bims-celmim 2025-10-12 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–10–12
25 papers selected by
Marc Segarra Mondejar, AINA

Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies.
Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
Activity-dependent citrate dynamics in neurons.
Acidosis orchestrates adaptations of energy metabolism in tumors.
Neurons in Need: Glucose, but Not Lactate, Is Required to Support Energy-Demanding Synaptic Transmission.
PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.
Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.
Mitochondrial sodium-calcium exchange-Can TMEM65 do it alone?
Metabolic tug-of-war: Mitochondria starve Toxoplasma of folate.
Physical exercise protects neurons from energy deficit and improves cognitive function by upregulating astrocytic Slc2a1 in Alzheimer's disease.
Astrocytes as Metabolic Sensors Orchestrating Energy-Driven Brain Vulnerability in Alzheimer's Disease.
Modular Nanoassemblies Mimicking p62 Aggregates for Targeted Organelle Sequestration and Degradation against Breast Cancer.
Metabolic interplay between exogenous cystine and glutamine dependence in triple-negative breast cancer.
Lactate Transport via Glial MCT1 and Neuronal MCT2 Is Not Required for Synchronized Synaptic Transmission in Hippocampal Slices Supplied With Glucose.
Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
Purin Metabolism Is Crucial for Regulatory T Cell Stability and Function.
UBE2J2 sensitizes the ERAD ubiquitination cascade to changes in membrane lipid saturation.
Size-variable self-feedback nanomotors for glioblastoma therapy via mitochondrial mineralization.
Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling.
STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
Discovery of a CNS active GSK3 degrader using orthogonally reactive linker screening.
Metabolic controls on the carbon isotope fractionations of bacterial fermentation.
CRISPR-Cas9 screening reveals G2E3 as a novel ubiquitin-linked factor controlling autophagosome-lysosome fusion and cancer cell progression.
TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.

Nat Commun. 2025 Oct 08. 16(1): 8952

Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.

Vidhi Pareek, Stephen Benkovic.

Cancer cells have the unique capability to upregulate the de novo nucleotide biosynthesis supporting cell survival under nucleotide deprivation. We probe the role of metabolic channeling and membrane-less metabolic compartmentalization by mitochondria-proximal dynamic de novo pyrimidine and purine biosynthesis metabolons, the pyrimidinosome and the purinosome, respectively. We designed in-cell stable isotope label incorporation assays (13C6 glucose, 15N2 glutamine) for detection of metabolic channeling, revealing the function and enzymatic composition of these complexes. Moreover, we discovered that the mitochondrially compartmentalized GOT2 dependent generation of aspartic acid feeds the channeled nucleotide synthesis instead of the bulk cytosolic pool or the GOT1 activity. While a low flux diffusive pathway generates the pathway intermediates in an accumulative process, it's the channeled pathway that successfully generates the end product nucleotides. Our results demonstrate how metabolic channeling and efficient de novo nucleotide biosynthesis is fueled by coordination of mitochondrially compartmentalized metabolic events with cytosolic metabolons in cancer cells.

DOI: https://doi.org/10.1038/s41467-025-64013-w
Immunology. 2025 Oct 08.

Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies.

Sana Ahuja, Sufian Zaheer.

  Metabolic reprogramming is a hallmark of cancer, enabling tumour cells to flexibly adapt to fluctuating microenvironmental conditions, sustain uncontrolled proliferation, and acquire resistance to conventional therapies. Tumour metabolism is not limited to the classical Warburg effect but encompasses a dynamic interplay between glycolysis, oxidative phosphorylation (OXPHOS), fatty acid metabolism, and amino acid utilisation, each fine-tuned according to tissue context, tumour type, and stage of progression. Central regulators such as hypoxia-inducible factor-1 (HIF-1), MYC, p53, peroxisome proliferator-activated receptors (PPARs), oestrogen receptor (ER), and sterol regulatory element-binding proteins (SREBPs) orchestrate these pathways, linking nutrient availability to oncogenic signalling and transcriptional control. This review synthesises current evidence on these interconnected metabolic circuits and critically evaluates existing controversies, such as the dual reliance on glycolysis and OXPHOS, metabolic plasticity under therapeutic pressure, and the role of stromal-tumor metabolic crosstalk. Beyond established pathways, emerging areas are transforming our understanding of tumour metabolism. Single-cell metabolic profiling and spatial metabolomics reveal profound intratumoral heterogeneity, while immunometabolism highlights the bidirectional influence of cancer cells and immune cells within the tumour microenvironment (TME). Epigenetic regulation, driven by metabolites that serve as cofactors for chromatin-modifying enzymes, further integrates metabolic states with transcriptional reprogramming and therapy response. Translationally, targeting metabolic dependencies remains challenging; promising therapeutic opportunities are being developed, including inhibitors of lactate transporters, fatty acid oxidation, and glutamine metabolism. This review integrates mechanistic insights with translational perspectives, providing conceptual models, summary tables, and schematic illustrations to clarify complex networks and highlight clinically relevant opportunities. By mapping the evolving landscape of cancer metabolism, we aim to illuminate both the challenges and the therapeutic potential of exploiting metabolic vulnerabilities in oncology.

