bims-celmim 2025-11-09 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–11–09
thirty papers selected by
Marc Segarra Mondejar, AINA

2-Deoxy-D-Glucose restores glial cell mitochondrial function and attenuates neuroinflammation.
Mitochondrial metabolic alterations fuel bladder cancer initiation.
The ER thioredoxin-related transmembrane protein TMX2 controls redox-mediated tethering of ER-mitochondria contacts.
Elevating cytosolic NADPH metabolism in endothelial cells ameliorates vascular aging.
Golgiphagy mediated by TM9SF3 acts as quality control for stressed Golgi.
Ammonium metabolism rewiring in the prostate cancer microenvironment: Mechanisms and clinical prospects.
Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.
Endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.
An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.
Membrane curvature at the ER-PM contact sites.
Direct measurements of luminal Ca2+ with endo-lysosomal GFP-aequorin reveal functional IP3 receptors.
The integral membrane protein smim4 modulates redox balance via malate compartmentalization in pancreatic cancer.
Emerging Roles of De Novo Proline Biosynthesis in Human Diseases.
Metabolites associated with abnormal glucose metabolism responding to primary care lifestyle intervention.
A mitochondria-targeted fluoropolymer nanoparticle with inherent mitophagy-inducing and red fluorescence properties for treatment of atherosclerosis.
Monitoring phospholipid dynamics in vivo with a fluorescent dye octadecyl rhodamine B.
Metabolic reprogramming in ischemic stroke: when glycolytic overdrive meets lipid storm.
A Single-Cell Methodology for Energy Metabolism Analysis in Parasitic Protozoa.
Microfluidic Chip for Axonal Injury Models Construction and Enabling Multi-Omics Analysis.
Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.
Multi-omics analysis reveals metabolic regulation of phosphatidylcholine, triglycerides, phosphatidylethanolamine, and cardiolipin metabolism in mouse liver with metabolic dysfunction-associated steatotic liver disease.
Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.
Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function.
TRIM8-dependent K63-ubiquitinated PGK1 promotes glycolysis and angiogenesis in gastric cancer via interaction with ACAT1.
Mitochondria-transliterated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy.
Systematic membrane thickness variation across cellular organelles revealed by cryo-ET.
Combining NAD(P)H-FLIM and PLIM of Ir5 pH sensor to optimize photodynamic therapy through metabolic intracellular pattern segmentation.
The photoswitchable cannabinoid azo-HU308 enables optical control of Ca2+ dynamics in INS-1 β-cells via off-target effects on TRPC channels.
KDM6A phosphorylation suppresses PER2 to confer a glycolytic vulnerability in HNSCC.
The role of the ventromedial hypothalamus in glycemic responses.

Sci Rep. 2025 Nov 06. 15(1): 38885

2-Deoxy-D-Glucose restores glial cell mitochondrial function and attenuates neuroinflammation.

Payam Gharibani, Yu Guo, Shruthi Shanmukha, Judy J Lee, Katherine Kopp, Paul M Kim, Michael D Kornberg.

  Neuroinflammation plays a central role in a wide spectrum of neurological diseases, driven generally by reactive microglia and astrocytes. Inflammatory stimulation of microglia and astrocytes leads to a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, which is required to support pro-inflammatory effector functions. This metabolic reprogramming is associated with impaired mitochondrial dynamics, including reduced biogenesis, increased fragmentation, and loss of membrane potential. Targeting microglia and astrocyte metabolism may offer a novel therapeutic approach for modulating neuroinflammation and restoring homeostatic immune functions. Here, we examined the potential of 2-Deoxy-D-Glucose (2DG), a glycolysis inhibitor, to attenuate neuroinflammation by restoring mitochondrial dynamics. In BV2 and primary glial cultures, low-dose 2DG reversed LPS-induced metabolic reprogramming, restoring OXPHOS, reducing mitochondrial fragmentation, and enhancing biogenesis. In vivo, it preserved spare respiratory capacity and increased complex-V activity in brain mitochondria from LPS-treated mice without affecting oxidative stress. At a mechanistic level, 2DG restored activation of AMP-activated protein kinase, a master regulator of mitochondrial dynamics. In conjunction with these metabolic effects, 2DG suppressed LPS-induced pro-inflammatory gene expression while enhancing markers associated with the resolution of inflammation and tissue repair. Critically, systemic low-dose 2DG reduced neuroinflammation and restored immune homeostasis in two LPS-induced mouse models, highlighting its therapeutic potential in neurological disorders.

Keywords:  2-Deoxy-D-Glucose; Immunometabolism; Mitochondrial dynamics; Mitochondrial function; Neuroinflammation

DOI:  https://doi.org/10.1038/s41598-025-22677-w
Nat Rev Urol. 2025 Nov 04.

Mitochondrial metabolic alterations fuel bladder cancer initiation.

Maria Chiara Masone.

DOI: https://doi.org/10.1038/s41585-025-01110-x
Cell Rep. 2025 Oct 30. pii: S2211-1247(25)01257-4. [Epub ahead of print]44(11): 116486

The ER thioredoxin-related transmembrane protein TMX2 controls redox-mediated tethering of ER-mitochondria contacts.

Junsheng Chen, Megan C Yap, Arthur Bassot, Danielle M Pascual, Tadashi Makio, Jannik Zimmermann, Heather Mast, Rakesh Bhat, Samuel G Fleury, Yuxiang Fan, Adriana Zardini Buzatto, Jack Moore, Klaus Ballanyi, Liang Li, Michael Overduin, M Joanne Lemieux, Hélène Lemieux, Grazia M S Mancini, Bruce Morgan, Paul C Marcogliese, Thomas Simmen.

