Pub Date : 2024-01-02DOI: 10.1016/j.cmet.2023.12.003
Yingsheng Zhang, Meng-Ju Wu, Wan-Chi Lu, Yi-Chuan Li, Chun Ju Chang, Jer-Yen Yang
Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid β-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.
{"title":"Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.","authors":"Yingsheng Zhang, Meng-Ju Wu, Wan-Chi Lu, Yi-Chuan Li, Chun Ju Chang, Jer-Yen Yang","doi":"10.1016/j.cmet.2023.12.003","DOIUrl":"10.1016/j.cmet.2023.12.003","url":null,"abstract":"<p><p>Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid β-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139089673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-05Epub Date: 2023-10-19DOI: 10.1016/j.cmet.2023.09.011
Yuerong Zhang, Xiaoyan Yu, Rujuan Bao, Haiyan Huang, Chuanjia Gu, Qianming Lv, Qiaoqiao Han, Xian Du, Xu-Yun Zhao, Youqiong Ye, Ren Zhao, Jiayuan Sun, Qiang Zou
Fructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8+ T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8+ T cells reveals that dietary fructose mediates attenuated transition of CD8+ T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates adipocyte-derived leptin production in an mTORC1-dependent manner, thereby triggering leptin-boosted antitumor CD8+ T cell responses. Importantly, high plasma leptin levels are correlated with elevated plasma fructose concentrations and improved antitumor CD8+ T cell responses in patients with lung cancer. Our study characterizes a critical role for dietary fructose in shaping adipocyte metabolism to prime antitumor CD8+ T cell responses and highlights that the fructose-leptin axis may be harnessed for cancer immunotherapy.
{"title":"Dietary fructose-mediated adipocyte metabolism drives antitumor CD8<sup>+</sup> T cell responses.","authors":"Yuerong Zhang, Xiaoyan Yu, Rujuan Bao, Haiyan Huang, Chuanjia Gu, Qianming Lv, Qiaoqiao Han, Xian Du, Xu-Yun Zhao, Youqiong Ye, Ren Zhao, Jiayuan Sun, Qiang Zou","doi":"10.1016/j.cmet.2023.09.011","DOIUrl":"10.1016/j.cmet.2023.09.011","url":null,"abstract":"<p><p>Fructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8<sup>+</sup> T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8<sup>+</sup> T cells reveals that dietary fructose mediates attenuated transition of CD8<sup>+</sup> T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates adipocyte-derived leptin production in an mTORC1-dependent manner, thereby triggering leptin-boosted antitumor CD8<sup>+</sup> T cell responses. Importantly, high plasma leptin levels are correlated with elevated plasma fructose concentrations and improved antitumor CD8<sup>+</sup> T cell responses in patients with lung cancer. Our study characterizes a critical role for dietary fructose in shaping adipocyte metabolism to prime antitumor CD8<sup>+</sup> T cell responses and highlights that the fructose-leptin axis may be harnessed for cancer immunotherapy.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49686264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-05DOI: 10.1016/j.cmet.2023.11.005
Alok Kumar, Greg M Delgoffe
The malate shuttle is known to maintain the balance of NAD+/NADH between the cytosol and mitochondria. However, in Tex cells, it primarily detoxifies ammonia (via GOT1-mediated production of 2-KG in an atypical reaction) and provides longevity to chronic-infection-induced Tex cells against ammonia-induced cell death.