Keywords:  OXPHOS; glycolysis; mediators; metabolic reprogramming; tumour microenvironment

DOI:  https://doi.org/10.1111/imm.70045
Nat Commun. 2025 Oct 10. 16(1): 9053

Quantitative cellular characterization of extracellular mitochondria uptake and delivery.

Zahra Al Amir Dache, Maud Chevé, Julia Dancourt, Grégory Lavieu.

Mitochondria are essential intracellular organelles responsible for energy production. Over the past two decades, unconventional intercellular mitochondrial transfer has been reported, but the nature of the transport intermediates, the efficiency of the process, and the cellular mechanisms involved in their uptake and putative integration by acceptor cells remain poorly understood. This gap in knowledge is especially significant given the potential therapeutic applications of mitochondrial transplantation. In this study, we use quantifiable cell biology and biochemical approaches to assess intercellular mitochondria exchange. Our findings suggest that low amount of free mitochondria can be released into conditioned media and subsequently internalized by recipient cells, primarily via fluid-phase uptake, although alternative or concurrent endocytic pathways may also contribute. Notably, we show that a subset of internalized mitochondria escapes the endosomal compartment, reaches the cytosol, and may integrate into the host cell's pre-existing mitochondrial network.

DOI: https://doi.org/10.1038/s41467-025-64147-x
Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2519902122

Activity-dependent citrate dynamics in neurons.

Paul C Rosen, Panhui Fu, Beatriz Ferrán, Erica Kim, Daniel J Brooks, Daniel C Lim, Carlos Manlio Díaz-García, Gary Yellen.

  Glycolytic enzymes sense metabolite levels to adapt rapidly to changing energy demands, but measuring the levels of these effectors with spatiotemporal precision in live cells has been challenging. We addressed this question in the context of neuronal depolarization, which activates glycolysis, focusing on the glycolysis inhibitor citrate. We engineered a pair of quantitative fluorescent biosensors for citrate that address several limitations (affinity, pH, Mg2+, and temperature) of existing citrate biosensors. Using two-photon fluorescence lifetime imaging, we found that free citrate in the cytosol of neurons in acute mouse brain slices declines two-to-threefold within seconds of neuronal activation and then returns to baseline over a few minutes. The stimulation-dependent citrate transient depends at least in part on the mitochondrial calcium uniporter. These types of live metabolite measurements are essential for achieving a nuanced understanding of the fast control of glycolysis.

Keywords:  fluorescence lifetime; genetically encoded fluorescent biosensor; glycolytic regulation; mitochondrial calcium uniporter

DOI:  https://doi.org/10.1073/pnas.2519902122
Science. 2025 Oct 09. 390(6769): eadp7603

Acidosis orchestrates adaptations of energy metabolism in tumors.

Sven Groessl, Robert Kalis, Marteinn T Snaebjornsson, Leon Wambach, Jakob Haider, Florian Andersch, Almut Schulze, Wilhelm Palm, Johannes Zuber.

Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal-regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.

DOI: https://doi.org/10.1126/science.adp7603
J Neurochem. 2025 Oct;169(10): e70255

Neurons in Need: Glucose, but Not Lactate, Is Required to Support Energy-Demanding Synaptic Transmission.

Jens V Andersen, Mary C McKenna.

