bims-glucam 2024-11-24 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–11–24
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University

Rotavirus rewires host cell metabolic pathways toward glutamine catabolism for effective virus infection.
Is ASCT2 a suitable vector for the selective delivery of anticancer drugs? Modification of glutamine at either the carboxylate or the side chain hinders binding and transport.
Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.
Ginsenoside compound K restrains hepatic fibrotic response by dual-inhibition of GLS1 and LDHA.
A glutamine metabolish-associated prognostic model to predict prognosis and therapeutic responses of hepatocellular carcinoma.
Altered Metabolites in Hepatocellular Carcinoma (HCC) Paving the Road for Metabolomics Signature and Biomarkers for Early Diagnosis of HCC.
Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer.
GLS2 links glutamine metabolism and atherosclerosis by remodeling artery walls.
Exploring the impact of mitochondrial-targeting anthelmintic agents with GLUT1 inhibitor BAY-876 on breast cancer cell metabolism.
Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.
CKS2 induces autophagy-mediated glutathione metabolic reprogramming to facilitate ferroptosis resistance in colon cancer.
NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency.

Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2428425

Rotavirus rewires host cell metabolic pathways toward glutamine catabolism for effective virus infection.

Suvrotoa Mitra, Ratul Datta Chaudhuri, Rakesh Sarkar, Shreya Banerjee, Arpita Mukherjee, Ranjana Sharma, Animesh Gope, Kei Kitahara, Shin-Ichi Miyoshi, Mamta Chawla-Sarkar.

  Rotavirus (RV) accounts for 19.11% of global diarrheal deaths. Though GAVI assisted vaccine introduction has curtailed RV induced mortality, factors like RV strain diversity, differential infantile gut microbiome, malnutrition, interference from maternal antibodies and other administered vaccines, etc. often compromise vaccine efficacy. Herein emerges the need of antivirals which can be administered adjunct to vaccination to curb the socio-economic burden stemming from frequent RV infection. Cognisance of pathogen-perturbed host cellular physiology has revolutionized translational research and aided precision-based therapy, particularly for viruses, with no metabolic machinery of their own. To date there has been limited exploration of the host cellular metabolome in context of RV infection. In this study, we explored the endometabolomic landscape of human intestinal epithelial cells (HT-29) on RV-SA11 infection. Significant alteration of host cellular metabolic pathways like the nucleotide biosynthesis pathway, alanine, aspartate and glutamate metabolism pathway, the host citric acid cycle was observed in RV-SA11 infection scenario. Detailed study further revealed that RV replication is exclusively dependent on glutamine metabolism for their propagation in host cells. Glutamine metabolism generates glutamate, aspartate, and asparagine which facilitates virus infection. Abrogation of aspartate biogenesis from glutamine by use of Aminooxyacetic acid (AOAA), significantly curbed RV-SA11 infection in-vitro and in-vivo. Overall, the study improves our understanding of host-rotavirus interactome and recognizes host glutamine metabolism pathway as a suitable target for effective therapeutic intervention against RV infection.

Keywords:  Rotavirus; antiviral; aspartate aminotransferase; glutamine metabolism; metabolomics

DOI:  https://doi.org/10.1080/19490976.2024.2428425
ChemMedChem. 2024 Nov 19. e202400759

Is ASCT2 a suitable vector for the selective delivery of anticancer drugs? Modification of glutamine at either the carboxylate or the side chain hinders binding and transport.

Trevor William Hambley, Vinitha M, Chelsea Briot, Renae Ryan, Adnan Mohammed.

