bims-celmim 2025-10-05 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–10–05
23 papers selected by
Marc Segarra Mondejar, AINA

Evaluating the effects of synthetic POM cycles and NAD+ kinase expression on fatty alcohol production in Saccharomyces cerevisiae.
Three-dimensional human mucopolysaccharidosis IVA chondrocyte culture reveals significant impairments in the lysosomal-mitochondrial crosstalk.
Changes in the endoplasmic reticulum‑mitochondria communication in dermal fibroblasts from early‑stage bipolar disorder patients: Skin‑brain axis as a new route to understand the pathophysiology of mental illness?
Rewiring amino acids in cancer.
Targeted LC-MS profiling reveals dysregulated glycolytic flux and TCA cycle stalling in POAG plasma.
Lipid reprogramming and ferroptosis crosstalk in clear cell renal cell carcinoma: metabolic vulnerabilities and therapeutic targeting.
An extended network for regulation of heme homeostasis in cells.
Fundamentals of Gas-Free Calibrated fMRI for Oxidative Metabolic Neuroimaging.
Metabolic coupling of ROS generation and antioxidant synthesis by the GABA shunt pathway in myeloid-like blood progenitor cells of Drosophila.
Clinicopathological analysis of GLUT-1, GLS1, and GLS2 expression in breast cancer tissues from Jordanian patients.
Metabolic profiles of squamous cell lung carcinoma and diagnostic model construction.
Lysosome-dependent nutrient scavenging underlies stress adaptation during epithelial-to-mesenchymal transition.
Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
Dietary methionine restriction primes T cell metabolism for activation and tumor inhibition and enhances the efficacy of immune checkpoint blockade.
AMPK-activated BAP1 regulates pVHL stability and tumor-suppressive functions.
Systematic metabolomic study on the plasma and urine of a mouse model of Alport syndrome.
The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.
MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes.
Ceramide Links Alzheimer's Disease to Decreased Cancer Risk: A Lipid Behind the Enigma of Inverse Comorbidity.
DUSP6 is upregulated in metastasis and influences migration and metabolism in pancreatic cancer cells.
Calmodulin binding is required for calcium mediated TRPA1 desensitization.
Identification of biomarkers for renal cell carcinoma in plasma samples measured using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry.
Spatial distribution of hyperpolarized [1-13C]pyruvate MRI and metabolic PET in the human brain.

PLoS One. 2025 ;20(9): e0333299

Evaluating the effects of synthetic POM cycles and NAD+ kinase expression on fatty alcohol production in Saccharomyces cerevisiae.

Bonnie A McNeil, Charfeddine Khalifa, Anagha Krishnan, David T Stuart.

Efficient regeneration of NADPH can be a limiting factor for anabolic processes in engineered microbial cells. We tested the ability of four distinct Pyruvate-Oxaloacetate-Malate "POM" cycles composed of Saccharomyces cerevisiae pyruvate carboxylase (PYC1 or PYC2), malate dehydrogenase ('MDH1 or 'MDH2), and malic enzyme (sMAE1) to improve NADPH regeneration. Only the PYC1, 'MDH2, sMAE1 combination increased the titer of fatty alcohols produced by engineered S. cerevisiae indicating that not all combinations of POM cycle enzymes could drive this pathway. Metabolomic analysis revealed that introduction of the POM cycle altered the concentration of intermediates in amino acid biosynthetic pathways and the trichloroacetic acid cycle suggesting that the POM cycle had wider effects than previously anticipated. Overexpression of the endogenous NAD+ kinases UTR1, YEF1, and a cytosolic version of POS5 were also tested. Only expression of POS5c resulted a significant increase in fatty alcohol titer. In these minimally engineered strains, combined overexpression of the PYC1, 'MDH2, sMAE1 POM cycle and POS5c did not further increase titers. These findings indicate that more extensive metabolomic and proteomic investigations are required to identify combinations of enzymes that will yield an optimal increase in NADPH to meet anabolic demands without imposing excessive metabolic burden or disrupting pathways that might compromise bioproduct synthesis.

DOI: https://doi.org/10.1371/journal.pone.0333299
Sci Rep. 2025 Oct 01. 15(1): 34140

Three-dimensional human mucopolysaccharidosis IVA chondrocyte culture reveals significant impairments in the lysosomal-mitochondrial crosstalk.

Andrés Felipe Leal, Sampurna Saikia, Shaukat A Khan, Shunji Tomatsu.

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder (LSD) caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase enzyme. MPS IVA patients suffer from skeletal dysplasia due to the abnormal function of chondrocytes. Given the interactions of lysosomes with various intracellular organelles, it is not surprising that lysosomal dysfunction can lead to improper functioning of lysosome-interacting organelles such as mitochondria. Mitochondrial alterations have been evaluated in several LSDs; nevertheless, they have not been fully addressed in MPS IVA. In this study, we assessed the mitochondrial alterations in MPS IVA chondrocytes using a three-dimensional culture approach. Our findings revealed that MPS IVA chondrocytes exhibited an increased mitochondrial-triggered apoptosis profile, mitochondrial depolarization, and heightened oxidative stress. Additionally, the proteins associated with mitophagy, PINK1/Parkin, were significantly reduced in MPS IVA chondrocytes, whereas LC3-II and p62 were elevated. Our assessment of mitochondrial dynamics revealed increased levels of Drp1 and Fis1 along with decreased levels of Opa1. Regarding biogenesis, the mitochondrial regulators TFAM and PGC-α were upregulated in MPS IVA chondrocytes. Finally, MPS IVA chondrocytes showed a metabolic shift from mitochondrial respiration towards a glycolytic profile. Collectively, these data indicate that alterations in mitochondrial homeostasis may play a critical role in the pathogenesis of MPS IVA.

