Metabolism
Abstract
The metabolic microenvironment plays important roles in tumorigenesis, but how leukemia-initiating cells (LICs) response to the acidic BM niche remains largely unknown. Here, we show that acid-sensing ion channel 3 (ASIC3) dramatically delays leukemogenesis. Asic3 deletion results in a remarkably enhanced self-renewal, reduced differentiation, and 9-fold greater number of murine acute myeloid LICs. We developed an ultrasensitive, ratiometric, genetically encoded fluorescent pH sensor (pHluorin3) and demonstrated that LICs prefer localizing in the endosteal niche with a neutral pH range of 7.34–7.42, but not in the vascular niche with a lower pH range of 6.89–7.22. Unexpectedly, acid-ASIC3 signaling inhibits both murine and human LIC activities in a noncanonical manner by interacting with the N-terminal of STIM1 to reduce calcium-mediated CAMK1-CREB-MEIS1-LDHA levels, without inducing cation currents. This study reveals a pathway in suppression of leukemogenesis in the acidic BM niche and provides insight into targeting LICs or other cancer stem cells through pH-dependent ASICs.
Authors
Hao Gu, Lietao Weng, Chiqi Chen, Xiaoxin Hao, Rongkun Tao, Xin Qi, Xiaoyun Lai, Ligen Liu, Tinghua Zhang, Yiming Jiang, Jin Wang, Wei-Guang Li, Zhuo Yu, Li Xie, Yaping Zhang, Xiaoxiao He, Ye Yu, Yi Yang, Dehua Wu, Yuzheng Zhao, Tian-Le Xu, Guo-Qiang Chen, Junke Zheng
Abstract
Mitochondrial metabolism orchestrates T cell functions, yet the role of specific mitochondrial components in distinct T cell subsets remains poorly understood. Here, we explored the role of mitochondrial complex II (MC II), the only complex from the electron transport chain (ETC) that plays a role in both ETC and metabolism, in regulating T cell functions. Surprisingly, MC II exerts divergent effects on CD4+ and CD8+ T cell activation and function. Using T cell–specific MC II subunit, succinate dehydrogenase A–deficient (SDHA-deficient) mice, we integrated single-cell RNA-seq and metabolic profiling, with in vitro and in vivo T cell functional assays to illuminate these differences. SDHA deficiency induced metabolic changes and remodeled gene expression exclusively in activated T cells. In CD4+ T cells, SDHA loss dampened both oxidative phosphorylation (OXPHOS) and glycolysis, impaired cytokine production, proliferation, and reduced CD4+ T cell–mediated graft-versus-host disease after allogeneic stem cell transplantation (SCT). In contrast, SDHA deficiency in CD8+ T cells reduced OXPHOS but paradoxically upregulated glycolysis and demonstrated enhanced cytotoxic functions in vitro and in vivo. This metabolic reprogramming endowed SDHA-KO CD8+ T cells with superior in vivo antitumor efficacy after immune checkpoint inhibitor therapy and allogeneic SCT. These findings reveal MC II as a bifurcation point for metabolic and functional specialization in CD4+ and CD8+ T cells.
Authors
Keisuke Seike, Shih-Chun A. Chu, Yuichi Sumii, Takashi Ikeda, Meng-Chih Wu, Laure Maneix, Dongchang Zhao, Yaping Sun, Marcin Cieslik, Pavan Reddy
Abstract
Statins lower cholesterol, reducing the risk of heart disease, and are among the most frequently prescribed drugs. Approximately 10% of individuals develop statin-associated muscle symptoms (SAMS; myalgias, rhabdomyolysis, and muscle weakness), often rendering them statin intolerant. The mechanism underlying SAMS remains poorly understood. Patients with mutations in the skeletal muscle ryanodine receptor 1 (RyR1)/calcium release channel can be particularly intolerant of statins. High-resolution structures revealed simvastatin binding sites in the pore region of RyR1. Simvastatin stabilized the open conformation of the pore and activated the RyR1 channel. In a mouse expressing a mutant RyR1-T4709M found in a patient with profound statin intolerance, simvastatin caused muscle weakness associated with leaky RyR1 channels. Cotreatment with a Rycal drug that stabilizes the channel closed state prevented simvastatin-induced muscle weakness. Thus, statin binding to RyR1 can cause SAMS, and patients with RyR1 mutations may represent a high-risk group for statin intolerance.