  The brain derives its energy from a combination of several metabolic substrates. The principal energy substrate of the brain is glucose, but the metabolic role of cerebral lactate has been debated for decades. In particular, the hypothesis that astrocyte-derived lactate is needed to fuel neuronal metabolism during activation remains a heated topic. This Editorial highlights a study in the current issue of Journal of Neurochemistry exploring the metabolic relationship between glucose and lactate metabolism in sustaining neuronal network signaling. The study by Söder et al. demonstrates that neurons are only able to sustain energy-demanding synchronized synaptic transmission when glucose is freely available. Blocking lactate transport had no effect on neuronal signaling when glucose was present, highlighting that any potential transfer of lactate is not required during high neuronal workload. In fact, when lactate was supplied as the primary fuel, neurons were unable to sustain synchronized signaling. Using a lactate biosensor, the authors further show that neurons produce and release lactate, both during resting and stimulated conditions. As synchronized synaptic transmission underlies higher brain function, this paper underscores the absolute necessity of neuronal glucose metabolism to maintain brain function.

Keywords:  astrocyte‐neuron lactate shuttle hypothesis; brain energy metabolism; glucose metabolism; metabolic shuttles; neuronal signaling

DOI:  https://doi.org/10.1111/jnc.70255
J Cell Sci. 2025 Oct 09. pii: jcs.263903. [Epub ahead of print]

PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.

Sudeshna Nag, Kaitlin Szederkenyi, Christopher M Yip, G Angus McQuibban.

  Mitochondrial dynamics relies on the function of dynamin family GTPase proteins including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and dynamin-related protein 1 (DRP1). The mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) protein can regulate the phosphorylation levels and the function of both MFN2 and DRP1, however, the precise regulation of PGAM5 activity is unknown. We show that PGAM5 oligomerization and localization controls its function. Under depolarization and/or metabolic stress PGAM5 changes its association from dodecamers to dimers. These PGAM5 oligomers have differential affinity towards MFN2 and DRP1. Simultaneously, PGAM5 is cleaved by the inner mitochondrial membrane resident proteases PARL and OMA1 and a fraction of the cleaved PGAM5 translocates to the cytosol. These two events play an important role in regulating mitochondrial dynamics under depolarization and/or metabolic stress. Taken together, our results identify PGAM5 oligomerization and cleavage-induced relocalization as critical regulators of its function.

Keywords:  DRP1; Glucose-Starvation; MFN2; Mitochondrial morphology; PGAM5

DOI:  https://doi.org/10.1242/jcs.263903
Nat Commun. 2025 Oct 10. 16(1): 9022

Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.

Fan Yu, Jingsi Duan, Zhengyin Lou, Guo-Ping Shi, Fuzhe Gong, Lingfeng Zhong, Derong Chen, Li Xu, Tingting Hong, Xinyang Hu, Jinghai Chen, Jian'an Wang, Deling Yin.

Myocardial energy metabolism disorders are essential pathophysiology in sepsis-associated myocardial injury. Yet, the underlying mechanisms involving impaired mitochondrial respiratory function upon myocardial injury remain poorly understood. Here we identify an unannotated and cardiomyocyte-enriched long non-coding RNA, Cpat (cardiac-protector-associated transcript), that plays an important role in regulating the dynamics of cardiomyocyte mitochondrial tricarboxylic acid (TCA) cycle. Cpat is essential to the mitochondrial respiratory function by targeting key metabolic enzymes and modulating TCA cycle flux. Specifically, Cpat enhances the association of TCA cycle core components malate dehydrogenase (MDH2), citrate synthase (CS), and aconitase (ACO2). Acetyltransferase general control non-repressed protein-5 (GCN5) acetylates CS and destabilizes the MDH2-CS-ACO2 complex formation. Cpat inhibits this GCN5 activity and facilitates MDH2-CS-ACO2 complex formation and TCA cycle flux. We reveal that Cpat-mediated mitochondrial metabolic homeostasis is vital in mitigating myocardial injury in sepsis-induced cardiomyopathy, positioning Cpat as a promising therapeutic target for preserving myocardial cellular metabolism and function.

DOI: https://doi.org/10.1038/s41467-025-64072-z
Cell Metab. 2025 Oct 07. pii: S1550-4131(25)00390-0. [Epub ahead of print]37(10): 1927-1928

Mitochondrial sodium-calcium exchange-Can TMEM65 do it alone?

Joanne F Garbincius, John W Elrod.

The mechanisms mediating calcium transport into and out of the mitochondrial matrix have critical implications for signaling, bioenergetics, and cell death. Zhang et al.1 propose that the protein TMEM65, recently identified as a key component of the mitochondrial calcium efflux machinery, functions as the mitochondrial sodium/calcium exchanger. Their report encourages critical re-examination of the components required for mitochondrial calcium handling.

DOI: https://doi.org/10.1016/j.cmet.2025.09.005
Cell Host Microbe. 2025 Oct 08. pii: S1931-3128(25)00363-4. [Epub ahead of print]33(10): 1645-1647

Metabolic tug-of-war: Mitochondria starve Toxoplasma of folate.