DOI: https://doi.org/10.1038/s41598-025-04871-y
Int J Mol Med. 2025 Dec;pii: 213. [Epub ahead of print]56(6):

Changes in the endoplasmic reticulum‑mitochondria communication in dermal fibroblasts from early‑stage bipolar disorder patients: Skin‑brain axis as a new route to understand the pathophysiology of mental illness?

Ana Catarina Pereira, Ana Patrícia Marques, Rosa Resende, Laura Serrano-Cuñarro, Margarida Caldeira, Tânia Fernandes, Mariana Batista, António Macedo, Joana Barbosa De Melo, Nuno Madeira, Cláudia Cavadas, Maria Teresa Cruz, Cláudia Fragão Pereira.

  Compromised cellular resilience in bipolar disorder (BD) has been associated with structural brain changes and cognitive deficits caused by perturbation of redox status, endoplasmic reticulum (ER) stress and innate immunity. These crucial cellular events are regulated by the ER‑mitochondria close contacts at mitochondria‑associated membranes (MAM) through Ca2+ transfer and lipids exchange between these organelles. The present study aimed to investigate the structural and functional alterations in MAM during BD early stages using patient‑ and control‑derived cellular models, namely dermal fibroblasts. Morphological alterations in close ER‑mitochondria contacts at MAM occur in BD cells and correlate with functional changes, as shown by lipid droplets accumulation. The MAM dysfunction in BD cells parallels changes in Ca2+ homeostasis, namely inhibition of store‑operated Ca2+ entry (SOCE), ER Ca2+ depletion and attenuation of ER‑mitochondria Ca2+ transfer, as well as enhanced ER and oxidative stress and NOD‑like receptor family pyrin domain‑containing 3 (NLRP3) inflammasome activation leading to sterile inflammation. The absence of inflammasome activation upon lipopolysaccharide exposure supports the compromised ability of BD cells (fibroblasts as well as monocytes) to deal with stressful conditions. In conclusion, MAM disruption is highlighted as a potential pathophysiological mechanism driving impaired cellular resilience in BD. Skin fibroblasts are a particularly attractive cellular model for studying mental illnesses, such as BD, due to the shared developmental origin of epidermal and neural tissues. The ectodermal origins of the skin‑brain axis have been proposed as a novel route for understanding brain development, neurodevelopmental conditions and behavior modulation.

Keywords:  bipolar disorder; endoplasmic reticulum; mitochondria; mitochondria-associated membranes; skin fibroblasts

DOI:  https://doi.org/10.3892/ijmm.2025.5654
Biochim Biophys Acta Rev Cancer. 2025 Sep 26. pii: S0304-419X(25)00207-0. [Epub ahead of print]1880(6): 189465

Rewiring amino acids in cancer.

Yiqing Zhang, Jianxin Lyu, Hezhi Fang.

  Cancer cells often survive in harsh microenvironments. To sustain rapid growth and proliferation, they reprogram metabolic pathways through multiple mechanisms to meet the demands of biosynthesis and energy production. Both essential and non-essential amino acids support cancer cell synthesis of macromolecules such as proteins and nucleotides. They also participate in diverse biological processes, including oxidative stress defense, epigenetic regulation, and signaling pathway modulation. In this review, we summarize the role of amino acid metabolism in cancer initiation and progression, and highlight recent advances in therapies targeting amino acid metabolism. The aim of this review is to stimulate both basic research and translational studies on cancer therapy through targeting amino acid metabolism.

Keywords:  Amino acid; Cancer metabolism; Metabolism reprogramming; Targeted therapy

DOI:  https://doi.org/10.1016/j.bbcan.2025.189465
Sci Rep. 2025 Oct 01. 15(1): 34212

Targeted LC-MS profiling reveals dysregulated glycolytic flux and TCA cycle stalling in POAG plasma.

Yizhen Tang, Xuanqi Zhang, Xiaoxiao Chen, Jiayong Li, Minyue Xie, Qianru Wu, Yinghan Zhang, Chi-Wai Do, Xinghuai Sun.