{"title":"Redox and detox: Malate shuttle metabolism keeps exhausted T cells fit.","authors":"Alok Kumar, Greg M Delgoffe","doi":"10.1016/j.cmet.2023.11.005","DOIUrl":"10.1016/j.cmet.2023.11.005","url":null,"abstract":"<p><p>The malate shuttle is known to maintain the balance of NAD<sup>+</sup>/NADH between the cytosol and mitochondria. However, in T<sub>ex</sub> cells, it primarily detoxifies ammonia (via GOT1-mediated production of 2-KG in an atypical reaction) and provides longevity to chronic-infection-induced T<sub>ex</sub> cells against ammonia-induced cell death.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138500520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-05Epub Date: 2023-10-31DOI: 10.1016/j.cmet.2023.10.003
Anni M Y Zhang, Yi Han Xia, Jeffrey S H Lin, Ken H Chu, Wei Chuan K Wang, Titine J J Ruiter, Jenny C C Yang, Nan Chen, Justin Chhuor, Shilpa Patil, Haoning Howard Cen, Elizabeth J Rideout, Vincent R Richard, David F Schaeffer, Rene P Zahedi, Christoph H Borchers, James D Johnson, Janel L Kopp
The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown, and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are dispensable for glucose homeostasis but necessary for hyperinsulinemia-driven PanIN formation in the context of diet-induced hyperinsulinemia and obesity. Mechanistically, this was attributed to amplified digestive enzyme protein translation, triggering of local inflammation, and PanIN metaplasia in vivo. In vitro, insulin dose-dependently increased acinar-to-ductal metaplasia formation in a trypsin- and Insr-dependent manner. Collectively, our data shed light on the mechanisms connecting obesity-driven hyperinsulinemia and pancreatic cancer development.
{"title":"Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation.","authors":"Anni M Y Zhang, Yi Han Xia, Jeffrey S H Lin, Ken H Chu, Wei Chuan K Wang, Titine J J Ruiter, Jenny C C Yang, Nan Chen, Justin Chhuor, Shilpa Patil, Haoning Howard Cen, Elizabeth J Rideout, Vincent R Richard, David F Schaeffer, Rene P Zahedi, Christoph H Borchers, James D Johnson, Janel L Kopp","doi":"10.1016/j.cmet.2023.10.003","DOIUrl":"10.1016/j.cmet.2023.10.003","url":null,"abstract":"<p><p>The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown, and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that insulin receptors (Insr) in Kras<sup>G12D</sup>-expressing pancreatic acinar cells are dispensable for glucose homeostasis but necessary for hyperinsulinemia-driven PanIN formation in the context of diet-induced hyperinsulinemia and obesity. Mechanistically, this was attributed to amplified digestive enzyme protein translation, triggering of local inflammation, and PanIN metaplasia in vivo. In vitro, insulin dose-dependently increased acinar-to-ductal metaplasia formation in a trypsin- and Insr-dependent manner. Collectively, our data shed light on the mechanisms connecting obesity-driven hyperinsulinemia and pancreatic cancer development.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71430184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-05Epub Date: 2023-11-09DOI: 10.1016/j.cmet.2023.10.014
Hugo Lee, Gulcan Semra Sahin, Chien-Wen Chen, Shreyash Sonthalia, Sandra Marín Cañas, Hulya Zeynep Oktay, Alexander T Duckworth, Gabriel Brawerman, Peter J Thompson, Maria Hatzoglou, Decio L Eizirik, Feyza Engin
During the progression of type 1 diabetes (T1D), β cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve β cell function and survival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6α or Ire1α in β cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the β cell secretome that significantly enhances the leukemia inhibitory factor-mediated recruitment of M2 macrophages to islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflammation, the removal of terminally senesced β cells, the reduction of β cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual β cells of T1D patients. Our findings reveal a previously unrecognized link between β cell UPR and senescence that, if leveraged, may represent a novel preventive strategy for T1D.