  Thioredoxin-related transmembrane proteins (TMXs) of the endoplasmic reticulum (ER) determine not only redox conditions within the ER lumen but also the formation and function of ER-mitochondria membrane contact sites (ERMCS). The presence of cytosolic, reactive oxygen species (ROS)-derived redox nanodomains at ERMCS suggests TMXs could also control these. The prime candidate for such a function is TMX2, the sole TMX family protein with a cytosolic thioredoxin domain. Indeed, TMX2 controls the extent of ERMCS through interaction with outer mitochondrial membrane proteins, including TOM70. Assisted by cytosolic peroxiredoxins, TMX2 moderates the sulfenylation of the TOM70 C206 residue. Thereby, TMX2 reduces mitochondrial Ca2+ uptake and metabolism. Accordingly, mutation of the TMX2 gene in cells from a patient with a neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS) results in hyperactive mitochondria. In a fly in vivo NEDMCMS model, TMX2 knockdown manifests predominantly in glial cells, where it prevents seizure-like behavior.

Keywords:  CP: Molecular biology; Ca(2+); ER; MCS; PRDX; TMX2; TOM70; endoplasmic reticulum; membrane contact sites; mitochondria; peroxiredoxin; redox

DOI:  https://doi.org/10.1016/j.celrep.2025.116486
Nat Commun. 2025 Nov 03. 16(1): 9667

Elevating cytosolic NADPH metabolism in endothelial cells ameliorates vascular aging.

Dan Wu, Bo Tan, Zijie Cheng, Haoqi Li, Huimin Li, Yun Yin, Fenfen Ma, Tao Chen, Xin Dong, Wang Wang, Qingxun Hu.

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) metabolism is independently regulated in different compartments in endothelial cells (EC). The metabolic profile and functional impact of NADPH during EC senescence remain largely unknown. Using a genetically encoded fluorescent indicator, we find that cytosolic, but not mitochondrial, NADPH level increases during EC senescence. Upregulation of glucose-6-phosphate dehydrogenase (G6PD) further elevates cytosolic NADPH level during EC senescence. Suppression of G6PD S-nitrosylation at C385 potentiates G6PD activity. G6PD overexpression alleviates, while its knockdown aggravates, vascular aging. NADPH is indispensable for G6PD to protect against vascular aging through increasing reduced glutathione and inhibiting HDAC3 activity. Among 1419 FDA-approved drugs, folic acid, catalyzed by methylenetetrahydrofolate dehydrogenase to generate NADPH, effectively alleviates vascular aging in angiotensin II-infused mice and naturally aged mice. The connection between NADPH metabolism and EC senescence provides a unique angle for understanding vascular aging and an efficient target for therapy.

DOI: https://doi.org/10.1038/s41467-025-64652-z
Dev Cell. 2025 Nov 03. pii: S1534-5807(25)00604-5. [Epub ahead of print]60(21): 2841-2843

Golgiphagy mediated by TM9SF3 acts as quality control for stressed Golgi.

Hallvard L Olsvik, Terje Johansen.

Selective autophagy is important for organelle quality control. In this issue of Developmental Cell, Yang et al. identify the Golgi resident transmembrane protein TM9SF3 as a selective autophagy receptor required for lysosomal degradation of Golgi fragments (Golgiphagy) following nutrient stress, pH disruption, blockade of ER-to-Golgi trafficking, and defects in Golgi-mediated glycosylation functions.

DOI: https://doi.org/10.1016/j.devcel.2025.09.019
Front Oncol. 2025 ;15 1673513

Ammonium metabolism rewiring in the prostate cancer microenvironment: Mechanisms and clinical prospects.

Zihao Ye, Hao Wu, Zhanhao Li, Ruizhe Ye, Yingliang Rao, Bin Liu, Baoshan Gao.

  Ammonium metabolism represents a critically understudied yet pivotal driver of prostate tumorigenesis and tumor microenvironment (TME) remodeling. The interplay between tumor metabolic reprogramming and the tumor microenvironment has emerged as a critical frontier in oncology research. While previous studies on prostate cancer metabolism have predominantly focused on lipid metabolism and the Warburg effect, the role of ammonium metabolism, particularly the urea cycle in tumor immune regulation remains insufficiently explored. This metabolic reprogramming constitutes a central node connecting catabolic nutrient breakdown to anabolic biosynthesis by integrating upstream amino acid deamination and transamination reactions with downstream pathways, generating key intermediates including α-ketoglutarate, coenzyme A, and citrate that concurrently fuel the tricarboxylic acid cycle and macromolecular synthesis. Crucially, oncogenic drivers such as Myc and p53 modulate this flux through epigenetic regulation of core enzymes such as glutaminase, glutamine synthetase and ornithine transcarbamylase, thereby channeling metabolism toward tumor progression. The immunomodulatory consequences manifest through dual mechanisms including TME immunosuppression driven by M2 macrophage polarization and immune evasion mediated via glutathione dependent redox homeostasis disruption. Beyond its established role in modulating redox homeostasis, ammonium metabolic reprogramming may additionally trigger novel cell death modalities such as ferroptosis by GSH/GPX4 axis. This emerging pathway offers promising therapeutic avenues for prostate cancer intervention. Synthesizing mechanistically validated insights from in vivo or in vitro models and clinical trials of ammonium-targeting inhibitors, this review proposes novel therapeutic strategies and candidate biomarkers. Moreover, the unique citrate and polyamine metabolism characteristics of prostate cancer may be impacted by these processes, offering promising avenues for future treatments.

Keywords:  ADT; SLC; TME; ammonium metabolism; prostate cancer

DOI:  https://doi.org/10.3389/fonc.2025.1673513
Nat Commun. 2025 Nov 03. 16(1): 9690

Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.

Yulseung Sung, Ya Chun Yu, Mirim Lee, Seonghun Lim, Yechan Lee, Mincheol Kang, Doru Kwon, Apeksha Parajulee, Junjeong Choi, Do Sik Min, Kuglae Kim, Wan Namkung, Yun-Hee Kim, Sang Myung Woo, Nam Doo Kim, Hee Chan Yoo, Jung Min Han.