Glaucoma is the leading cause of irreversible blindness. Primary open-angle glaucoma (POAG) is the most common form globally and has been linked to mitochondrial dysfunction and energy deficiency. Plasma was used to investigate the energy metabolomic profiles of patients with POAG and controls, and to determine the metabolite flux within the core interconnected energy pathways. Targeted liquid chromatography-mass spectrometry (LC-MS) was used to analyze plasma energy metabolism in POAG patients and controls. Differential metabolite expression analysis, correlation analysis, and pathway flux analysis were then conducted to elucidate the metabolic alterations and the mechanisms underlying POAG. Our findings reveal elevated levels of D-Glucose-6-phosphate(G6P), 6-Phosphogluconic acid(6PGA), Adenosine diphosphate(ADP), Adenosine monophosphate(AMP), Adenosine triphosphate(ATP), Guanosine diphosphate(GDP), Inosine monophosphate(IMP), Phosphoenolpyruvic acid(PEP), Phosphorylethanolamine(pEtN), and uridine diphosphate N-acetylglucosamine(UDP-GlcNAc) in POAG patients. Conversely, POAG patients showed reduced ratios of ATP/ADP, Glycerol-3-phosphate(G3P)/ Dihydroxyacetone phosphate(DHAP), 1,3-Bisphosphoglyceric acid(BPG)/DHAP, PYR/PEP, Fumarate/Succinate, Arginine/ASA, and Citrulline/Ornithine. These findings collectively suggest disrupted flux in glycolysis, the TCA cycle, urea cycle, and tyrosine metabolism, offering new insights into POAG mechanisms and potential therapeutic strategies targeting energy metabolic pathways.

DOI: https://doi.org/10.1038/s41598-025-15836-6
Mol Cancer. 2025 Oct 02. 24(1): 236

Lipid reprogramming and ferroptosis crosstalk in clear cell renal cell carcinoma: metabolic vulnerabilities and therapeutic targeting.

Qing Deng, Yu Ji, Jian Liu, Tao Wen.

  Clear cell renal cell carcinoma (ccRCC) features metabolic dysregulation, with altered lipid metabolism and ferroptosis dysregulation driving malignancy. This review examines the interplay between lipid reprogramming and ferroptosis resistance in ccRCC pathogenesis and therapy. Tumor cells exploit lipid accumulation for growth and evade ferroptosis adaptively. Preclinical studies show targeting lipid metabolism or inducing ferroptosis synergizes with anti-angiogenic/immunotherapy, improving survival. This study provides a framework for dual therapeutic strategies.

Keywords:  CcRCC; Ferroptosis; Lipid reprogramming; Metabolic vulnerabilities; Therapeutic targeting

DOI:  https://doi.org/10.1186/s12943-025-02457-w
Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2508237122

An extended network for regulation of heme homeostasis in cells.

Andrea E Gallio, Noa A Marson, Kate J Heesom, Philip A Lewis, Dominic Alibhai, Celyn A Dugdale, Andrew Herman, Jaswir Basran, Andrew J Hudson, Emma L Raven.

  Iron-bound tetrapyrroles (hemes) are essential for the regulation of cellular functions and bioenergetics. The processes of heme biosynthesis, transport, and degradation are responsible for the supply of heme in mitochondria and its insertion into other downstream proteins. What remains unresolved is how these processes interconnect and the wider implications for the cell in the restoration of homeostasis when heme concentrations change. We demonstrate a wide-ranging and coordinated response to changes in intracellular heme in HEK293 cells through a network of complementary mechanisms that extend well beyond the direct regulation of heme biosynthesis and degradation. These responses connect changes in heme homeostasis to mitochondrial function, including core metabolic processes such as the tricarboxylic acid cycle and oxidative phosphorylation, as well as to enzymes involved in the control and storage of iron. Our findings demonstrate far-reaching consequences to perturbations of heme homeostasis and provide insights into the complexity of the cellular hemome.

Keywords:  biosensing; heme; heme biosynthesis; proteomics; tetrapyrroles

DOI:  https://doi.org/10.1073/pnas.2508237122
J Neurochem. 2025 Oct;169(10): e70217

Fundamentals of Gas-Free Calibrated fMRI for Oxidative Metabolic Neuroimaging.

Fahmeed Hyder, Peter Herman.

  Brain's high energy demands require abundant production of ATP from glucose oxidation, mandating coupling between neural activity and nutrient supply. Understanding how neural activity augments blood flow (CBF) to support metabolism of glucose (CMRglc) and oxygen (CMRO2) can help unravel mysteries of neurovascular and neurometabolic couplings underlying functional MRI (fMRI) with blood oxygenation level-dependent (BOLD) contrast. Key to this enigma is oxygen extraction fraction (OEF). Fundamentally, OEF is defined by flow-metabolism (i.e., CBF-CMRO2) coupling generating mitochondrial ATP to signify limits of hypoxia and ischemia. However, to fully account for observed CBF-CMRO2 coupling, the OEF must include a term for oxygen diffusivity (DO2) that is regulated by rheological properties of blood. BOLD contrast depends on intravoxel spin dephasing of tissue water protons due to paramagnetic fields generated by deoxyhemoglobin. During augmented neural activity, if CBF increases more than CMRO2, then deoxyhemoglobin (paramagnetic) is replaced by perfusing oxyhemoglobin (diamagnetic) to increase BOLD signal. Calibrated fMRI converts BOLD contrast into OEF according to the deoxyhemoglobin dilution model. Agreement across these OEF models (i.e., OEF trifecta) authenticates calibrated fMRI, both gas-based and gas-free methods. CMRO2 by gas-free calibrated fMRI easily and reproducibly tracks neural activity, while combining it with CMRglc can also reveal aerobic glycolysis. In summary, there is translational potential of gas-free calibrated fMRI for metabolic imaging in the resting and stimulated brain, from neurodegeneration to neurological disorders.