{"title":"Stress-induced β cell early senescence confers protection against type 1 diabetes.","authors":"Hugo Lee, Gulcan Semra Sahin, Chien-Wen Chen, Shreyash Sonthalia, Sandra Marín Cañas, Hulya Zeynep Oktay, Alexander T Duckworth, Gabriel Brawerman, Peter J Thompson, Maria Hatzoglou, Decio L Eizirik, Feyza Engin","doi":"10.1016/j.cmet.2023.10.014","DOIUrl":"10.1016/j.cmet.2023.10.014","url":null,"abstract":"<p><p>During the progression of type 1 diabetes (T1D), β cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve β cell function and survival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6α or Ire1α in β cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the β cell secretome that significantly enhances the leukemia inhibitory factor-mediated recruitment of M2 macrophages to islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflammation, the removal of terminally senesced β cells, the reduction of β cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual β cells of T1D patients. Our findings reveal a previously unrecognized link between β cell UPR and senescence that, if leveraged, may represent a novel preventive strategy for T1D.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10842515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72212321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-05Epub Date: 2023-11-20DOI: 10.1016/j.cmet.2023.10.017
Venkat Krishnan Sundaram, Vlad Schütza, Nele H Schröter, Aline Backhaus, Annika Bilsing, Lisa Joneck, Anna Seelbach, Clara Mutschler, Jose A Gomez-Sanchez, Erik Schäffner, Eva Ernst Sánchez, Dagmar Akkermann, Christina Paul, Nancy Schwagarus, Silvana Müller, Angela Odle, Gwen Childs, David Ewers, Theresa Kungl, Maren Sitte, Gabriela Salinas, Michael W Sereda, Klaus-Armin Nave, Markus H Schwab, Mario Ost, Peter Arthur-Farraj, Ruth M Stassart, Robert Fledrich
The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.
{"title":"Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration.","authors":"Venkat Krishnan Sundaram, Vlad Schütza, Nele H Schröter, Aline Backhaus, Annika Bilsing, Lisa Joneck, Anna Seelbach, Clara Mutschler, Jose A Gomez-Sanchez, Erik Schäffner, Eva Ernst Sánchez, Dagmar Akkermann, Christina Paul, Nancy Schwagarus, Silvana Müller, Angela Odle, Gwen Childs, David Ewers, Theresa Kungl, Maren Sitte, Gabriela Salinas, Michael W Sereda, Klaus-Armin Nave, Markus H Schwab, Mario Ost, Peter Arthur-Farraj, Ruth M Stassart, Robert Fledrich","doi":"10.1016/j.cmet.2023.10.017","DOIUrl":"10.1016/j.cmet.2023.10.017","url":null,"abstract":"<p><p>The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10722468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138292582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-05DOI: 10.1016/j.cmet.2023.10.015
Sophie E Claudel, Ashish Verma
In a recent Presidential Advisory report, the American Heart Association (AHA) defined cardiovascular-kidney-metabolic (CKM) syndrome as a spectrum of pathology associated with dysfunctional or excess adiposity and leading to adverse cardiovascular outcomes. Implementing the guidelines set forth by the AHA has the potential to improve population-wide CKM health.
{"title":"Cardiovascular-kidney-metabolic syndrome: A step toward multidisciplinary and inclusive care.","authors":"Sophie E Claudel, Ashish Verma","doi":"10.1016/j.cmet.2023.10.015","DOIUrl":"10.1016/j.cmet.2023.10.015","url":null,"abstract":"<p><p>In a recent Presidential Advisory report, the American Heart Association (AHA) defined cardiovascular-kidney-metabolic (CKM) syndrome as a spectrum of pathology associated with dysfunctional or excess adiposity and leading to adverse cardiovascular outcomes. Implementing the guidelines set forth by the AHA has the potential to improve population-wide CKM health.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138500519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-05Epub Date: 2023-11-17DOI: 10.1016/j.cmet.2023.10.016
Meng-Kai Ge, Cheng Zhang, Na Zhang, Ping He, Hai-Yan Cai, Song Li, Shuai Wu, Xi-Li Chu, Yu-Xue Zhang, Hong-Ming Ma, Li Xia, Shuo Yang, Jian-Xiu Yu, Shi-Ying Yao, Xiao-Long Zhou, Bing Su, Guo-Qiang Chen, Shao-Ming Shen
Mammalian target of rapamycin complex 1 (mTORC1) monitors cellular amino acid changes for function, but the molecular mediators of this process remain to be fully defined. Here, we report that depletion of cellular amino acids, either alone or in combination, leads to the ubiquitination of mTOR, which inhibits mTORC1 kinase activity by preventing substrate recruitment. Mechanistically, amino acid depletion causes accumulation of uncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner. Accordingly, mutation of mTOR Lys2066 abolished mTOR ubiquitination in response to amino acid depletion, rendering mTOR insensitive to amino acid starvation both in vitro and in vivo. Collectively, these data reveal a novel mechanism of amino acid sensing by mTORC1 via a previously unknown GCN2-FBXO22-mTOR pathway that is uniquely controlled by uncharged tRNAs.