The mitochondrial glutamine transporter SLC1A5_var plays a central role in the metabolic reprogramming of cancer cells by facilitating glutamine import into mitochondria for energy production and redox homeostasis. Despite its critical function, the development of effective and selective inhibitors targeting SLC1A5_var has remained a significant challenge. Here, we introduce iMQT_020, a selective allosteric inhibitor identified through structure-based screening. iMQT_020 disrupts the trimeric assembly of SLC1A5_var, causing metabolic crisis in cancer cells and selectively suppressing their growth. Mechanistically, iMQT_020 reduces glutamine anaplerosis and oxidative phosphorylation, resulting in a broad disruption of cancer metabolism. Additionally, iMQT_020 treatment epigenetically upregulates PD-L1 expression, enhancing the efficacy of combination therapies with anti-PD-L1 immune checkpoint inhibitors. These findings highlight the therapeutic potential of targeting SLC1A5_var as a critical metabolic vulnerability in cancer and demonstrate that targeting allosteric interprotomer interactions is a novel and promising therapeutic strategy for cancer treatment.

DOI: https://doi.org/10.1038/s41467-025-64730-2
J Cell Sci. 2025 Nov 03. pii: jcs.263920. [Epub ahead of print]

Endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.

Sebabrata Maity, Anwesha Dutta Gupta, Izaz Monir Kamal, Rajdeep Das, Rupsha Mondal, Arpit Tyagi, Deepak Sharma, Joy Chakraborty, Saikat Chakrabarti, Oishee Chakrabarti.

  The endoplasmic reticulum (ER) and mitochondria are known to affect myriad cellular mechanisms. More recently, dynamic association between them has been identified in different eukaryotes; these interactions vary in their composition and involvement in regulation of intracellular machineries. FAM134B or RETREG1, originally identified as an oncogene, regulates ER membrane shape and curvature. It is a key ER-phagy or reticulophagy receptor, which promotes autophagy of not only the ER but also simultaneous dual autophagy of ER and mitochondria. While it is known that FAM134B can potentiate contact with mitochondria, its direct involvement in affecting mitochondrial dynamics remains unexplored. Here we show that FAM134B can interact with the canonical fission-promoting protein, DRP1. Functional depletion of FAM134B leads to local Actin rearrangement and reduced DRP1 recruitment onto mitochondria, resulting in hyperfusion. A decrease in FAM134B levels is observed with aging in rat brains, cell and mouse models of Parkinson's disease and patient-derived samples. Our study establishes FAM134B as the ER partner that helps in maintaining mitochondrial morphology and dynamics.

Keywords:  DRP1; FAM134B; Fission; Mitochondrial hyperfusion

DOI:  https://doi.org/10.1242/jcs.263920
Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00858-5. [Epub ahead of print]85(21): 3893-3894

An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.

Zachary L Sebo, Navdeep S Chandel.

Solute carrier (SLC) genes encode the largest membrane transporter superfamily, with many orphan members of unknown function. In recent Cell Metabolism and Molecular Cell articles, Khan et al. and Dias et al. identify SLC25A45 as essential for mitochondrial import of methylated amino acids and subsequent carnitine synthesis.

DOI: https://doi.org/10.1016/j.molcel.2025.10.017
Trends Cell Biol. 2025 Nov 06. pii: S0962-8924(25)00225-9. [Epub ahead of print]

Membrane curvature at the ER-PM contact sites.

Yang Yang, Luis A Valencia, Bianxiao Cui.

  Membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) are essential for lipid transfer, calcium signaling, and membrane organization. While the formation and function of ER-PM contacts are increasingly well-characterized, the spatiotemporal regulation of their localization remains elusive. Emerging evidence using nanopatterned substrates, ultrastructural imaging, and protein localization analyses indicates that membrane curvature can act as a spatial cue for the recruitment of specific tethering proteins, influencing where contact sites form. This opinion article synthesizes recent advances linking membrane topography ER-PM contact organization and highlights systems where curvature actively orchestrates contact position through curvature-sensing proteins. It also outlines key unanswered questions about how membrane curvature integrates into broader signaling networks that govern organelle contact communication.

Keywords:  ER–PM contact; RyR2; calcium signaling; junctophilin; membrane curvature

DOI:  https://doi.org/10.1016/j.tcb.2025.10.002
J Cell Biol. 2025 Dec 01. pii: e202410094. [Epub ahead of print]224(12):

Direct measurements of luminal Ca2+ with endo-lysosomal GFP-aequorin reveal functional IP3 receptors.

Belén Calvo, Patricia Torres-Vidal, Alba Delrio-Lorenzo, Carla Rodriguez, Francisco J Aulestia, Jonathan Rojo-Ruiz, Beatriz Callejo, Bridget M McVeigh, Marco Keller, Christian Grimm, Viola Oorschot, Vera Moiseenkova-Bell, David I Yule, Javier Garcia-Sancho, Sandip Patel, M Teresa Alonso.

Endo-lysosomes are considered acidic Ca2+ stores, but direct measurements of luminal Ca2+ within them are limited. Here, we report that the Ca2+-sensitive luminescent protein aequorin does not reconstitute with its cofactor at highly acidic pH but that a significant fraction of the probe is functional within a mildly acidic compartment when targeted to the endo-lysosomal system. We leveraged this probe (ELGA) to report Ca2+ dynamics in this compartment. We show that Ca2+ uptake is ATP-dependent and sensitive to blockers of ER Ca2+ pumps. We find that the Ca2+ mobilizing messenger IP3 evokes robust luminal responses in wild-type cells, but not in IP3R knockout cells. Responses were comparable to those evoked by activation of the endo-lysosomal ion channels TPCs and TRPMLs. Stimulation with IP3-forming agonists also mobilized the store in intact cells. Super-resolution microscopy analysis was consistent with the presence of IP3Rs within the endo-lysosomal system. Our data reveal a physiologically relevant, IP3-sensitive store of Ca2+ within the endo-lysosomal system.

DOI: https://doi.org/10.1083/jcb.202410094
Nat Commun. 2025 Nov 05. 16(1): 9772

The integral membrane protein smim4 modulates redox balance via malate compartmentalization in pancreatic cancer.