Evie R Hodgson, Diana Stojanovski.

In a recent Science paper, Medeiros et al. describe how infected cells use mitochondria as metabolic guardians, outcompeting Toxoplasma parasites for folate, an essential vitamin for DNA synthesis. This metabolic immunity strategy transforms the cell's powerhouse to an active defender, sequestering nutrients away from invaders in a metabolic tug-of-war.

DOI: https://doi.org/10.1016/j.chom.2025.09.002
Exp Neurol. 2025 Oct 06. pii: S0014-4886(25)00358-9. [Epub ahead of print] 115493

Physical exercise protects neurons from energy deficit and improves cognitive function by upregulating astrocytic Slc2a1 in Alzheimer's disease.

Shiyin Li, Fang Zheng, Shuhua Liu, Rui Wu, Liying Zhang, Xiaofei He, Mingyue Li, Lili Li.

  Alzheimer's disease (AD) has been associated with impaired energy metabolism and neuronal mitochondrial dysfunction, which contribute to the development of anxiety-like behaviors and spatial memory deficits. Astrocytes are recognized as a critical source of metabolites for neurons, supporting mitochondrial respiration. Although physical exercise (PE) has shown therapeutic potential in AD models, the molecular mechanisms linking PE to metabolic reprogramming remain elusive. In a 5xFAD mouse model, this study shows that PE increased the expression of solute carrier family 2 member 1 (Slc2a1) and decreased the expression of GFAP in astrocytes. We demonstrate that both PE and the overexpression of astrocytic Slc2a1 alleviated neuronal mitochondria damage and neuron death, shifts astrocytes to an anti-inflammatory phenotype and reduced Aβ accumulation. Conversely, knockdown of Slc2a1 abrogated the protective effects of PE. In vitro, we established an AD glucose-deficiency cell model by incubating cells with 5.5 mM glucose and oligomeric Aβ (oAβ). Our results showed that Slc2a1 overexpression increased lactate secretion in the supernatant of C8-D1A astrocytes. Furthermore, both Slc2a1 overexpression in C8-D1A cells and lactate treatment rescued oAβ-induced mitochondrial oxidative stress and membrane potential alterations in energy-deficient HT22 neurons, thereby enhancing lactate secretion from astrocytes and promoting the lactate shuttle to neuron for energy supply. Collectively, our findings indicate that PE ameliorates anxiety-like behavior and spatial memory deficits, mitigates mitochondrial damage in neurons, and reduces Aβ accumulation in 5xFAD mice through the upregulation of Slc2a1 in astrocytes. Our findings identify Slc2a1 as a pivotal mediator of metabolic support induced by PE and highlights astrocyte-neuron lactate shuttling as a promising therapeutic target for AD.

Keywords:  Alzheimer's disease; Astrocytes; Energy deficit; Physical exercise; Slc2a1

DOI:  https://doi.org/10.1016/j.expneurol.2025.115493
J Neurochem. 2025 Oct;169(10): e70252

Astrocytes as Metabolic Sensors Orchestrating Energy-Driven Brain Vulnerability in Alzheimer's Disease.

Leyre Sánchez de Muniain, Paula Escalada, María J Ramírez, Maite Solas.

  Alzheimer's disease (AD), the leading neurodegenerative disorder linked to aging, emerges within a paradoxical metabolic landscape. Despite rising cellular energy demands due to accumulated damage and stress, overall energy expenditure remains stable or declines with age. The brain, acting as the central regulator, responds to hypermetabolic signals from aged tissues by activating energy-conserving mechanisms. In this scenario, astrocytes, strategically located between blood vessels and neurons, play a pivotal role as energy sensors, adapting to systemic stress and modulating brain metabolism. This review explores how astrocytes undergo metabolic reprogramming in the early stages, potentially becoming maladaptive over time, fueling neuroinflammation, oxidative stress, and accelerating AD. By understanding astrocyte energetics, we uncover new avenues for biomarkers and therapies that could transform AD treatment.

Keywords:  aging; allostasis; glycolysis; hypermetabolism; neurodegeneration

DOI:  https://doi.org/10.1111/jnc.70252
ACS Nano. 2025 Oct 08.

Modular Nanoassemblies Mimicking p62 Aggregates for Targeted Organelle Sequestration and Degradation against Breast Cancer.