{"title":"The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency.","authors":"Meng-Kai Ge, Cheng Zhang, Na Zhang, Ping He, Hai-Yan Cai, Song Li, Shuai Wu, Xi-Li Chu, Yu-Xue Zhang, Hong-Ming Ma, Li Xia, Shuo Yang, Jian-Xiu Yu, Shi-Ying Yao, Xiao-Long Zhou, Bing Su, Guo-Qiang Chen, Shao-Ming Shen","doi":"10.1016/j.cmet.2023.10.016","DOIUrl":"10.1016/j.cmet.2023.10.016","url":null,"abstract":"<p><p>Mammalian target of rapamycin complex 1 (mTORC1) monitors cellular amino acid changes for function, but the molecular mediators of this process remain to be fully defined. Here, we report that depletion of cellular amino acids, either alone or in combination, leads to the ubiquitination of mTOR, which inhibits mTORC1 kinase activity by preventing substrate recruitment. Mechanistically, amino acid depletion causes accumulation of uncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner. Accordingly, mutation of mTOR Lys2066 abolished mTOR ubiquitination in response to amino acid depletion, rendering mTOR insensitive to amino acid starvation both in vitro and in vivo. Collectively, these data reveal a novel mechanism of amino acid sensing by mTORC1 via a previously unknown GCN2-FBXO22-mTOR pathway that is uniquely controlled by uncharged tRNAs.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138049044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-07Epub Date: 2023-10-26DOI: 10.1016/j.cmet.2023.10.002
Jie Li, Cuimiao Zheng, Qiuwen Mai, Xi Huang, Wenfeng Pan, Jingyi Lu, Zhengfan Chen, Suman Zhang, Chunyu Zhang, Hua Huang, Yangyang Chen, Hongbo Guo, Zhenyin Wu, Chunnuan Deng, Yiting Jiang, Bo Li, Junxiu Liu, Shuzhong Yao, Chaoyun Pan
Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.
{"title":"Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer.","authors":"Jie Li, Cuimiao Zheng, Qiuwen Mai, Xi Huang, Wenfeng Pan, Jingyi Lu, Zhengfan Chen, Suman Zhang, Chunyu Zhang, Hua Huang, Yangyang Chen, Hongbo Guo, Zhenyin Wu, Chunnuan Deng, Yiting Jiang, Bo Li, Junxiu Liu, Shuzhong Yao, Chaoyun Pan","doi":"10.1016/j.cmet.2023.10.002","DOIUrl":"10.1016/j.cmet.2023.10.002","url":null,"abstract":"<p><p>Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61567020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-07Epub Date: 2023-10-30DOI: 10.1016/j.cmet.2023.10.008
Panu K Luukkonen, Kimmo Porthan, Noora Ahlholm, Fredrik Rosqvist, Sylvie Dufour, Xian-Man Zhang, Tiina E Lehtimäki, Wenla Seppänen, Marju Orho-Melander, Leanne Hodson, Kitt Falk Petersen, Gerald I Shulman, Hannele Yki-Järvinen
The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.
{"title":"The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans.","authors":"Panu K Luukkonen, Kimmo Porthan, Noora Ahlholm, Fredrik Rosqvist, Sylvie Dufour, Xian-Man Zhang, Tiina E Lehtimäki, Wenla Seppänen, Marju Orho-Melander, Leanne Hodson, Kitt Falk Petersen, Gerald I Shulman, Hannele Yki-Järvinen","doi":"10.1016/j.cmet.2023.10.008","DOIUrl":"10.1016/j.cmet.2023.10.008","url":null,"abstract":"<p><p>The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71430185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}