Bo Wang, Xinyu Han, Xianlong Lin, Jinjing Wang, Chang You, Keke Chen, Yu Chen, Fanhao Meng, Huihui Jiang, Fulong Zheng, Yiqing Zhang, Jinya Lyu, Yuxiao Bai, Xiaoning Qu, Danyi Zhou, Minghua Jiang, Wei Cui, Jianxin Lyu, Hezhi Fang.

Reshaping metabolic compartmentalization is frequently observed in cancer cells, however, the underlying mechanisms and physiological implications are less known. Here, we show that pancreatic ductal adenocarcinoma (PDAC) patients with low integral membrane protein SMIM4 expression exhibits a poor prognosis and reduces oxidative stress in tumors, which can be confirmed in cultured human PDAC cells and mice Pdx1-Cre/KrasG12D/+/Trp53R172H/+ (KPC) cells. Mechanistically, SMIM4 interacts with and facilitates the assembly of SLC25A1-containing complexes, enabling SLC25A1-mediated malate/citrate exchange. Depleting SMIM4 has little effect on mitochondrial respiration but impairs the assembly of SLC25A1-containing complexes, thereby reshaping of malate compartmentalization. This shift promotes NADPH generation through increased cytosolic conversion of malate to pyruvate, protecting cells from glucose deprivation-induced apoptosis. Moreover, PDAC cells with low level of SMIM4 are resistant to RSL3-induced toxicity, indicating that PDAC tumors with high SMIM4 expression are promising candidates for treatment with oxidative stress inducers.

DOI: https://doi.org/10.1038/s41467-025-64734-y
FASEB Bioadv. 2025 Nov;7(11): e70071

Emerging Roles of De Novo Proline Biosynthesis in Human Diseases.

Ethan Pei, Junfeng Ma.

  De novo proline synthesis is a highly conserved and essential biochemical pathway in mammals. Beyond serving as a fundamental building block for proteins, proline also plays key roles in diverse cellular functions and maintaining tissue homeostasis. Over the past decade, accumulating evidence has underscored the significance of this pathway in regulating critical cellular processes, including redox balance, cell growth, signal transduction, and the synthesis of nucleotides and proteins, as well as overall cellular metabolism. The biosynthesis of proline is tightly controlled by multiple evolutionarily conserved mechanisms to ensure proper cellular function. Importantly, disruptions in proline metabolism-particularly changes in the activity or expression of enzymes involved in its synthesis and degradation-have been implicated in the onset and progression of several diseases, notably cancer and fibrosis. In this review, we highlight recent advances in understanding the regulation of de novo proline synthesis. We also examine how dysregulation of this pathway contributes to disease development and influences therapeutic outcomes. Finally, we explore the therapeutic potential of targeting proline metabolism in disease treatment.

Keywords:  biochemistry; de novo synthesis; metabolism; proline

DOI:  https://doi.org/10.1096/fba.2025-00147
Sci Rep. 2025 Nov 07. 15(1): 39093

Metabolites associated with abnormal glucose metabolism responding to primary care lifestyle intervention.

Ville M Koistinen, Suvi Manninen, Marjo Tuomainen, Kirsikka Aittola, Elina Järvelä-Reijonen, Tanja Tilles-Tirkkonen, Reija Männikkö, Niina Lintu, Leila Karhunen, Marjukka Kolehmainen, Santtu Mikkonen, Marko Lehtonen, Janne Martikainen, Kaisa Poutanen, Ursula Schwab, Pilvikki Absetz, Jaana Lindström, Timo A Lakka, Kati Hanhineva, Jussi Pihlajamäki.

  Type 2 diabetes can be prevented by lifestyle intervention. We aimed to identify metabolites that associate with glucose metabolism and respond to lifestyle intervention with evidence-based targets for nutrition and physical activity in individuals at high risk of type 2 diabetes. Standard oral glucose tolerance test (OGTT) was used to categorize 624 participants into those having normal glucose tolerance (NGT), isolated impaired glucose tolerance (IGT), IGT with increased fasting glucose (IGT + IFG), and type 2 diabetes. Plasma LC-MS metabolomics was performed to reveal metabolic signatures. The baseline group differences were analysed with the Kruskal-Wallis test and the effect of intervention with a linear mixed-effects model. Significant differences in the metabolite signature were observed between the baseline groups, particularly in amino acids, acylcarnitines, and phospholipids. Fatty acid amides, phospholipids, amino acids, dimethylguanidinovaleric acid, and 5-aminovaleric acid betaine responded most to the lifestyle intervention. Lysophosphatidylcholines containing odd-chain fatty acids showed associations with improved glucose metabolism. Twenty-five metabolites differed between the baseline groups, responded to the intervention, and were associated with changes in glucose metabolism. The findings suggest a metabolite panel could be used in distinguishing individuals with varying degrees of glucose metabolism and in predicting response to lifestyle interventions.

Keywords:  Acylcarnitines; Amino acids; Fatty acid amides; Impaired glucose metabolism; Metabolomics; Personalized treatment; Phospholipids

DOI:  https://doi.org/10.1038/s41598-025-25749-z
Nat Commun. 2025 Nov 07. 16(1): 9845

A mitochondria-targeted fluoropolymer nanoparticle with inherent mitophagy-inducing and red fluorescence properties for treatment of atherosclerosis.

Mengxiao Liang, Shengzhe Ruan, Qian Wang, Yuxue Cheng, Jiaqi Li, Changping Wang, Yiyun Cheng, Hui Wang.

Mitophagy is crucial for the selective autophagic degradation of damaged mitochondria, helping to maintain both mitochondrial and cellular homeostasis. Here, we report a fluoroalkylated polypyridinium that specifically targets mitochondria and exhibits high activity in mitophagy induction. The polymer effectively restores mitochondrial function and alleviates the inflammatory response in foam cells by activating mitophagy, and displays inherent red fluorescence under physiological conditions, allowing for direct tracing of its biodistribution in cells and in vivo. Besides, the polymer nanoparticle shows high serum stability due to the antifouling properties of fluoroalkyl tags. After intravenous administration, the nanoparticle reduces oxidative stress, promotes mitophagy, and decreases cellular senescence in atherosclerotic plaques, contributing to high therapeutic efficacy. This study presents an innovative and effective strategy for the treatment of atherosclerosis and other mitochondrial dysfunction-related inflammatory conditions.