Yuai Li, Yunting Zhang, Jingwen Wang, Yujie Che, Tao Gong, Zhirong Zhang, Renhe Liu, Yao Fu.

  Selective autophagy relies on multivalent recognition by receptors like SQSTM1/p62 to form aggregates that cluster disperse organelles, undergoing liquid-liquid phase separation to facilitate their clearance and maintain cellular homeostasis. Inspired by this, we present the multivalent nanoparticle-based organelle targeting chimera (NanoTACOrg) to efficiently degrade organelles by flexibly clustering organelles for sequestration and facilitating targeted recruitment of autophagosomes. NanoTACOrg, assembled with a PLGA core, lysosomal escape modules, organelle-targeting modules, and LC3B binding modules, is programmed to selectively degrade various organelles, including mitochondria, endoplasmic reticulum, and Golgi apparatus. After endocytosis and lysosomal escape, NanoTACOrg targets subcellular compartments and mimics p62 aggregate-driven organelle clustering and degradation, without exhibiting the "hook effect". Specifically, NanoTACMito-mediated mitochondrial degradation disrupts oxidative phosphorylation (OXPHOS) while enhancing compensatory glycolysis, thus sensitizing tumor cells to the glucose transporter 1 (GLUT1) inhibitor BAY-876. BAY-876 loaded NanoTACMito potently inhibits tumor growth, recurrence, and metastasis, demonstrating superior therapeutic efficacy by simultaneously targeting OXPHOS and glycolysis. These findings highlight the potential of NanoTACOrg as a versatile and effective platform for cancer therapy, particularly through organelle-specific degradation and metabolic reprogramming.

Keywords:  metabolic plasticity; multivalent binding; nanoparticle-mediated targeted degradation; organelle; tumor metastasis

DOI:  https://doi.org/10.1021/acsnano.5c10801
Cell Death Discov. 2025 Oct 06. 11(1): 430

Metabolic interplay between exogenous cystine and glutamine dependence in triple-negative breast cancer.

Ziqian Ge, Martina Wallace, Rory Turner, Maureen Yin, Mary F Rooney, Richard K Porter.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by high recurrence rates and limited treatment options due to the absence of hormone receptors. Despite advancements in breast cancer research, effective therapies for TNBC remain inadequate, highlighting the need to elucidate subtype-specific metabolic vulnerabilities. TNBC cells exhibit a strong dependence on the exogenous amino acids cystine and glutamine, yet the interplay between these metabolic dependencies remains poorly understood. Here, we demonstrate that TNBC cells exhibit sensitivity to individual nutrient deprivation but can survive dual cystine and glutamine deprivation via distinct mechanisms. Exogenous glutamine primarily fuels glutamine anaplerosis, supporting TNBC cell proliferation. Notably, when exogenous glutamine is absent, restricted cystine uptake restores intracellular glutamate levels, fulfilling metabolic demands and sustaining TNBC cell growth. Under cystine deprivation, inhibition of glutaminolysis rescues TNBC cells by mitigating lipid peroxidation and reducing ROS production, whereas supplementation with the TCA cycle intermediates ɑ-ketoglutarate (ɑ-KG) and succinate induces profound cell death in both TNBC and luminal breast cancer cells under glutaminolysis blockade. Collectively, these findings highlight the metabolic interdependence of glutamine and cystine in TNBC, providing mechanistic insights into potential metabolic-targeted and dietary interventions for TNBC therapy.

DOI: https://doi.org/10.1038/s41420-025-02714-3
J Neurochem. 2025 Oct;169(10): e70251

Lactate Transport via Glial MCT1 and Neuronal MCT2 Is Not Required for Synchronized Synaptic Transmission in Hippocampal Slices Supplied With Glucose.

Lennart Söder, Felipe Baeza-Lehnert, Babak Khodaie, Amr Elgez, Lena Noack, Andrea Lewen, Stefan Hallermann, Gernot Poschet, Karin Borges, Oliver Kann.