  The Alanine, Serine, and Cysteine Transporter 2 (ASCT2) transports glutamine into cells and is upregulated in many cancers. Attachment to glutamine to enable ASCT2 to transport anticancer agents into cells has been proposed, but the impact of such modifications is a critical determinant of the potential of this strategy. Transport via ASCT2 of two glutamine analogues modified in ways that reflect possible mechanisms for attaching anticancer agents was studied. The aim was to determine if the modification of glutamine interferes with its transport via ASCT2 and thereby establish whether the conjugation of drugs to glutamine can facilitate the accumulation of anticancer drugs in cancer cells. L-theanine and a glutamine derivative modified at the carboxylate (7) were applied to Xenopus laevis oocytes expressing ASCT2. Two-electrode voltage clamp electrophysiology was used to measure substrate-elicited currents over a range of membrane potentials. Compound 7 was identified as neither a substrate nor an inhibitor while L-theanine was identified as an inhibitor of ASCT2. Thus, modification of glutamine in these ways prevents it from acting as a substrate and suggests that ASCT2 may not be a suitable target for delivery of anticancer drugs attached via either the carboxylate or side chain positions.

Keywords:  Glutamine Cytotoxin Transport ASCT2 Selective accumulation

DOI:  https://doi.org/10.1002/cmdc.202400759
bioRxiv. 2024 Nov 07. pii: 2024.11.06.622291. [Epub ahead of print]

Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.

Ozan Baytas, Shawn M Davidson, Julie A Kauer, Eric M Morrow.

Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tightly regulated to sustain excitatory neurotransmission, here we investigate the role of GPT2 in synaptic function. GPT2 catalyzes a reversible reaction interconverting glutamate and pyruvate with alanine and alpha-ketoglutarate, a TCA cycle intermediate; thereby, GPT2 may play an important role in linking mitochondrial tricarboxylic acid (TCA) cycle with synaptic transmission. In mouse brain, we find that GPT2 is enriched in mitochondria of synaptosomes (isolated synaptic terminals). Loss of Gpt2 in mouse appears to lead to reprogramming of glutamate and glutamine metabolism, and to decreased glutamatergic synaptic transmission. Whole-cell patch-clamp recordings in pyramidal neurons of CA1 hippocampal slices from Gpt2- null mice reveal decreased excitatory post-synaptic currents (mEPSCs) without changes in mEPSC frequency, or importantly, changes in inhibitory post-synaptic currents (mIPSCs). Additional evidence of defective glutamate release included reduced levels of glutamate released from Gpt2- null synaptosomes measured biochemically. Glutamate release from synaptosomes was rescued to wild-type levels by alpha-ketoglutarate supplementation. Additionally, we observed evidence of altered metabolism in isolated Gpt2- null synaptosomes: decreased TCA cycle intermediates, and increased glutamate dehydrogenase activity. Notably, alterations in the TCA cycle and the glutamine pool were alleviated by alpha-ketoglutarate supplementation. In conclusion, our data support a model whereby GPT2 mitochondrial activity may contribute to glutamate availability in pre-synaptic terminals, thereby highlighting potential interactions between pre-synaptic mitochondrial metabolism and synaptic transmission.

DOI: https://doi.org/10.1101/2024.11.06.622291
Phytomedicine. 2024 Nov 08. pii: S0944-7113(24)00881-X. [Epub ahead of print]135 156223

Ginsenoside compound K restrains hepatic fibrotic response by dual-inhibition of GLS1 and LDHA.

Wen-Hui Wu, Ya-Lan Yang, Ting Wang, Xiao-Meng Sun, Meng-Guang Wei, Xin-Yue Zhou, Li-Zeng Zhu, Gaoxiang Ma, Baolin Liu, Lian-Wen Qi, Qun Liu.