Keywords:  astrocyte; erythrocytes; excitation; glucose; glycogen; inhibition; lactate; neuron; oxygen

DOI:  https://doi.org/10.1111/jnc.70217
PLoS Genet. 2025 Sep 29. 21(9): e1011602

Metabolic coupling of ROS generation and antioxidant synthesis by the GABA shunt pathway in myeloid-like blood progenitor cells of Drosophila.

Manisha Goyal, Sakshi Tiwari, Jagriti Arora, Bruce Cooper, Ramaswamy Subramanian, Tina Mukherjee.

Redox balance is crucial for normal development of stem and progenitor cells that reside in oxidative environments. In this study, we explore the mechanisms of redox homeostasis in such niches and show that myeloid-like blood progenitor cells of the Drosophila larval lymph gland, that generate reactive oxygen species (ROS), moderate it developmentally by de novo synthesizing glutathione (GSH) to ensure redox balance. During lymph gland development, as the blood-progenitor cells oxidize pyruvate via the TCA cycle leading to the generation of ROS, GABA-shunt restricts pyruvate dehydrogenase (PDH) activity and consequently TCA cycle flux. This moderation enables a metabolic rerouting of TCA-derived oxaloacetate (OAA) to pyruvate via gluconeogenesis, which is necessary to sustain serine levels, the rate-limiting precursor for de novo GSH synthesis. Disruption of GABA metabolism causes metabolic imbalance, marked by excessive PDH activity and heightened TCA cycle flux. This results in reduced OAA availability, impaired gluconeogenic capacity, and insufficient serine/GSH production, ultimately leading to ROS dysregulation. Overall, this study identifies a unique metabolic framework in blood progenitor cells, where the GABA shunt, by restraining PDH and TCA cycle activity, maintains ROS at developmental levels. By coupling TCA-derived metabolites to GSH production, this state enables the TCA cycle to support both ROS generation and ROS scavenging, ensuring the developmental roles of ROS while preserving progenitor homeostasis.

DOI: https://doi.org/10.1371/journal.pgen.1011602
Sci Rep. 2025 Oct 01. 15(1): 34135

Clinicopathological analysis of GLUT-1, GLS1, and GLS2 expression in breast cancer tissues from Jordanian patients.

Haneen A Basheer, Ahlam Zaid Alkilani, Samir Al Bashir, Maram A Alhusban, Lina Elsalem, Sura Bilal AlOmari, Qosay Mahmoud Sharqiah, Kamyar Afarinkia.

  Breast cancer remains the most common malignancy among women, with significant heterogeneity in molecular subtypes and clinical outcomes. This study examines the clinicopathological significance of GLUT-1, GLS1, and GLS2 expression in breast cancer tissues from Jordanian patients, focusing on their role in metabolic reprogramming and potential as therapeutic targets. Using tissue microarray analysis and immunohistochemistry, we evaluated 306 invasive breast cancer cases and 52 normal tissue samples. Overexpression of all three markers was observed in tumor tissues compared to normal samples (p ≤ .01). GLUT-1 and GLS2 showed significant associations with higher tumor grades and triple-negative breast cancer (TNBC) subtypes, highlighting their potential role in aggressive tumor biology. Conversely, GLS1 expression was consistently elevated in cancer tissues but did not vary significantly across grades or subtypes. Strong correlations between high GLUT-1/GLS2 expression and Ki-67 proliferative index underscore their contributions to tumor proliferation and metabolic adaptation. Population-specific patterns, such as the higher GLS2 expression in HER2-negative cases, reflect potential genetic or environmental influences unique to Jordanian patients. These findings emphasize the critical role of metabolic reprogramming in breast cancer progression and underscore the translational potential of targeting GLUT-1 and GLS2, particularly in aggressive subtypes like TNBC. Further research is warranted to explore functional mechanisms and validate these markers in diverse populations. This study provides novel insights into the metabolic dynamics of breast cancer, offering a foundation for regionally tailored therapeutic strategies.

Keywords:  Breast cancer; GLUT-1; Glutaminases; Metabolic reprogramming; Triple-negative breast cancer

DOI:  https://doi.org/10.1038/s41598-025-03123-3
Sci Rep. 2025 Sep 30. 15(1): 34015

Metabolic profiles of squamous cell lung carcinoma and diagnostic model construction.

Kyung Soo Kim, Seok Whan Moon, Mi Hyung Moon, Seung Joon Kim, Kwang Youl Kim, Dong Wook Jekarl.

  Cancer cells exhibit metabolic reprogramming to fulfill their increased demands for abnormal growth and proliferation. We studied metabolic profiles of squamous cell lung carcinoma (LUSC).Elevated arginine levels and reduced acylcarnitine C18:2, along with decreased phosphatidylcholine (PC) with acyl-alkyl residues C38:0 were associated with the diagnosis and prognosis of LUSC. Most of the PCs demonstrated a decrease, while lysophosphatidylcholines (LPC) exhibited an increase in LUSC patients. Network analysis unveiled that LPCs mediated PC and amino acids subgroup in LUSC compared to the control group. Analysis of public LUSC data confirmed associations between the expression levels of genes encoding enzymes involved in the biosynthesis pathways of arginine, proline (ASL, OTC, PYCR2), PC (CEPT1, CHPT1, LPCAT1) and LPC (LCAT, PLA2G16, PLB1) with a 5-yr survival outcome. The observed metabolic reprogramming in LUSC patients suggested the potential utility of metabolites as a supportive biomarkers for LUSC diagnosis.