  The metabolite lactate (L-lactate) has been hypothesized to represent an important energy source during brain activation. The contribution of lactate in fueling synchronized synaptic transmission during fast neural network oscillations underlying complex cortex function such as visual perception, memory formation, and motor activity is less clear, however. We explored the role of cellular lactate production and lactate transport (uptake and release) via the monocarboxylate transporters 1 and 2 (glial MCT1 and neuronal MCT2) during persistent gamma oscillations (frequency at around 40 Hz) and recurrent rhythmic events called sharp wave-ripples (with "ripples" at around 250 Hz) in cultured rat and acute mouse hippocampal slices (ex vivo) that received energy substrate supply with glucose (D-glucose) only. In addition, we assessed neuronal lactate dynamics during spontaneous activity ("resting state") and during electrical stimulation (10 Hz) in mouse primary neuron-astrocyte cultures (in vitro) receiving glucose only. We combined electrophysiology (local field potential recordings), tissue lactate analysis [ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)], and live-cell fluorescence imaging [Förster resonance energy transfer (FRET) sensor Laconic]. We report that (1) lactate is produced during gamma oscillations when glucose is supplied and oxygen availability is unlimited (high oxygenation) for mitochondrial respiration. (2) The properties of gamma oscillations remain regular in the presence of the MCT1/2 blocker AR-C155858. (3) By contrast, MCT1/2 blockade fully suppresses gamma oscillations when mainly lactate is supplied. (4) The properties of sharp wave-ripples remain regular during MCT1/2 inhibition. (5) Lactate is produced in primary hippocampal neurons during spontaneous activity and electric stimulus-induced excitation, and it accumulates in the neuronal cytosol during MCT1/2 inhibition. In conclusion, lactate is produced in cortical tissue, including neurons fueled by glucose only. Moreover, lactate transport and lactate exchange ("shuttling") via glial MCT1 and neuronal MCT2 are not required to sustain synchronized synaptic transmission during fast neural network oscillations.

Keywords:  aerobic glycolysis; brain energy metabolism; lactate oxidation; monocarboxylate transporter; neurotransmission; tissue oxygenation

DOI:  https://doi.org/10.1111/jnc.70251
Science. 2025 Oct 09. 390(6769): 156-163

Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.

Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.

Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.

DOI: https://doi.org/10.1126/science.adr5438
Eur J Immunol. 2025 Oct;55(10): e70070

Purin Metabolism Is Crucial for Regulatory T Cell Stability and Function.

Young S Lee, Marina W Shirkey, Vikas Saxena, Dejun Kong, Bing Ma, Reza Abdi, Jonathan S Bromberg.

  Cellular metabolism intricately directs the differentiation, stability, and function of regulatory T cells (Tregs), which are pivotal in immune regulation. Metabolic reprogramming enables Tregs to adapt to diverse tissue environments; however, it can also disturb immune equilibrium, driving their conversion into unfavorable states like exTregs that hinder regulation in autoimmunity and transplantation. Purine metabolism has emerged as a critical but underexplored regulator of Treg biology. Beyond their traditional roles in nucleotide synthesis and energy balance, purine metabolites also serve as potent second messengers shaping Treg phenotype, suppressive capacity, and adaptability in inflammatory, autoimmune, and transplant environments. Extracellular ATP promotes inflammation, while adenosine supports Treg-mediated immunosuppression, highlighting a dual and context-dependent nature of purinergic signaling. This review outlines current findings on intracellular and extracellular purine metabolism in Tregs, emphasizing key enzymes and purinergic receptors that sustain Treg phenotype and resilience. It discusses disruptions in purine signaling compromising Treg functions, identifies knowledge gaps, and proposes future research directions for potential therapeutic strategies in immune-related ailments.

Keywords:  Treg stability; exTregs; purine metabolism; purinergic receptors; regulatory T cells (Tregs)

DOI:  https://doi.org/10.1002/eji.70070
Nat Commun. 2025 Oct 09. 16(1): 8973

UBE2J2 sensitizes the ERAD ubiquitination cascade to changes in membrane lipid saturation.

Aikaterini Vrentzou, Florian Leidner, Claudia C Schmidt, Helmut Grubmüller, Alexander Stein.

Protein-lipid crosstalk is fundamental to homeostasis in the endoplasmic reticulum (ER). The ER-associated degradation (ERAD) pathway, a branch of the ubiquitin-proteasome system, maintains ER membrane properties by degrading lipid metabolic enzymes. However, the ERAD components that sense membrane properties and their mechanisms remain poorly defined. Using reconstituted systems with purified ERAD factors, we show that membrane composition modulates the ubiquitination cascade at multiple levels. The membrane-anchored E2 UBE2J2 acts as a sensor for lipid packing: in loosely packed membranes, UBE2J2 becomes inactive due to membrane association that impedes ubiquitin loading, while tighter packing promotes its active conformation and interaction with E1. UBE2J2 activity directs ubiquitin transfer by the E3 ligases RNF145, MARCHF6, and RNF139, targeting both themselves and the substrate squalene monooxygenase. Additionally, RNF145 senses cholesterol, altering its oligomerization and activity. These findings reveal that ERAD integrates multiple lipid signals, with UBE2J2 relaying and extending the effect of lipid signals through its cooperation with multiple E3 ligases.