   BACKGROUND: Liver fibrosis is a dynamic process marked by the accumulation of extracellular matrix due to hepatic stellate cells (HSCs) activation. Ginsenoside compound K (CK), a rare derivative of its parent ginsenosides, is known to significantly ameliorate metabolic disorders.
PURPOSE: The aim of this study was to elucidate the protective effects of CK against liver fibrosis with a focus on metabolic regulation.
METHODS: We established liver fibrosis models in mice using carbon tetrachloride (CCl4) challenge, bile duct ligation, or a methionine-choline deficient diet, with continuous oral administration of CK at specified doses and intervals. Simultaneously, we examined the impact of CK on metabolic regulation in cultured HSCs and investigated the associated mechanisms.
RESULTS: CK was found to alleviate liver injury and curb fibrotic responses in mouse models, as well as decrease elevated levels of liver enzyme. Metabolomic analysis in vitro highlighted the crucial roles of pyruvate and glutamine metabolism in metabolic remodeling. Immunohistochemical staining indicated significantly elevated expressions of lactate dehydrogenase A (LDHA) (p = 0.014) and glutaminase 1 (GLS1) (p = 0.024) in liver cirrhosis patients. Comparable alterations were noted in the liver of model mice and in cultured HSCs. Molecular docking and bio-layer interferometry demonstrated that CK interacts with and inhibits the activities of LDHA and GLS1. As expected, CK attenuated glycolysis and glutaminolysis, reducing HSC growth dependently on lactate and α-ketoglutarate (α-KG). Upon HSC activation, metabolism is reprogrammed with Myc as a key regulator, transcriptionally controlling LDHA, GLS1, and glutamine transporters SLC1A5 and SLC38A5. CK inhibited Myc induction, integrating glycolysis and glutaminolysis regulation to counteract the fibrotic response.
CONCLUSION: CK inhibited LDHA and GLS1 activities, thereby inhibiting hepatic fibrosis. These findings offer new insights into the role of ginsenosides in liver protection, especially regarding metabolic disorders.

Keywords:  Ginsenoside compound K; Glutaminolysis; Glycolysis; Liver fibrosis; Myc

DOI:  https://doi.org/10.1016/j.phymed.2024.156223
Biol Direct. 2024 Nov 20. 19(1): 118

A glutamine metabolish-associated prognostic model to predict prognosis and therapeutic responses of hepatocellular carcinoma.

Hao Xu, Hui Pan, Lian Fang, Cangyuan Zhang, Chen Xiong, Weiti Cai.

  Hepatocellular carcinoma (HCC) ranks among the most lethal malignancies around the world. However, the current management strategies for predicting prognosis in HCC patients remain unreliable. Our study developed a robust prognostic model based on glutamine metabolism associated-genes (GMAGs), utilizing data from The Cancer Genome Atlas database. The prognostic values of model were validated through the databases of the Gene Expression Omnibus and International Cancer Genome Consortium via Kaplan‒Meier curves and receiver operating characteristic (ROC). The potential biological pathways associated with prognostic risk were investigated through different enrichment analysis, and Gene variation analysis. The correlation between prognostic model and therapeutic responses were analyzed. Quantitative real-time PCR (qRT-PCR) and cellular experiments were measured to analyze the GMAGs. Consequently, a prognostic model was constructed of 4 GMAGs (RRM1, RRM2, G6PD, and GPX7) through least absolute shrinkage and selection operator (LASSO) regression analysis. The Kaplan‒Meier curves and ROC curves showed a reliable predictive capacity of prognosis for HCC patients (p < 0.05). The enrichment analyses revealed a multitude of biological pathways that are significantly associated with cancer. Patients with high prognostic risk might be sensitive to immunotherapy (p < 0.05). The results of qRT-PCR revealed that all 4 GMAGs exhibited significantly higher expression levels in HCC samples compared to normal samples (p < 0.05). Moreover, the knockdown of RRM1 suppresses the progression of HCC cells. In this study, we developed a robust prognostic model for predicting the prognosis of HCC patients based on GMAGs, and identified RRM1 as a potential therapeutic target for HCC.

Keywords:  Glutamine; Hepatocellular carcinoma; Metabolism; Prognostic model

DOI:  https://doi.org/10.1186/s13062-024-00567-x
Cureus. 2024 Oct;16(10): e71968

Altered Metabolites in Hepatocellular Carcinoma (HCC) Paving the Road for Metabolomics Signature and Biomarkers for Early Diagnosis of HCC.