DOI: https://doi.org/10.1038/s41467-025-64813-0
Cell Struct Funct. 2025 Oct 31.

Monitoring phospholipid dynamics in vivo with a fluorescent dye octadecyl rhodamine B.

Li Hao, Caiyi Zhao, Kuninori Suzuki.

  Phospholipids are major components of biological membranes. They play an essential role in intracellular signaling and organelle dynamics; however, the availability of suitable lipid-specific probes is limited, which has hindered studies on their spatial distribution and functional dynamics in living cells. Previously, we demonstrated that octadecyl rhodamine B chloride (R18) is transported to the endoplasmic reticulum via nonvesicular membrane transport. In this study, we showed that R18 is internalized in a phosphatidylethanolamine (PE)-dependent manner in vivo. The internalization of R18 in Saccharomyces cerevisiae is blocked in PE-deficient mutants, but restored by ethanolamine supplementation, which suggests strict PE dependence. Moreover, R18 delivered to vacuoles through autophagy was not terminally retained, but underwent Pep4- and Atg15-dependent export from the vacuoles. The exported R18 was then redirected to endosomes following prolonged autophagy. These results suggest that R18 may serve as an indicator of PE dynamics and vacuole-endosome lipid transport, which contributes to lipid homeostasis inside vacuoles.Key words: autophagy, in vivo lipid dynamics, octadecyl rhodamine B (R18), phospholipase, phospholipid, vacuole, yeast.

Keywords:  autophagy; in vivo lipid dynamics; octadecyl rhodamine B (R18); phospholipase; phospholipid; vacuole; yeast

DOI:  https://doi.org/10.1247/csf.25126
Cell Death Dis. 2025 Nov 03. 16(1): 788

Metabolic reprogramming in ischemic stroke: when glycolytic overdrive meets lipid storm.

Yuchun Wang, Minyan Ge, Jinling Wang, Yiming Xu, Nianhong Wang, Shumao Xu.

Ischemic stroke, a leading cause of global disability and mortality, remains inadequately treated beyond reperfusion, with persistent translational failures in neuroprotection. We posit metabolic reprogramming in ischemic stroke (MRIS) as the unifying pathophysiological driver, where acute compensatory glycolysis collides with enzymatic lipid peroxidation to ignite neuroinflammation and early deficits. This metabolic crisis transcends neuron-centric models, integrating single-cell heterogeneity with bidirectional brain-peripheral crosstalk: hepatic ketogenesis releases neuroprotective β-hydroxybutyrate; adipose lipolysis fuels inflammatory storms; and gut dysbiosis disrupts barrier integrity, amplifying neuroinflammation. MRIS progresses through temporally stratified phases. An acute glycolytic-excitotoxic crisis and nicotinamide adenine dinucleotide (NAD+) depletion trigger neuroimmune dysfunction. Subacute lipid peroxidation cascades trigger ferroptosis and microglial polarization, whereas chronic-phase recovery of executive networks is scaffolded by sirtuin-mediated mitochondrial biogenesis and the interplay between adenosine monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR). Spatial metabolomics and single-cell omics decode cell-type-specific vulnerabilities, revealing astrocytic lipid droplets, microglial succinate accumulation, and neuron-glia lactate shuttles as targetable nodes. Chronobiology further dictates therapeutic windows: lactate dehydrogenase A (LDHA) inhibition mitigates hyperacute acidosis, while NAD+ salvage pathways optimize chronic mitochondrial plasticity. We propose that metabolic reprogramming is a central amplifier of both ischemic injury and recovery, linking cerebral vascular occlusion to systemic organ dysfunction. By reframing stroke within a vascular-metabolic continuum, MRIS shifts the paradigm from a neuron-centric view to one of systemic bioenergetic failure, accounting for past translational gaps and opening pathways for precision therapies, from pentose phosphate pathway modulation to nanoparticle-based metabolite delivery and microbiome interventions. In this framework, metabolic plasticity becomes not just a consequence but a therapeutic target, transforming stroke from an untreatable vascular event to a modifiable metabolic disorder.

DOI: https://doi.org/10.1038/s41419-025-08114-w
Methods Mol Biol. 2026 ;2982 339-351

A Single-Cell Methodology for Energy Metabolism Analysis in Parasitic Protozoa.

Salomé C Vilchez-Larrea, Rafael J Argüello, Guillermo D Alonso.

  The metabolic adaptability of Trypanosoma cruzi, the causative agent of Chagas disease, and other trypanosomatids across their life cycle stages is a defining feature of their biology and pathogenicity. Studying parasite and host cell metabolic profiles during infections is crucial to understanding disease progression and developing targeted therapeutic interventions. Traditionally, researchers have faced limitations in effectively capturing the dynamic nature of metabolic shifts in real time, hindering our ability to unravel the complex interplay between the host and the pathogen. Approaching these questions requires a high-throughput technique capable of assessing the metabolic changes and preferences of both the parasite and the host cell under physiological conditions in infected cells and tissues. A novel analytical technique that promises to push forward our understanding of metabolic profiles during Trypanosoma cruzi infections has now been developed. Here, we describe the potential to exploit the Single-Cell Energetic Metabolism by Profiling Translation Inhibition (SCENITH™) to examine the energetic metabolism of T. cruzi during its distinct developmental stages-epimastigote, trypomastigote, and amastigote-allowing to unveil the metabolic shifts that underpin their survival and proliferation in diverse host environments. Additionally, SCENITH allows to study how infected host cells' metabolism changes in the presence of parasites. The variability in metabolic pathways offers a unique perspective for identifying and developing stage-specific drug targets, presenting opportunities for more effective therapeutic interventions.