Authors
Gunnar Weninger, Haikel Dridi, Steven Reiken, Qi Yuan, Nan Zhao, Linda Groom, Jennifer Leigh, Yang Liu, Carl Tchagou, Jiayi Kang, Alexander Chang, Estefania Luna-Figueroa, Marco C. Miotto, Anetta Wronska, Robert T. Dirksen, Andrew R. Marks
Abstract
During the progression of acute myeloid leukemia (AML), extramedullary hematopoiesis (EMH) compensates for impaired bone marrow hematopoiesis. However, the specific cellular dynamics of EMH and its influence on AML progression remain poorly understood. In this study, we identified a substantial expansion of the CD81+ erythroblast subpopulation (CD81+ Erys) in the spleens of AML mice, which promoted AML cell proliferation and reduced survival. Mechanistically, CD81+ Erys secrete elevated levels of macrophage migration-inhibitory factor (MIF), which interacted with the CD74 receptor on AML cells, activating the mTORC1 signaling pathway and upregulating Egln3. Consequently, AML cells cocultured with CD81+ Erys exhibited reprogrammed phospholipid metabolism, characterized by an increased phospholipid-to-lysophospholipid ratio. Modulating this metabolic shift, either by supplementing exogenous lysophospholipids or depleting Egln3 in AML cells, restored the phospholipid balance and mitigated the protumorigenic effects induced by CD81+ Erys. Overall, our findings elucidate the molecular crosstalk between erythroblasts and AML cells, extend our insights into the mechanisms driving AML progression, and suggest potential therapeutic strategies.
Authors
Yue Li, Jiaxuan Cao, Jingyuan Tong, Peixia Tang, Haoran Chen, Guohuan Sun, Zining Yang, Xiaoru Zhang, Fang Dong, Shangda Yang, Jie Gao, Xiangnan Zhao, Jinfa Ma, Di Wang, Lei Zhang, Lin Wang, Tao Cheng, Hui Cheng, Lihong Shi
Abstract
Macrophage-mediated phagocytosis plays a critical role in the elimination of cancer cells and shaping antitumor immunity. However, the tumor-intrinsic pathways that regulate cancer cell sensitivity to macrophage-mediated phagocytosis remain poorly defined. In this study, we performed a genome-wide CRISPR screen in murine pancreatic cancer cells cocultured with primary macrophages and identified that disruption of the tumor-intrinsic pyrimidine synthesis pathway enhances phagocytosis. Mechanistically, we discovered that macrophages inhibit the pyrimidine salvage pathway in tumor cells by upregulating Upp1-mediated uridine degradation through cytokines TNF-α and IL-1. This shift increased tumor cells’ reliance on de novo pyrimidine synthesis. As a result, tumor cells with impaired de novo pyrimidine synthesis showed depleted UMP and displayed enhanced exposure of phosphatidylserine (PtdSer), a major “eat-me” signal, thereby promoting macrophage-mediated phagocytosis. In multiple pancreatic cancer models, Cad-deficient tumors exhibited markedly reduced tumor burden with increased levels of phagocytosis by macrophages. Importantly, the Cad-mediated suppression of pancreatic cancer was dependent on TAMs and cytokines IL-1 and TNF-α. Pharmacological inhibition of DHODH, which blocks de novo pyrimidine synthesis, similarly decreased tumor burden with enhanced phagocytosis in pancreatic cancer models. These findings highlight the critical role of the tumor-intrinsic pyrimidine synthesis pathway in modulating macrophage-mediated antitumor immunity, with potential therapeutic implications.
Authors
Jie Zhao, Xinghao Li, Xinyu Li, Pengfei Ren, Yilan Wu, Hao Gong, Lijian Wu, Junran Huang, Saisai Wang, Ziwei Guo, Mo Chen, Zexian Zeng, Deng Pan
Abstract
Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by adipose tissue loss and redistribution, and metabolic dysfunction. FPLD2 is caused by pathogenic variants in the LMNA gene, encoding nuclear lamins A/C, structural proteins that control nuclear function and gene expression. However, the mechanisms driving adipocyte loss in FPLD2 remain poorly defined. In this study, we recruited eight families with developing or established FPLD2 and performed clinical, histological, and transcriptomic analyses of subcutaneous adipose tissue biopsies. Bulk and single-nuclei RNA-sequencing revealed suppression of lipid metabolism and mitochondrial pathways, alongside increased inflammation. These signatures were mirrored in tamoxifen-inducible adipocyte-specific Lmna knockout mice, in which lamin A/C-deficient adipocytes shrank and disappeared. Lmna-deficient fibroblasts shared similar gene expression changes, linked to altered chromatin accessibility, underscoring lamin A/C’s potential regulatory role in lipid metabolism and inflammatory programs. By directly comparing atrophic and hypertrophic adipose depots in FPLD2, and integrating human, mouse, and in vitro models, this study provides new insights into disease progression and potential therapeutic targets.