Keywords:  Feature selection; LASSO; Lung squamous cell carcinoma; Mass spectormetry; Metabolic profiles

DOI:  https://doi.org/10.1038/s41598-025-12412-w
bioRxiv. 2025 Sep 23. pii: 2025.09.22.677807. [Epub ahead of print]

Lysosome-dependent nutrient scavenging underlies stress adaptation during epithelial-to-mesenchymal transition.

Michal J Nagiec, Paola M Cavaliere, Friederike Dundar, Derrick M Spencer, Nikolaos Koundouros, Joana B Nunes, Sejeong Shin, Sang-Oh Yoon, Julie Han, Andre Chavez, Olivia M Kester, Rabia Khan, Paul Zumbo, Eric E Gardner, Bobak Parang, Anders P Mutvei, John M Asara, Steven P Gygi, Doron Betel, Noah Dephoure, John Blenis.

Metastatic cancer cells invade tissue, overcome nutrient stress, and survive transit to distant sites. Many of the mechanisms that support these processes are incompatible with proliferation. This study defines cellular transition states in breast epithelial cells undergoing epithelial-mesenchymal transition (EMT) driven by ERK2 and TGF-β signaling. EMT triggers robust endolysosomal system upregulation and metabolic adaptations that balance proliferative and invasive states. Surprisingly, invasive cells rely on scavenging via lysosomes and macropinocytosis to acquire amino acids, rather than plasma membrane transport, even in nutrient-rich conditions. Macropinocytosis increases intracellular amino acid storage, promoting survival during amino acid deprivation. This metabolic shift depends on c-MYC downregulation, an early EMT event. Reintroducing c-MYC suppresses the metabolic switch, endolysosomal induction, macropinocytosis, and the proliferation-to-migration transition. These findings reveal how cells dynamically balance proliferation and invasion, offering insights into transition states difficult to capture in models of breast cancer metastasis.

DOI: https://doi.org/10.1101/2025.09.22.677807
Nat Commun. 2025 Sep 30. 16(1): 8685

Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.

Sirikrishna Thatavarthy, Luciano A Abriata, Fernando Teixeira Pinto Meireles, Kelly E Zuccaro, Akhil Gargey Iragavarapu, Gabriela May Sullivan, Frank R Moss, Adam Frost, Matteo Dal Peraro, Halil Aydin.

Cardiolipin is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which cardiolipin influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics simulations, we determined that cardiolipin molecules extensively engage with the paddle domain of mitochondrial fusion protein OPA1, which controls membrane-shaping mechanisms. Structure-function analysis confirmed the interactions between cardiolipin and two conserved motifs of OPA1 at the membrane-binding sites. We further developed a bromine-labeled cardiolipin probe to enhance cryoEM contrast and characterized the structure of OPA1 assemblies bound to the cardiolipin brominated lipid bilayers. Our images provide direct evidence of cardiolipin enrichment within the OPA1-binding leaflet. Last, we observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin. This suggests that the partial replacement of cardiolipin by monolyso-cardiolipin, as observed in Barth syndrome, alters the malleability of the membrane and compromises proper remodeling. Together, these data provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.

DOI: https://doi.org/10.1038/s41467-025-63813-4
bioRxiv. 2025 Sep 23. pii: 2025.09.18.676961. [Epub ahead of print]

Dietary methionine restriction primes T cell metabolism for activation and tumor inhibition and enhances the efficacy of immune checkpoint blockade.

Xiaoqing Qing, Binita Chakraborty, Panpan Liu, Sandeep Artham, Patrick K Juras, Dongyin Guan, Kristen E Pauken, Ching-Yi Chang, Xia Gao.

The proliferation of many cancer cells is methionine dependent and dietary methionine restriction (MR) has shown anti-tumor effects in a wide variety of immunodeficiency preclinical models. Yet, whether MR exerts an anti-tumor effect in the presence of an immune-competent background remains inconclusive. Accumulating evidence has shown an essential role of methionine in immune cell differentiation and function. Thus, competition for methionine between tumor cells and immune cells in the tumor microenvironment may drive tumor growth and tumor response to therapy. Here, we aim to define the impact of MR on tumor growth and associated immunity. We first assessed the effect of MR in a series of immunocompetent mouse models of melanoma, colorectal cancer, breast cancer, and lung. MR led to a broad tumor inhibition effect across these models and such tumor inhibition was not sex-or genetic background-dependent but appears to be fully or partially immune-dependent. Through flow cytometry analysis, we found a consistent increase in intratumoral activated CD8 + T cells across different tumor models and depletion of CD8 + T cells partially or completely reversed MR-induced tumor inhibition in a model dependent manner. Interestingly in young healthy non-tumor-bearing mice, MR increased spleen CD3 + and CD8 + T cell populations. Metabolomics and RNAseq analysis of spleen-derived CD8 + T cells revealed significant increase in purine metabolism and amino acid metabolism and that are in line with the metabolic feature of activated T cells. Furthermore, MR improved the efficacy of anti-PD1 immune checkpoint blockade. Together, MR primes T cell metabolism for its anti-tumor effect and improves the efficacy of anti-PD1 checkpoint blockade.