Keywords:  Flow Cytometry; Host–Parasite interaction; Metabolic profile; SCENITH; Trypanosoma cruzi

DOI:  https://doi.org/10.1007/978-1-0716-4848-3_22
J Vis Exp. 2025 Oct 14.

Microfluidic Chip for Axonal Injury Models Construction and Enabling Multi-Omics Analysis.

Bing Zhou, Ruixuan Liu, Jiaxin Sun, Maoliang Lu, Qianwen Zhang.

Neurons polarize to form dendrites and axons, enabling intercellular communication. Axonal injury disrupts these connections and transmits damage signals to the soma, often leading to neuronal degeneration. Thus, maintaining axonal homeostasis is essential for promoting local axon regeneration and protecting against neurodegeneration. This process relies on cellular metabolism to supply energy and biosynthetic precursors and is sustained by mechanisms that regulate metabolic balance and eliminate by-products. However, neuronal metabolism is compartmentalized between the soma and axon and is further influenced in vivo by the surrounding microenvironment, such as astrocyte-derived metabolic activity (e.g., the astrocyte-neuron lactate shuttle). These factors complicate the investigation of neurons' intrinsic metabolic mechanisms. To address these challenges, here we developed a microfluidic platform for culturing primary cortical neurons in vitro that preserves key metabolic characteristics observed in vivo, including physiological glycolytic flux and mitochondrial respiration. This system provides a simplified model for investigating intrinsic metabolic remodeling in neurons after axonal injury. Conventional microfluidic chips support in vitro axonal injury models and are compatible with live-cell imaging, immunofluorescence staining, and hypoxia treatment. To accommodate large-scale transcriptomic and metabolomic analyses involving millions of cells, we further designed and fabricated high-throughput microfluidic chips with optimized operational protocols. The device features alternately arranged soma and axon chambers connected by microchannels, and axonal injury is induced by vacuum aspiration of fluid from the axon compartment. This platform enables rapid assessment of metabolite and enzyme dynamics, improving the accuracy and reproducibility of multi-omics investigations.

DOI: https://doi.org/10.3791/68915
J Biochem. 2025 Nov 04. pii: mvaf062. [Epub ahead of print]

Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.

Soumyadip Pal, Takaya Ishihara, Daiki Setoyama, Chang-Lin Chen, Kenta Onoue, Shigenobu Yonemura, Emi Ogasawara, Naotada Ishihara.

  Mitochondria contain their own DNA (mtDNA), which is essential for respiratory function. Multiple copies of mtDNA are assembled into dot-like structures called nucleoids. Nucleoids move dynamically within mitochondria, and their size and distribution are influenced by mitochondrial membrane fission and fusion. However, the molecular mechanisms and their pathophysiological significance, particularly in vivo, remain largely unknown. Here, we identify a novel role for ubiquinone, as well as natural quinones lacking electron-carrying capacity, in the organization of nucleoids and respiratory complexes, independent of their conventional roles. These quinones facilitate the association and packaging of mtDNA on the cardiolipin-enriched mitochondrial inner membrane. This quinone-dependent maintenance of nucleoids protects against mitochondrial dysfunction and heart failure induced by the anticancer drug doxorubicin. Our RNAi screen identifies a set of genes involved in mitochondrial diseases that exhibit nucleoid deformation, suggesting a novel therapeutic approach targeting mitochondrial nucleoids for various pathological conditions associated with mitochondrial dysfunction.

Keywords:  Mitochondrial DNA; cardiotoxicity; nucleoid; respiratory complex; ubiquinone

DOI:  https://doi.org/10.1093/jb/mvaf062
PLoS One. 2025 ;20(11): e0332177

Multi-omics analysis reveals metabolic regulation of phosphatidylcholine, triglycerides, phosphatidylethanolamine, and cardiolipin metabolism in mouse liver with metabolic dysfunction-associated steatotic liver disease.

Hong Liang, Kang Song.

The dysregulation of phosphatidylcholine (PC), triglycerides (TG), phosphatidylethanolamine (PE), and cardiolipin (CL) metabolism is believed to contribute to the development of MASLD. However, little is known about the mechanisms underlying the onset of this condition. To establish a mouse model of MASLD, C57BL/6J mice were fed a high-fat diet (HFD). Lipidomics was applied to identify differences in liver lipids. RNA-sequencing and bioinformatics analyses were conducted to investigate changes in the expression of genes and pathways associated with these metabolic processes. 49 lipid classes and 3221 lipid species were identified using positive- and negative-ion pattern identification. A total of 678 differentially expressed genes were identified, of which 364 were upregulated and 314 were downregulated in the MASLD group. KEGG enrichment pathway analysis highlighted the downregulation of four genes such as Gpat4, Gpcpd1, Chkb, and Etnppl. These findings contribute to our understanding of the metabolic changes associated with MASLD.

DOI: https://doi.org/10.1371/journal.pone.0332177
Nat Commun. 2025 Nov 04. 16(1): 9664

Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.

Berwini B Endaya, Lukáš Kučera, Dan-Diem Thi Le, Jessica B Spinelli, Andrea Brožková, Dominika Luptáková, Kryštof Klíma, Gabriela L Oliveira, Petra Brisudová, Klára Boháčová, Štěpána Boukalová, Renata Zobalová, František Kolář, Karel Chalupsky, Klára Dohnalová, Arash Yarmohammadi-Barzegar, Šárka Dvořáková, Evgeniya Biryukova, Marta Kaliaeva, Vladimír Havlíček, Radislav Sedláček, Jan Procházka, Libor Vítek, Sunghyouk Park, Pavel Martásek, Zdeněk Krška, Paulo J Oliveira, Michael V Berridge, Jiří Neužil.