DOI: https://doi.org/10.1038/s41467-025-64777-1
Nat Commun. 2025 Oct 09. 16(1): 8990

Size-variable self-feedback nanomotors for glioblastoma therapy via mitochondrial mineralization.

Tiantian Chen, Yu Duan, Yingjie Wang, Tiantian Liang, Shiluan Liu, Xue Xia, Chun Mao, Mimi Wan.

Developing targeted treatment for glioblastoma is crucial but challenging. Herein, we propose a size-variable self-feedback nanomotor system, utilizing the unique high-calcium microenvironment of glioblastoma to prevent its progression through mitochondrial mineralization. It comprises three components: a self-feedback degradable lipid shell (containing nitric oxide-releasing lipid and nitric oxide-responsive degradable lipid), a motion nanomotor core (containing L-arginine derivatives and carboxyl-rich zwitterionic monomers for Ca2+ recruitment), and curcumin (inhibiting Ca2+ efflux). Nitric oxide-releasing lipid can be catalyzed by inducible nitric oxide synthase to release nitric oxide, triggering nitric oxide-responsive degradable lipid degradation. Initially, the larger nanomotors (~ 500 nm) penetrate the blood-brain barrier via chemotaxis towards glioblastoma microenvironment. During chemotaxis, the lipid shell gradually degrades, releasing smaller nanomotor core (~50 nm), which can target mitochondria and recruit Ca2+ to induce mitochondrial mineralization together with curcumin, inhibiting glioblastoma progression. This work may provide a glioblastoma-specific treatment strategy.

DOI: https://doi.org/10.1038/s41467-025-64020-x
Nat Commun. 2025 Oct 08. 16(1): 8932

Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling.

Jung Seok Hwang, JiHoon Kang, Jaehyun Kim, Kiyoung Eun, Sophia West, Hannah E Bacho, Vanessa Avalos, Sydney Shuff, Dong M Shin, Nabil F Saba, Kelly R Magliocca, Cheng-Kui Qu, Haian Fu, Suresh S Ramalingam, Andrey A Ivanov, Taro Hitosugi, Sumin Kang.

Chemotherapy is often a primary treatment for cancer. However, resistance leads to therapeutic failure. Acetylation dynamics play important regulatory roles in cancer cells, but the mechanisms by which acetylation mediates therapy resistance remain poorly understood. Here, using acetylome-focused RNA interference (RNAi) screening, we find that acetylation induced by mitochondrial dihydrolipoyl transacetylase (DLAT), independent of the pyruvate dehydrogenase complex, is pivotal in promoting resistance to chemotherapeutics, such as cisplatin. Mechanistically, DLAT acetylates methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) at lysine 44 and promotes 10-formyl-tetrahydrofolate (10-formyl-THF) and consequent mitochondrially encoded cytochrome c oxidase II (MT-CO2) induction. DLAT signaling is elevated in cancer patients refractory to chemotherapy or chemoimmunotherapy. A decoy peptide DMp39, designed to target DLAT signaling, effectively sensitizes cancer cells to cisplatin in patient-derived xenograft models. Collectively, our study reveals the crucial role of DLAT in shaping chemotherapy resistance, which involves an interplay between acetylation signaling and metabolic reprogramming, and offers a unique decoy peptide technology to overcome chemotherapy resistance.

DOI: https://doi.org/10.1038/s41467-025-63892-3
Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2508809122

STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.

Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.

  The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.

Keywords:  cholesterol; intermembrane space; lipoid congenital adrenal hyperplasia; mitochondria; steroidogenesis

DOI:  https://doi.org/10.1073/pnas.2508809122
Nat Commun. 2025 Oct 06. 16(1): 8857

Discovery of a CNS active GSK3 degrader using orthogonally reactive linker screening.

Andreas Holmqvist, Nur Mehpare Kocaturk, Christina Duncan, Jennifer Riley, Steven Baginski, Graham Marsh, Joel Cresser-Brown, Hannah Maple, Kristiina Juvonen, Gajanan Sathe, Nicola Morrice, Calum Sutherland, Kevin D Read, William Farnaby.