DOI: https://doi.org/10.1101/2025.09.18.676961
Cell Death Differ. 2025 Sep 27.

AMPK-activated BAP1 regulates pVHL stability and tumor-suppressive functions.

Mei Li, Lei Huang, Jiayi Chen, Tangming Guan, Yalei Wen, Yingjie Zhu, Xiao Yang, Caishi Zhang, Xiuqing Ma, Rui Wan, Yuanqiao He, Yang Zhou, Yan Song, Haoxing Zhang, Tongzheng Liu.

The von Hippel-Lindau (VHL) protein (pVHL) functions as a potent tumor suppressor by mediating the degradation or inactivation of various substrates, including HIFα and Akt. However, pVHL is frequently downregulated in numerous cancers harboring wild-type VHL, and underlying mechanisms remains elusive. Aberrant glucose metabolism is a hallmark of cancer, driving tumor progression and therapeutic resistance. Despite this, the connection between glucose homoeostasis and pVHL turnover and functions has yet to be defined. In this study, we demonstrate that dysregulated glucose metabolism destabilizes pVHL in pancreatic ductal adenocarcinoma (PDAC), colorectal, and ovarian cancer cells. Mechanistically, energy stress induced by glucose starvation, 2-deoxyglucose (2-DG), or metformin activates AMP-activated protein kinase (AMPK), which subsequently phosphorylates and activates BAP1, a deubiquitinase whose specific function in targeting pVHL for deubiquitination and stabilization had not been previously characterized. Specifically, AMPKα phosphorylates BAP1 at residues S123, S469, and S583, enhancing the interaction between BAP1 and pVHL and promoting pVHL stabilization and tumor-suppressive function both in vitro and in vivo. Conversely, disrupting BAP1 phosphorylation through AMPKα depletion or reconstitution with a phosphorylation-defective BAP1 mutant (S123A/S469A/S583A) abolishes the BAP1-pVHL interaction, leading to impaired pVHL stabilization and accelerated tumor progression in cancer cell lines and patient-derived xenograft models. Clinically, our analysis reveals a positive correlation between levels of phosphorylated AMPKα (p-AMPKα), phosphorylated Ser123-BAP1 (pSer123-BAP1), and pVHL levels in PDAC, colorectal cancer, and ovarian cancer specimens. Collectively, these findings elucidate a novel mechanism linking dysregulated glucose metabolism to compromised function of the BAP1-pVHL tumor-suppressive axis. Our results suggest that therapeutic strategies designed to activate this pathway may represent a promising approach for treating cancers characterized by downregulated wild-type VHL and aberrant glucose metabolism.

DOI: https://doi.org/10.1038/s41418-025-01590-9
Sci Rep. 2025 Oct 02. 15(1): 34452

Systematic metabolomic study on the plasma and urine of a mouse model of Alport syndrome.

Hong Sang Choi, Songjin Oh, Moongi Ji, Byeongchan Choi, Sang Heon Suh, Chang Seong Kim, Seong Kwon Ma, Soo Wan Kim, Man-Jeong Paik, Eun Hui Bae.

  Chronic kidney disease (CKD) progression involves metabolic alterations that remain poorly understood. We conducted a comprehensive metabolomic study by using an Alport syndrome (AS) mouse model, which is a hereditary form of CKD characterized by progressive nephropathy and hearing loss, to identify key metabolic disturbances associated with disease progression. Plasma and urine samples were collected from male Col4a3 knockout (AS) and wild-type mice at 4 and 7 weeks and analyzed using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry. We identified 28 plasma and 42 urine metabolites that differed significantly (p < 0.05, VIP > 1.0 by PLS-DA) between AS and wild-type groups. At 4 weeks, the levels of metabolites involved in glycolysis/gluconeogenesis and the TCA cycle increased in the AS mice. By 7 weeks, the pathways related to amino acid metabolism (e.g., tryptophan metabolism and alanine, aspartate, and glutamate metabolism) and ketone body metabolism were significantly disrupted. Notably, palmitic acid and 5-methylcytidine emerged as potential biomarkers of disease progression. Our study provided novel insights into metabolic dysregulation and highlighted specific metabolites as potential biomarkers for early diagnosis and disease monitoring of CKD. These results might facilitate the development of targeted metabolic interventions for CKD.

Keywords:  Alport syndrome; Disease progression; Metabolic profile; Metabolomics; Renal insufficiency

DOI:  https://doi.org/10.1038/s41598-025-17620-y
Sci Adv. 2025 Oct 03. 11(40): eadw7376

The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.

Valentina Cianfanelli, Monica Nanni, Samantha Corrà, Sofia Mauri, David Sumpton, Sergio Lilla, Rossella De Cegli, Matteo Bordi, Giacomo Milletti, Caterina Ferraina, Arnaldur Hall, Michele Petraroia, Valentina Clausi, Ezio Giorda, Marco Scarsella, Alessandra Barbiera, Giulia Cadeddu, Marco Colasanti, Tiziana Persichini, Kenji Maeda, Apolinar Maya-Mendoza, Jiri Bartek, Chiara Di Malta, Franco Locatelli, Sara Zanivan, Shehab Ismail, Elena Ziviani, Francesco Cecconi.

Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the insult, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS. PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.