Hiba S Al-Amodi, Hala F Kamel.

  Globally, hepatocellular carcinoma (HCC) is one of the most commonly encountered cancers. Because the current early diagnostic tests for HCC are not very sensitive, most cases of the disease are discovered late when it is in its terminal stage. Cellular metabolism changes during carcinogenesis to enable cancer cells to adapt to the hypoxic milieu, boost anabolic synthesis, promote survival, and evade apoptotic death signals. Omic techniques represent a breakthrough in the field of diagnostic technology. For example, Metabolomics analysis could be used to identify these metabolite alterations. Understanding the metabolic alterations linked to HCC is crucial for improving high-risk patients' surveillance and understanding the illness's biology. This review highlights the metabolic alterations linked to energy production in cancer cells, as well as the significantly altered metabolites and pathways associated with hepatocarcinogenesis, including acylcarnitines (ACs), amino acids, proteins, lipids, carbohydrates, glucose, and lactate, which reflect the anabolic and catabolic changes occurring in these cells. Additionally, it discusses the clinical implications of recent metabolomics that may serve as potential biomarkers for early diagnosis and monitoring of the progression of HCC.

Keywords:  acylcarnitines; carcinogenesis; hepatocellular carcinoma; metabolism; metabolomics

DOI:  https://doi.org/10.7759/cureus.71968
Mol Cancer. 2024 Nov 21. 23(1): 261

Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer.

Shan Liu, Xingda Zhang, Wenzheng Wang, Xue Li, Xue Sun, Yuqian Zhao, Qi Wang, Yingpu Li, Fangjie Hu, He Ren.

Metabolic alterations, a hallmark of cancer, enable tumor cells to adapt to their environment by modulating glucose, lipid, and amino acid metabolism, which fuels rapid growth and contributes to treatment resistance. In primary breast cancer, metabolic shifts such as the Warburg effect and enhanced lipid synthesis are closely linked to chemotherapy failure. Similarly, metastatic lesions often display distinct metabolic profiles that not only sustain tumor growth but also confer resistance to targeted therapies and immunotherapies. The review emphasizes two major aspects: the mechanisms driving metabolic resistance in both primary and metastatic breast cancer, and how the unique metabolic environments in metastatic sites further complicate treatment. By targeting distinct metabolic vulnerabilities at both the primary and metastatic stages, new strategies could improve the efficacy of existing therapies and provide better outcomes for breast cancer patients.

DOI: https://doi.org/10.1186/s12943-024-02165-x
Nat Cardiovasc Res. 2024 Nov 19.

GLS2 links glutamine metabolism and atherosclerosis by remodeling artery walls.

Florent Murcy, Coraline Borowczyk, Samuel Gourion-Arsiquaud, Stéphanie Torrino, Nessrine Ouahrouche, Thibault Barouillet, Sébastien Dussaud, Marie Couralet, Nathalie Vaillant, Johanna Merlin, Alexandre Berquand, Minna U Kaikkonen, Robyn L McClelland, William Tressel, James Stein, Edward B Thorp, Thomas Bertero, Pascal Barbry, Béatrice Bailly-Maitre, Emmanuel L Gautier, Minna K Karjalainen, Johannes Kettunen, Laurent Duca, Steven Shea, Laurent Yvan-Charvet.

Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common among patients with cardiovascular diseases, but the underlying mechanisms remain largely unknown. Using the human MESA cohort, here we show that plasma glutamine-glutamate ratio is an independent risk factor for carotid plaque progression. Mice deficient in glutaminase-2 (Gls2), the enzyme that mediates hepatic glutaminolysis, developed accelerated atherosclerosis and susceptibility to catastrophic cardiac events, while Gls2 overexpression partially protected from disease progression. High-throughput transcriptional profiling and high-resolution structural biology imaging of aortas showed that Gls2 deficiency perturbed extracellular matrix composition and increased vessel stiffness. This results from an imbalance of glutamine- and glutamate-dependent cross-linked proteins within atherosclerotic lesions and cellular remodeling of plaques. Thus, hepatic glutaminolysis functions as a potent regulator of glutamine homeostasis, which affects the aortic wall structure during atherosclerotic plaque progression.