Liver is endowed with high regenerative activity, so that the tissue regrows in mouse after partial hepatectomy within days. We reason that this requires de novo pyrimidine synthesis to support rapid progression via the cell cycle. We find that suppression of de novo pyrimidine synthesis prevents proliferation in regenerating liver, suppressing liver regrowth. Tracing studies and spatial metabolomics reveal a metabolic shift such that ammonia, normally detoxified to urea in the periportal region under homeostasis, is redirected for generating aspartate and carbamoyl phosphate periportally, and glutamine pericentrally, and these products are utilized as precursors by the de novo pyrimidine synthesis pathway. Our research uncovers a metabolic reprogramming leading to utilization of a toxic byproduct for anabolic pathways that are essential for liver regeneration.

DOI: https://doi.org/10.1038/s41467-025-65451-2
Nat Commun. 2025 Nov 03. 16(1): 9484

Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function.

Benjamin J Jenkins, Yasmin R Jenkins, Fernando M Ponce-Garcia, Chloe Moscrop, Iain A Perry, Matthew D Hitchings, Alejandro H Uribe, Federico Bernuzzi, Simon Eastham, James G Cronin, Ardena Berisha, Alexandra Howell, Joanne Davies, Julianna Blagih, Marta Williams, Morgan Marsden, Douglas J Veale, Luke C Davies, Micah Niphakis, David K Finlay, Linda V Sinclair, Benjamin F Cravatt, Andrew E Hogan, James A Nathan, Ian R Humphreys, Ursula Fearon, David Sumpton, Johan Vande Voorde, Goncalo Dias do Vale, Jeffrey G McDonald, Gareth W Jones, James A Pearson, Emma E Vincent, Nicholas Jones.

α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T-cell metabolism and function is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T-cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using murine models of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T-cells and delays the onset of diabetes in vivo in female mice. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T-cell-mediated inflammation.

DOI: https://doi.org/10.1038/s41467-025-65417-4
Cell Death Dis. 2025 Nov 03. 16(1): 780

TRIM8-dependent K63-ubiquitinated PGK1 promotes glycolysis and angiogenesis in gastric cancer via interaction with ACAT1.

Anqi Feng, Jianbin Zhang, Zeyu Wang, Zhukai Chen, Kang Fang, Zhaoxing Li, Hanyu Jiang, Zhuyun Leng, Shihan Zhang, Yuan Chu, Jingjing Lian, Tao Chen, Lechi Ye, Meidong Xu, Lingnan He.

Glycolysis is crucial for promoting cancer progression. However, the precise mechanism underlying glycolysis regulating the angiogenic process remains to be defined. Here, we demonstrate that in human gastric cancer cells, the E3 ligase TRIM8 promotes the K63-linked ubiquitination of the glycolytic enzyme PGK1 and improves its stability, which leads to acetyltransferase ACAT1 recruitment, increased interaction of PGK1 with ACAT1, and subsequent PGK1 acetylation-dependent glycolytic activity. This activity facilitates PGK1-mediated glycolysis, lactate accumulation and triggers a significant increase in endothelial cell migration and tube formation, which ultimately accelerates tumor angiogenesis in gastric cancer. TRIM8 levels are positively correlated with tumor angiogenesis and poor prognosis in gastric cancer patients. These findings elucidate a novel mechanism underlying the upregulation of angiogenesis mediated by K63 ubiquitination-regulated glycolysis in tumor cells and provide a molecular basis for eliminating gastric cancer angiogenesis by targeting TRIM8-dependent PGK1 K63 ubiquitination.

DOI: https://doi.org/10.1038/s41419-025-08015-y
Cell Death Differ. 2025 Nov 03.

Mitochondria-transliterated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy.

Dan Wu, Xin Zhao, Caiyu Shi, Jing Zhao, Zeyu Yan, Runjiao Zhang, Xianchun Lan, Jiaze An, Qichao Huang, Xianli He, Tingting Ren, Jinliang Xing.

To prevent cell death induced by elevated oxidative stress, cancer cells activate a series of antioxidant defense mechanisms to mitigate cytotoxicity, thereby enhancing the resistance to pro-oxidative therapy. However, the underlying antioxidant mechanisms in cancer cells remain inadequately understood. Through co-immunoprecipitation followed by quantitative mass spectrometry analysis, we for the first time identified that cytoplasmic ALDH1L1 translocates into mitochondria and co-localizes with mitochondrial transcription factor TFAM in cancer cells in a ROS-dependent feedback manner. Mitochondria-translocated ALDH1L1 maintains mitochondrial redox homeostasis by producing NADPH. Moreover, our findings revealed that the ROS-mediated oxidative modification of ALDH1L1 is necessary for its interaction with HSP90β and subsequent translocation into mitochondria via TOM70, where it binds to TFAM to prevent degradation by LONP1. Furthermore, we found that mitochondrial ALDH1L1 antagonized the double-edged role of ROS in cancer cell survival, indicating that disruption of ALDH1L1 expression promoted cancer cell proliferation and autophagy but concurrently diminished cellular capacity to counteract ROS-induced apoptosis. Consistently, ALDH1L1 knockout enhanced the anti-tumor effect of low-dose pro-oxidant Elesclomol, thereby achieving better efficacy and safety of pro-oxidant therapy. Furthermore, our results demonstrated that the combination of Elesclomol with HSP90 inhibitor Ganetespib exhibited synergistic anti-tumor effects. In conclusion, our findings that mitochondria-translocated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy can provide critical insights into developing effective pro-oxidative therapies against tumors.

DOI: https://doi.org/10.1038/s41418-025-01604-6
J Cell Biol. 2026 Jan 05. pii: e202504053. [Epub ahead of print]225(1):

Systematic membrane thickness variation across cellular organelles revealed by cryo-ET.

Desislava Glushkova, Stefanie Böhm, Martin Beck.