DOI: https://doi.org/10.1126/sciadv.adw7376
Nat Commun. 2025 Oct 03. 16(1): 8831

MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes.

Chunyan Wu, Tongtong Wang, Adhideb Ghosh, Fen Long, Anand Kumar Sharma, Tina Dahlby, Falko Noé, Ilenia Severi, Georgia Colleluori, Saverio Cinti, Antonio Giordano, Lianggong Ding, Radhika Khandelwal, Sarantos Kostidis, Martin Giera, Lucia Balazova, Vincent Gardeux, Laith Abu-Nawwas, Bart Deplancke, Sabita Chourasia, Sandra Kleiner, Bradford S Hamilton, Juan Manuel Alcántara Alcántara, Jonatan R Ruiz, Matthias Blüher, Anton Pekcec, Miroslav Balaz, Atan Gross, Heike Neubauer, Christian Wolfrum.

Metabolic disorders, including obesity and metabolic-associated steatohepatitis, arise from a chronic energy surplus. Thus, enhancing energy dissipation through increased respiration holds significant therapeutic potential for metabolic disorders. Through a comprehensive analysis of human and murine adipose tissues, along with a functional screen, we identify mitochondrial carrier homolog 2, a mitochondrial outer membrane protein, as a pivotal regulator of mitochondrial metabolism. Intriguingly, its expression in adipose tissue is a strong determinant of obesity in humans. Adipocyte-specific ablation of mitochondrial carrier homolog 2 improves mitochondrial function and whole-body energy expenditure, independent of uncoupling protein 1. Furthermore, mitochondrial carrier homolog 2 regulates mitochondrial influx of free fatty acids by modulating the sensitivity of carnitine palmitoyltransferase 1 to malonyl-CoA through direct physical interaction, leading to enhanced energy expenditure in adipocytes/adipose tissue. Here we show mitochondrial carrier homolog 2 functions as a negative regulator of energy metabolism in adipocytes and represents a potential target for treating obesity and related metabolic disorders.

DOI: https://doi.org/10.1038/s41467-025-63880-7
Cancer Res. 2025 Oct 01. 85(19): 3579-3581

Ceramide Links Alzheimer's Disease to Decreased Cancer Risk: A Lipid Behind the Enigma of Inverse Comorbidity.

Erhard Bieberich.

For decades, epidemiologic studies have consistently reported an inverse comorbidity between Alzheimer's disease (AD) and cancer: Individuals with AD are less likely to develop cancer and vice versa. The biological basis of this paradox has remained largely unresolved. A study by Kassir and colleagues in this issue of Cancer Research provides a compelling mechanistic insight into this paradox by demonstrating that amyloid precursor protein and its cleavage product Aβ40, known for their pathologic accumulation in the AD brain, also accumulate in peripheral T cells where they suppress mitochondrial ceramide production and lethal autophagy. This preservation of mitochondrial function enhances the antitumor immunity of T cells. Previous work has established that ceramide can promote neurodegeneration in the brain. The suppression of ceramide generation by amyloid precursor protein and Aβ40 in the periphery, thereby preserving mitochondrial integrity and supporting anticancer immunity, further establishes ceramide as a context-dependent regulator of cell fate and a key factor in the inverse AD-cancer relationship. See related article by Kassir et al., p. 3791.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2288
Sci Rep. 2025 Sep 30. 15(1): 33996

DUSP6 is upregulated in metastasis and influences migration and metabolism in pancreatic cancer cells.

Mariana T Ruckert, R McKinnon Walsh, Bailey A Bye, Austin E Eades, Wei Yan, Filip Bednar, Jiaqi Shi, Emily L Lasse Opsahl, Marina Pasca di Magliano, Costas A Lyssiotis, Michael N VanSaun, Vanessa S Silveira.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with KRAS mutations in ~ 95% of cases. While KRAS inhibitors have shown promise, therapeutic resistance necessitates combination approaches. In particular, it is important to understand how downstream signaling of KRAS supports PDAC growth. For example, DUSP6 has emerged as an important dual-specificity phosphatase regulating KRAS-MAPK signaling. DUSP6 is markedly overexpressed in PDAC tumors compared to normal pancreatic tissue, with transcriptomic and single-cell RNA-seq analyses revealing its enrichment in epithelial tumor cells, especially in metastatic lesions. High DUSP6 expression correlates with the quasi-mesenchymal/squamous molecular subtype and poorer survival outcomes. Gene set enrichment analyses linked DUSP6 to pathways involved in cell migration and metabolism in metastatic samples. Functionally, DUSP6 knockdown in PDAC cells increases ERK/MAPK activation and alters migration. Metabolic profiling revealed enhanced basal glycolysis upon DUSP6 suppression. However, combined glycolysis inhibition and DUSP6 knockdown did not affect migration, suggesting that glycolytic changes are not the driver of altered migratory behavior. These findings reveal that DUSP6 independently regulates migration and metabolism in PDAC, emphasizing its dual role in disease progression. This study underscores the significance of DUSP6 as a potential therapeutic target and provides new insights into its contributions to PDAC progression.

Keywords:  DUSP6; Glycolysis; Metastasis; Migration; Pancreatic cancer

DOI:  https://doi.org/10.1038/s41598-025-12967-8
Nat Commun. 2025 Sep 30. 16(1): 8640

Calmodulin binding is required for calcium mediated TRPA1 desensitization.