Authors
Jessica N. Maung, Rebecca L. Schill, Akira Nishii, Maria Foss de Freitas, Bonje N. Obua, Marcus Nygård, Maria D. Mendez-Casillas, Isabel D.K. Hermsmeyer, Donatella Gilio, Ozge Besci, Yang Chen, Brian Desrosiers, Rose E. Adler, Anabela D. Gomes, Merve Celik Guler, Hiroyuki Mori, Romina M. Uranga, Ziru Li, Hadla Hariri, Liping Zhang, Anderson de Paula Souza, Keegan S. Hoose, Kenneth T. Lewis, Taryn A. Hetrick, Paul Cederna, Carey N. Lumeng, Susanne Mandrup, Elif A. Oral, Ormond A. MacDougald
Abstract
Sulfite oxidase (SOX) deficiency is a rare inborn error of cysteine metabolism resulting in severe neurological damage. In patients, sulfite accumulates to toxic levels, causing a rise in the downstream products S-sulfocysteine, which mediates excitotoxicity, and thiosulfate, a catabolic intermediate/product of hydrogen sulfide (H2S) metabolism. Here, we report a full-body knockout mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Among the urinary biomarkers, thiosulfate showed a 45-fold accumulation in SOXD mice, representing the major excreted S-metabolite. Consistently, we found increased plasma H2S, which was derived from sulfite-induced release from persulfides, as demonstrated in vitro and in vivo. Mass spectrometry analysis of total protein persulfidome identified a major loss of S-persulfidation in 20% of the proteome, affecting enzymes in amino acids, fatty acid metabolism, and cytosolic iron-sulfur cluster biogenesis. Urinary amino acid profiles indicated metabolic rewiring and mitochondrial dysfunction, thus identifying an altered H2S metabolism and persulfidation in SOXD. Finally, oxidized glutathione and glutathione trisulfide were able to scavenge sulfite in vitro and in vivo, extending the lifespan of SOXD mice and providing a mechanistic concept of sulfite scavenging for the treatment of this severe metabolic disorder of cysteine catabolism.
Authors
Chun-Yu Fu, Joshua B. Kohl, Filip Liebsch, Davide D’Andrea, Tamás Ditrói, Seiryo Ogata, Franziska Neuser, Max Mai, Anna T. Mellis, Emilia Kouroussis, Masanobu Morita, Titus Gehling, José Angel Santamaria-Araujo, Sin Yuin Yeo, Heike Endepols, Michaela Křížková, Viktor Kozich, Marcus Krueger, Julia B. Hennermann, Uladzimir Barayeu, Takaaki Akaike, Peter Nagy, Milos Filipovic, Guenter Schwarz
Abstract
Obesity is a major driver of type 2 diabetes (T2D) and related metabolic disorders, characterized by chronic inflammation and adipocyte dysfunction. However, the molecular triggers initiating these processes remain poorly understood. We identify FAM20C, a serine/threonine kinase, as an early obesity-induced mediator of adipocyte dysfunction. Fam20c expression is substantially upregulated in adipocytes in response to obesity, correlating with a proinflammatory transcriptional signature. Forced expression of Fam20c in adipocytes promotes robust upregulation of proinflammatory cytokines and induces insulin resistance that is dependent on its kinase activity. Conversely, deletion of adipocyte Fam20c after established obesity and hyperglycemia improves glucose tolerance, augments insulin sensitivity, and reduces visceral adiposity, without altering body weight. Phosphoproteomic studies reveal that FAM20C regulates phosphorylation of intracellular and secreted proteins, modulating pathways critical to inflammation, metabolism, and extracellular matrix remodeling. We identify FAM20C-dependent substrates, such as CNPY4, whose phosphorylation contributes to proinflammatory adipocyte signaling. Of translational relevance, we show that in humans visceral adipose FAM20C expression positively correlates with insulin resistance. Our findings establish FAM20C as an early regulator of obesity-induced adipocyte dysfunction and systemic metabolic impairment. Our studies provide proof of concept that inhibition of FAM20C may serve as a potential therapy for T2D by restoring adipocyte health.