DOI: https://doi.org/10.1038/s44161-024-00566-1
BMC Cancer. 2024 Nov 16. 24(1): 1415

Exploring the impact of mitochondrial-targeting anthelmintic agents with GLUT1 inhibitor BAY-876 on breast cancer cell metabolism.

Tanner J Schumacher, Ananth V Iyer, Jon Rumbley, Conor T Ronayne, Venkatram R Mereddy.

   BACKGROUND: Cancer cells alter their metabolic phenotypes with nutritional change. Single agent approaches targeting mitochondrial metabolism in cancer have failed due to either dose limiting off target toxicities, or lack of significant efficacy in vivo. To mitigate these clinical challenges, we investigated the potential utility of repurposing FDA approved mitochondrial targeting anthelmintic agents, niclosamide, IMD-0354 and pyrvinium pamoate, to be combined with GLUT1 inhibitor BAY-876 to enhance the inhibitory capacity of the major metabolic phenotypes exhibited by tumors.
METHODS: To test this, we used breast cancer cell lines MDA-MB-231 and 4T1 which exhibit differing basal metabolic rates of glycolysis and mitochondrial respiration, respectively. Metabolic characterization was carried out using Seahorse XFe96 Bioanalyzer and statistical analysis was carried out via ANOVA.
RESULTS: Here, we found that specific responses to mitochondrial and glycolysis targeting agents elicit responses that correlate with tested cell lines basal metabolic rates and fuel preference, highlighting the potential to cater metabolism targeting treatment regimens based on specific tumor nutrient handling. Inhibition of GLUT1 with BAY-876 potently inhibited glycolysis in both MDA-MB-231 and 4T1 cells, and niclosamide and pyrvinium pamoate perturbed mitochondrial respiration that resulted in potent compensatory glycolysis in the cell lines tested.
CONCLUSION: In this regard, combination of BAY-876 with both mitochondrial targeting agents resulted in inhibition of compensatory glycolysis and subsequent metabolic crisis. These studies highlight targeting tumor metabolism as a combination treatment regimen that can be tailored by basal and compensatory metabolic phenotypes.

Keywords:  Anthelmintic; Anticancer; BAY-876; Drug repurposing; Niclosamide; Pyrvinium

DOI:  https://doi.org/10.1186/s12885-024-13186-6
Cancer Metab. 2024 Nov 19. 12(1): 35

Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.

Kenji Miki, Mikako Yagi, Ryusuke Hatae, Ryosuke Otsuji, Takahiro Miyazaki, Katsuhiro Goto, Daiki Setoyama, Yutaka Fujioka, Yuhei Sangatsuda, Daisuke Kuga, Nayuta Higa, Tomoko Takajo, Yonezawa Hajime, Toshiaki Akahane, Akihide Tanimoto, Ryosuke Hanaya, Yuya Kunisaki, Takeshi Uchiumi, Koji Yoshimoto.

   BACKGROUND: Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive.
METHODS: We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells.
RESULTS: The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth.
CONCLUSIONS: Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma.

Keywords:  Glioblastoma; Glutaminolysis; Metabolic changes; Mitochondria

DOI:  https://doi.org/10.1186/s40170-024-00364-0
Mol Med. 2024 Nov 15. 30(1): 219

CKS2 induces autophagy-mediated glutathione metabolic reprogramming to facilitate ferroptosis resistance in colon cancer.