In eukaryotes, membrane-bound organelles create distinct molecular environments. The compartmentalizing lipid bilayer is a dynamic composite material whose thickness and curvature modulate the structure and function of membrane proteins. In vitro, bilayer thickness correlates with lipid composition. Cellular membranes in situ, however, are continuously remodeled, and the spatial variation of their biophysical properties remains understudied. Here, we present a computational approach to measure local membrane thickness in cryo-electron tomograms. Our analysis of Chlamydomonas reinhardtii and human cells reveals systematic thickness variations within and across organelles. Notably, we observe thickness gradients across the Golgi apparatus that orthogonally support long-standing models of differential sorting of transmembrane proteins based on hydrophobic matching. Our publicly available workflow readily integrates within existing tomogram analysis pipelines and, when applied across experimental systems, provides a quantitative foundation for exploring relationships between membrane thickness and function in native cellular environments.

DOI: https://doi.org/10.1083/jcb.202504053
Photochem Photobiol Sci. 2025 Nov 03.

Combining NAD(P)H-FLIM and PLIM of Ir5 pH sensor to optimize photodynamic therapy through metabolic intracellular pattern segmentation.

D Dos Santos, K Reess, N Naskar, I S Kritchenkov, S P Tunik, A Rueck.

  Metabolic Fluorescence Lifetime Imaging Microscopy (FLIM) algorithms have become invaluable tools for exploring deep into the complex dynamics of cellular metabolism. Monitoring subcellular parameters is of interest, particularly during photodynamic therapy (PDT), to enhance treatment efficacy. By joining together Metabolic FLIM with PLIM, it is possible to evaluate cellular metabolic states, such as oxygen consumption, redox states, pH levels, and energy production pathways. The aim of this work is to use NADH FLIM and PLIM techniques to distinguish different metabolic pattern signatures in tumor and normal cell lines using a PLIM pH sensitive complex from the family of phosphorescent [(N^C)2Ir(N^N)]+ complexes. This investigation used a combination of 2-photon (2P) excited FLIM and PLIM techniques, coupled with time-correlated single-photon counting (TCSPC) detection. All the data were collected from living cells and were analyzed through exponential fitting. For the pattern segmentation we have used the phasor plot approach. By constructing a calibration curve and simultaneously acquiring NADH-FLIM and PLIM data from our pH sensor, we were able to identify metabolic regions and distinguished different pattern signatures in tumor and normal cell lines. This combined approach provides a comprehensive view of the tumor microenvironment, offering critical insights into parameters that influence photosensitizer localization, ROS generation, and therapeutic response. By identifying metabolic and pH heterogeneity at the single-cell level, this method contributes to improving the selectivity, precision, and overall efficacy of PDT treatments.

Keywords:  Metabolic FLIM; Metabolic pattern segmentation; PDT; PLIM; TCSPC

DOI:  https://doi.org/10.1007/s43630-025-00803-x
FEBS Open Bio. 2025 Nov 02.

The photoswitchable cannabinoid azo-HU308 enables optical control of Ca2+ dynamics in INS-1 β-cells via off-target effects on TRPC channels.

Alexander E G Viray, James A Frank.

  Intracellular Ca2+ regulates insulin secretion from pancreatic β-cells and is influenced by cannabinoid signaling. However, the hydrophobicity and complex pharmacology of cannabinoid ligands prevent precision receptor targeting, limiting our understanding of their roles in modulating insulin release. Here, we use fluorescent Ca2+ imaging to examine how the light-activatable CB2 receptor agonist azo-HU308 modulates Ca2+ dynamics in INS-1 β-cells. UV-A photoactivation of azo-HU308 triggered robust, repeatable Ca2+ transients, and pharmacological profiling revealed this effect was independent of CB2 receptor activation but was instead mediated by extracellular Ca2+ influx through TRPC channels. These findings position azo-HU308 as a novel optical tool for controlling β-cell Ca2+ levels and highlight a non-GPCR pathway by which synthetic cannabinoids can modulate Ca2+ dynamics in excitable cells.

Keywords:  azobenzene; beta‐cells; calcium imaging; cannabinoids; photopharmacology

DOI:  https://doi.org/10.1002/2211-5463.70146
Cell Death Dis. 2025 Nov 03. 16(1): 777

KDM6A phosphorylation suppresses PER2 to confer a glycolytic vulnerability in HNSCC.

Jun Chen, Yikang Ji, Xin Chen, Mi Zhang, Mei Zhang, Xin Hu, Xing Xu, Yu Zhang, Zhen Zhang, Xinhua Pan, Ming Yan, Jianjun Zhang, Qin Xu, Xi Yang, Wantao Chen, Xu Wang.

ABSTACT: As a key tumor suppressor, KDM6A plays critical roles in maintaining epigenetic homeostasis and suppressing tumorigenesis. However, the regulatory mechanisms controlling KDM6A activity in head and neck squamous cell carcinoma (HNSCC) are not well defined. In this study, we employed tissue microarray analysis of clinical specimens to identify Ser829 as a predominant phosphorylation site of KDM6A in HNSCC and other solid tumors. Using mass spectrometry and biochemical assays, we demonstrate that CDK1-mediated phosphorylation at Ser829 enhances KDM6A binding to SFN, leading to its nuclear export and functional inactivation. Integrated chromatin profiling and metabolic analyses revealed that phosphorylated KDM6A-pSer829 drives glycolytic reprogramming through H3K27Me3-dependent transcriptional silencing of PER2, ultimately promoting tumor growth in vitro and in vivo. These findings establish KDM6A post-translational modification as a pivotal regulator of metabolic adaptation in HNSCC progression, providing a potential therapeutic target for combating cancer through this epigenetic-metabolic axis.

DOI: https://doi.org/10.1038/s41419-025-08130-w
Cell Metab. 2025 Nov 04. pii: S1550-4131(25)00438-3. [Epub ahead of print]37(11): 2097-2098

The role of the ventromedial hypothalamus in glycemic responses.

Kaylee Zilinger, Rachel J Perry.

Mechanisms that preserve glucose homeostasis are highly conserved across species, with the brain playing a central role in regulating these counterregulatory responses. However, the exact neural circuits underlying this regulation remain poorly understood. The previewed papers illuminate how the ventromedial hypothalamus orchestrates glycemic responses through brain-liver communication during periods of increased glucose demand.

DOI: https://doi.org/10.1016/j.cmet.2025.10.004