Authors
Ankit Gilani, Benjamin D. Stein, Anne Hoffmann, Renan Pereira de Lima, Elizabeth E. Ha, Edwin A. Homan, Lunkun Ma, Alfonso Rubio-Navarro, Tint Tha Ra Wun, Gabriel Jose Ayala Carrascal, Bhavneet Bhinder, Adhideb Ghosh, Falko J. Noé, Olivier Elemento, Christian Wolfrum, Matthias Blüher, James C. Lo
Abstract
Deposits of hydroxyapatite called Randall's plaques are found in the renal papilla of calcium oxalate kidney stone formers and likely serve as the nidus for stone formation, but their pathogenesis is unknown. Claudin-2 is a paracellular ion channel that mediates calcium reabsorption in the renal proximal tubule. To investigate the role of renal claudin-2, we generated kidney tubule-specific claudin-2 conditional knockout mice (KS-Cldn2 KO). KS-Cldn2 KO mice exhibited transient hypercalciuria in early life. Normalization of urine calcium was accompanied by a compensatory increase in expression and function of renal tubule calcium transporters, including in the thick ascending limb. Despite normocalciuria, KS-Cldn2 KO mice developed papillary hydroxyapatite deposits, beginning at 6 months of age, that resembled Randall's plaques and tubule plugs. Bulk chemical tissue analysis and laser ablation-inductively coupled plasma mass spectrometry revealed a gradient of intrarenal calcium concentration along the corticomedullary axis in normal mice, that was accentuated in KS-Cldn2 KO mice. Our findings provide evidence for the “vas washdown” hypothesis for Randall's plaque formation, and identify the corticomedullary calcium gradient as a target for therapies to prevent kidney stone disease.
Authors
Christine V. Behm, Duuamene Nyimanu, Ony Araujo Galdino, Sadhana Kanoo, Young Chul Kim, Natalia Lopez, Helen Goodluck, Peter S. Rowe, Andrew P. Evan, André J. Sommer, Matthew N. Barr, Tracy Punshon, Volker Vallon, Brian P. Jackson, James C. Williams Jr., Alan S.L. Yu
Abstract
In peripheral tissues, an endothelial cell (EC) protein, GPIHBP1, captures lipoprotein lipase (LPL) from the interstitial spaces and transports it to the capillary lumen. LPL mediates the margination of triglyceride-rich (TG-rich) lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. TRL-derived fatty acids are used for fuel in oxidative tissues or stored in adipose tissue. In mice, GPIHBP1 is absent from capillary ECs of the brain (which uses glucose for fuel); consequently, LPL and TRL margination are absent in mouse brain capillaries. However, because fatty acids were reported to play signaling roles in the brain, we hypothesized that LPL-mediated TRL processing might occur within specialized vascular beds within the central nervous system. Here, we show that GPIHBP1 is expressed in capillary ECs of human and mouse choroid plexus (ChP) and that GPIHBP1 transports LPL (produced by adjacent ChP cells) to the capillary lumen. The LPL in ChP capillaries mediates both TRL margination and processing. Intracapillary LPL and TRL margination are absent in the ChP of Gpihbp1–/– mice. GPIHBP1 expression, intracapillary LPL, and TRL margination were also observed in the median eminence and subfornical organ, circumventricular organs implicated in the regulation of food intake.
Authors
Wenxin Song, Madison Hung, Ellen Kozlov, Megan Hung, Anh P. Tran, James Carroll, Le Phoung Nguyen, Troy L. Lowe, Paul Kim, Hyesoo Jung, Yiping Tu, Joonyoung Kim, Ashley M. Presnell, Julia Scheithauer, Jenna P. Koerner, Ye Yang, Shino D. Magaki, Christopher K. Williams, Michael Ploug, Haibo Jiang, Christer Betsholtz, Maarja Andaloussi Mäe, Liqun He, Anne P. Beigneux, Loren G. Fong, Stephen G. Young
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)