Leilei Yang, Chengfeng Fang, Jiaju Han, Yufeng Ren, Zaiping Yang, Lingyan Shen, Dinghai Luo, Ruili Zhang, Yan Chen, Shenkang Zhou.

   BACKGROUND: Ferroptosis, a form of cell death characterized by lipid peroxidation, plays a crucial role in tumor suppression, offering novel avenues for cancer therapy. Previous studies have indicated that high levels of cyclin-dependent kinase subunit 2 (CKS2) promote the progression of various cancers. However, the potential interplay between CKS2 and ferroptosis in colon cancer (CC) remains unclear.
METHODS: Bioinformatics and RNA-seq analyses were employed to study genes associated with the ferroptosis signaling pathway. CKS2 expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB). The in vitro and in vivo effects of CKS2 on CC cells were assessed through the CCK-8 assay, colony formation assay, propidium iodide (PI) staining, BODIPY staining, DCFH-DA staining, and animal experiments. Additionally, the impact of CKS2 on autophagy and glutathione (GSH) metabolism was investigated using a transmission electron microscope (TEM), immunofluorescence (IF) assays, WB experiments, and relevant assay kits.
RESULTS: CKS2 expression was elevated in CC, indicating a poor clinical outcome. Knockdown of CKS2 significantly enhanced Erastin-induced ferroptosis in CC cells, leading to reduced GSH metabolism. Conversely, CKS2 overexpression produced opposite effects. Mechanistically, CKS2-induced autophagy reinforced GSH metabolism, thereby increasing resistance to ferroptosis in CC cells. Furthermore, inhibiting CKS2 promoted tumor ferroptosis by downregulating GPX4 expression. Additionally, CKS2 knockdown effectively increased sorafenib-induced ferroptosis both in vitro and in vivo.
CONCLUSION: CKS2 suppresses ferroptosis in CC by modulating GSH metabolism in both in vitro and in vivo settings. These findings offer new insights into targeting CKS2 for CC treatment and shed light on the mechanism of ferroptosis in CC.

Keywords:  Autophagy; Colon cancer; Cyclin-dependent kinase subunit 2; Ferroptosis; Glutathione metabolism

DOI:  https://doi.org/10.1186/s10020-024-00979-5
Cell Mol Life Sci. 2024 Nov 19. 81(1): 458

NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency.

Jaroslaw Cendrowski, Marta Wrobel, Michal Mazur, Bartosz Jary, Ranjana Maurya, Surui Wang, Michal Korostynski, Anna Dziewulska, Maria Rohm, Patryk Kuropka, Natalia Pudelko-Malik, Piotr Mlynarz, Agnieszka Dobrzyn, Anja Zeigerer, Marta Miaczynska.

  Endosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation which provides the cell with lysosome-derived nutrients. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex. ESCRT-I deficiency reduced the expression of genes encoding enzymes involved in oxidation of fatty acids and amino acids, such as branched-chain amino acids, and increased the expression of genes encoding glycolytic enzymes. The changes in metabolic gene expression were associated with Warburg effect-like metabolic reprogramming that included intracellular accumulation of lipids, increased glucose/glutamine consumption and lactate production. Moreover, depletion of ESCRT-I components led to expansion of the ER and accumulation of small mitochondria, most of which retained proper potential and performed ATP-linked respiration. Mechanistically, the observed transcriptional reprogramming towards glycolysis in the absence of ESCRT-I occurred due to activation of the canonical NFκB and JNK signaling pathways and at least in part by perturbed lysosomal degradation. We propose that by activating the stress signaling pathways ESCRT-I deficiency leads to preferential usage of extracellular nutrients, like glucose and glutamine, for energy production instead of lysosome-derived nutrients, such as fatty acids and branched-chain amino acids.

Keywords:  ESCRT; JNK; NFκB; fatty acid oxidation; glycolysis; mitochondria

DOI:  https://doi.org/10.1007/s00018-024-05490-y