Justin H Sanders, Camila Garcia, Kehinde M Taiwo, Gregory Quevedo, Glory A Adekanye, Avnika Bali, Candice E Paulsen.

TRPA1 is an essential calcium (Ca2+)-permeable channel involved in nociception and inflammation. It exhibits complex and mechanistically elusive Ca2+ regulation with initial potentiation then rapid desensitization. We find that the universal Ca2+ sensor Calmodulin (CaM) binds TRPA1 in cells at rest and suppresses channel activity. Combining biochemical, biophysical, modeling, NMR spectroscopy, and functional approaches, we identify an evolutionarily conserved, high-affinity Ca2+/CaM binding element in the TRPA1 distal C-terminus. Genetic or biochemical perturbation of Ca2+/CaM binding to this site yields hyperactive channels that exhibit drastic slowing of desensitization with minor effect on potentiation. Higher extracellular Ca2+ partially rescues slowed desensitization. Our results identify a critical regulatory element in an unstructured TRPA1 region highlighting the importance of these domains, they reveal Ca2+/CaM is an essential TRPA1 auxiliary subunit required for proper channel function, and they suggest that Ca2+/CaM binding at this distal site stabilizes a long-range allosteric mechanism to drive rapid desensitization.

DOI: https://doi.org/10.1038/s41467-025-63767-7
Sci Rep. 2025 Sep 29. 15(1): 33509

Identification of biomarkers for renal cell carcinoma in plasma samples measured using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry.

Kun Zhai, Zhenkun Dong, Bingzhi Geng, Qiang Li, Zhaodu Liu, Di Wang, Hui Chen, Yan Cui.

  Metabolomics has been applied in several studies on cancer, but few studies have screened potential biomarkers for renal cell carcinoma (RCC) by integrating two mass mass spectrometers. This study aims to identify differentially expressed metabolites in plasma samples from patients with RCC compared with healthy individuals, which could be used as potential biomarkers to detect RCC. Plasma samples from 48 patients diagnosed with RCC and 22 healthy individuals were analyzed. Two mass spectrometers were utilized: liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). Ceramide m40:0 was significantly less abundant in plasma samples from patients with RCC (P < 0.05), whereas kynureine metabolites and glucose metabolites were significantly more abundant in plasma samples from patients with RCC compared with healthy controls (P < 0.05). A selection of 21 metabolites was utilized to construct an optimal diagnostic model, which achieved an area under the receiver operating characteristic curve (AUC) value of 0.860 (95% confidence interval 0.736-0.960). Significant differences were identified in the metabolic pathways of nicotinate and nicotinamide metabolism, pantothenate and coenzyme A biosynthesis, and beta-alanine metabolism between the RCC group and the control group (P < 0.05). The combined use of LC-MS and GC-MS effectively identified differentially expressed metabolites and dysregulated pathways based on analysis of plasma samples from patients with RCC compared with healthy individuals. The diagnostic model demonstrated robust performance with an AUC of 0.860, highlighting its reliability for RCC identification.

Keywords:  Biomarker; Gas chromatography-mass spectrometry; Liquid chromatography-mass spectrometry; Metabolite profiling; Metabolomics; Renal cell carcinoma

DOI:  https://doi.org/10.1038/s41598-025-17389-0
Imaging Neurosci (Camb). 2025 ;pii: IMAG.a.903. [Epub ahead of print]3

Spatial distribution of hyperpolarized [1-13C]pyruvate MRI and metabolic PET in the human brain.

Tyler Blazey, Andrei G Vlassenko, Manu S Goyal, Hany Soliman, Charles H Cunningham, Cornelius von Morze.

  Magnetic resonance imaging (MRI) of hyperpolarized (HP) [1-13C]pyruvate is a promising method for measuring cerebral energy metabolism in vivo. The substantial increase in signal provided by HP makes it possible to dynamically monitor the conversion of [1-13C]pyruvate to [1-13C]lactate and [13C]bicarbonate. The HP [1-13C]lactate signal is commonly associated with glycolic activity, whereas [13C]bicarbonate, a by-product of the reaction that forms acetyl-CoA, is linked to oxidative metabolism. However, there is compelling evidence that other factors, such as the concentration of monocarboxylate transporters, influence the production of HP [1-13C]lactate. To clarify the processes responsible for producing the topography of HP [1-13C]pyruvate and its metabolites, we spatially correlated group-average HP 13C MRI images with [18F]FDG, [15O]H2O, [15O]O2, and [15O]CO positron emission topography (PET) images from a separate group of 35 age- and sex-matched adults. We found that [1-13C]pyruvate correlated best with cerebral blood volume (CBV), whereas [1-13C]lactate and [13C]bicarbonate were most strongly associated with cerebral blood flow (CBF), glucose consumption (CMRglc), and oxygen metabolism (CMRO2). Neither [1-13C]lactate nor [13C]bicarbonate was correlated with non-oxidative glucose consumption, also known as aerobic glycolysis. These results are consistent with the view that in the healthy brain, the production of [1-13C]lactate reflects overall energy metabolism rather than being specific to glycolysis.

Keywords:  Lactate; MRI; brain imaging; energy metabolism; positron emission tomography

DOI:  https://doi.org/10.1162/IMAG.a.903