteomic strategies to provide a spatial proteome census of autophagic cargo during nutrient stress in mammalian cells. We find that macroautophagy has selectivity for recycling membrane-bound organelles (principally Golgi and ER). Through autophagic cargo prioritization, we identify a complex of membrane-embedded proteins, YIPF3 and YIPF4, as receptors for Golgiphagy. During nutrient stress, YIPF3 and YIPF4 interact with ATG8s via LIR motifs and are mobilized into autophagosomes that traffic to lysosomes in a process that requires the canonical autophagic machinery. Cells lacking YIPF3 or YIPF4 are selectively defective in elimination of a specific cohort of Golgi membrane proteins during nutrient stress. Moreover, YIPF3/4 play an analogous role in Golgi remodeling during programmed conversion of stem cells to the neuronal lineage in vitro. Collectively, this study reveals prioritization of membrane protein cargo during nutrient stress-dependent proteome remodeling and identifies an unanticipated Golgi remodeling pathway requiring membrane-embedded receptors.

DOI: https://doi.org/10.1038/s41586-023-06657-6
Sci Rep. 2023 Sep 27. 13(1): 16205

The bisphosphonates alendronate and zoledronate induce adaptations of aerobic metabolism in permanent human endothelial cells.

Adrianna Budzinska, Lukasz Galganski, Wieslawa Jarmuszkiewicz.

Nitrogen-containing bisphosphonates (NBPs), compounds that are widely used in the treatment of bone disorders, may cause side effects related to endothelial dysfunction. The aim of our study was to investigate the effects of chronic 6-day exposure to two common bone-preserving drugs, alendronate and zoledronate, on endothelial function and oxidative metabolism of cultured human endothelial cells (EA.hy926). NBPs reduced cell viability, induced oxidative stress and a pro-inflammatory state and downregulated the prenylation-dependent ERK1/2 signaling pathway in endothelial cells. In addition, NBPs induced increased anaerobic respiration and slightly increased oxidative mitochondrial capacity, affecting mitochondrial turnover through reduced mitochondrial fission. Moreover, by blocking the mevalonate pathway, NBPs caused a significant decrease in the level of coenzyme Q10, thereby depriving endothelial cells of an important antioxidant and mitochondrial electron carrier. This resulted in increased formation of reactive oxygen species (ROS), upregulation of antioxidant enzymes, and impairment of mitochondrial respiratory function. A general decrease in mitochondrial respiration occurred with stronger reducing fuels (pyruvate and glutamate) in NBP-treated intact endothelial cells, and significantly reduced phosphorylating respiration was observed during the oxidation of succinate and especially malate in NBP-treated permeabilized endothelial cells. The observed changes in oxidative metabolism caused a decrease in ATP levels and an increase in oxygen levels in NBP-treated cells. Thus, NBPs modulate the energy metabolism of endothelial cells, leading to alterations in the cellular energy state, coenzyme Q10 redox balance, mitochondrial respiratory function, and mitochondrial turnover.

DOI: https://doi.org/10.1038/s41598-023-43377-3
Oncogene. 2023 Sep 25.

GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway.

Jiamin Zhou, Weiqi Xu, Yibin Wu, Miao Wang, Ning Zhang, Longrong Wang, Yun Feng, Ti Zhang, Lu Wang, Anrong Mao.

Liver metastases are commonly detected in a range of malignancies including colorectal cancer (CRC), unfortunately no effectively strategies for CRC liver metastasis (CRLM). In this study, we found GPR37 expression dramatically increased in human CRLM specimens and associated poor prognosis. GPR37 depletion greatly suppressed the liver metastasis in the mouse models of CRLM. Functional experiments showed that GPR37 knockdown inhibited the growth by reducing the glycolysis of CRC cells. Also, GPR37 knockdown in tumor cells produced decreased levels of two chemokines involved in neutrophil accumulation, which abrogated neutrophil recruitment in the tumor microenvironment of CRLM. Finally, the mechanism studies revealed that GPR37 could activate the hippo pathway, thereby promoting LDHA expression and glycolysis. This leads to increased lactylation of H3K18la, resulting in up-regulation of CXCL1 and CXCL5. These results support a role of the GPR37 in modulating the tumor metabolism and microenvironment in CRLM and GPR37 could be a potential therapeutic target.

DOI: https://doi.org/10.1038/s41388-023-02841-0
Sci Transl Med. 2023 Sep 27. 15(715): eade3157

Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis.

Meghan Mooring, Grace A Yeung, Panu Luukkonen, Silvia Liu, Muhammad Waqas Akbar, Gary J Zhang, Oluwashanu Balogun, Xuemei Yu, Rigen Mo, Kari Nejak-Bowen, Masha V Poyurovsky, Carmen J Booth, Liza Konnikova, Gerald I Shulman, Dean Yimlamai.

Obesity is increasing worldwide and leads to a multitude of metabolic diseases, including cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis (NASH). Cysteine-rich angiogenic inducer 61 (CYR61) is associated with the progression of NASH, but it has been described to have anti- and proinflammatory properties. We sought to examine the role of liver CYR61 in NASH progression. CYR61 liver-specific knockout mice on a NASH diet showed improved glucose tolerance, decreased liver inflammation, and reduced fibrosis. CYR61 polarized infiltrating monocytes promoting a proinflammatory/profibrotic phenotype through an IRAK4/SYK/NF-κB signaling cascade. In vitro, CYR61 activated a profibrotic program, including PDGFa/PDGFb expression in macrophages, in an IRAK4/SYK/NF-κB-dependent manner. Furthermore, targeted-antibody blockade reduced CYR61-driven signaling in macrophages in vitro and in vivo, reducing fibrotic development. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis in NASH.

DOI: https://doi.org/10.1126/scitranslmed.ade3157
Mol Cell. 2023 Sep 21. pii: S1097-2765(23)00696-2. [Epub ahead of print]

Early fate decision for mitochondrially encoded proteins by a molecular triage.

Andreas Kohler, Andreas Carlström, Hendrik Nolte, Verena Kohler, Sung-Jun Jung, Sagar Sridhara, Takashi Tatsuta, Jens Berndtsson, Thomas Langer, Martin Ott.

  Folding of newly synthesized proteins poses challenges for a functional proteome. Dedicated protein quality control (PQC) systems either promote the folding of nascent polypeptides at ribosomes or, if this fails, ensure their degradation. Although well studied for cytosolic protein biogenesis, it is not understood how these processes work for mitochondrially encoded proteins, key subunits of the oxidative phosphorylation (OXPHOS) system. Here, we identify dedicated hubs in proximity to mitoribosomal tunnel exits coordinating mitochondrial protein biogenesis and quality control. Conserved prohibitin (PHB)/m-AAA protease supercomplexes and the availability of assembly chaperones determine the fate of newly synthesized proteins by molecular triaging. The localization of these competing activities in the vicinity of the mitoribosomal tunnel exit allows for a prompt decision on whether newly synthesized proteins are fed into OXPHOS assembly or are degraded.

Keywords:  assembly factors; complex assembly; m-AAA protease; mitochondria; mitoribosome; prohibitin; protein biogenesis; protein quality control; respiratory chain; translation

DOI:  https://doi.org/10.1016/j.molcel.2023.09.001