Bifunctional targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are an emerging drug modality that may offer a new approach for treating neurodegenerative diseases. Identifying chemical starting points for PROTACs remains a largely empirical process and the design rules for identifying Central Nervous System (CNS) active PROTACs have yet to be established. Here we demonstrate a concept of using orthogonally reactive linker reagents, that allow the construction of screening libraries whereby the E3 ligase binder, the target protein binder and the linker can be simultaneously varied and tested directly in cellular assays. This approach enabled the discovery of Glycogen Synthase Kinase 3 (GSK3) PROTACs which are CNS in vivo active in female mice. Our findings provide opportunities to investigate the role of GSK3 paralogs in cellular and in vivo disease models and for the rapid discovery of in vivo quality bifunctional chemical probes for CNS disease concepts.

DOI: https://doi.org/10.1038/s41467-025-63928-8
Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2511040122

Metabolic controls on the carbon isotope fractionations of bacterial fermentation.

Elliott P Mueller, Verena B Heuer, Jared R Leadbetter, Kai-Uwe Hinrichs, Alex L Sessions.

  Microbial fermentation facilitates the initial breakdown of organic matter into small molecules and is thought to be the rate-limiting step of anoxic organic mineralization. However, fermentation is understudied in modern and ancient biogeochemistry due to a lack of environmental biomarkers. It has long been assumed that fermentation, like respiration, does not express significant carbon isotope fractionations, precluding isotopic signals as a means of studying it in nature. Here, we tested this idea by growing pure cultures of four fermenting bacteria on glucose and measuring the carbon isotope compositions of the organic acids and alcohols produced. We found that fermentation exhibits a strong carbon isotope fractionation, ranging from [Formula: see text]6‰ to [Formula: see text]16‰, depending on the fermentation product. With bioisotopic models that track site-specific isotope enrichments through metabolism, we constrained the enzymes responsible for these fractionations. Our models reproduced in vivo organic acid [Formula: see text] values in all four organisms. These findings demonstrate that acetate 13C-enrichment is likely a widespread signature of fermentation. They also challenge traditional notions of controls on the isotope composition of lipids. Finally, our study suggests that fermentation imposes a trophic carbon isotope fractionation as organic carbon is passed from fermenters to secondary degraders like sulfate reducers. Looking to the geologic past, this trophic fractionation could have imprinted isotopic signals on the three billion year record of sedimentary organic carbon, specifically the inverse [Formula: see text] pattern of Precambrian acyclic isoprenoid and n-alkane biomarkers. Pervasive evidence of fermentation in the rock record would suggest its underappreciated role in biogeochemical cycles throughout Earth history.

Keywords:  Precambrian; fermentation; lipid biomarkers; organic acids; stable isotopes

DOI:  https://doi.org/10.1073/pnas.2511040122
Cell Death Discov. 2025 Oct 09. 11(1): 455

CRISPR-Cas9 screening reveals G2E3 as a novel ubiquitin-linked factor controlling autophagosome-lysosome fusion and cancer cell progression.

Yumei Gong, Marc Leon, Huaqing Mo, Premkamol Pengpaeng, Hai Yang, Yanxi Lu, Zhiqiang Yin, Alan Benard, Yong Zhou, Robert Grützmann, Christian Pilarsky.

Autophagy is a tightly regulated process essential for cellular homeostasis, with ubiquitination playing a crucial role in its regulation. However, the specific ubiquitin related factors involved in autophagic flux remain largely unexplored. Identifying these regulators is essential for advancing the mechanistic understanding of autophagy and its broader implications in cellular function. This study aimed to identify novel ubiquitination-associated regulators of autophagy. To achieve this, we conducted a CRISPR-Cas9 loss-of-function screen targeting 660 ubiquitination-related genes in pancreatic cancer cells expressing the mCherry-GFP-LC3 autophagy flux reporter system. Among the top candidates, we identified G2E3, a G2/M-phase-specific E3 ubiquitin ligase, as a previously unrecognized autophagy regulator. Subsequent functional analyses revealed that G2E3 knock out led to a significant accumulation of LC3B-II and GABARAPs, indicative of impaired autophagic flux. Further confocal imaging demonstrated that the co-localization of LC3B with LAMP1-positive lysosomes was significantly reduced in G2E3 knock out cells, suggesting defective autophagosome-lysosome fusion. Mechanistically, G2E3 directly interacts with GABARAP and GABARAPL1, but not LC3B, positioning it as a key regulator of late-stage autophagy. Additionally, G2E3 knock out cells exhibited reduction in migration and invasion capability, suggesting its role in cancer progression. These findings establish G2E3 as a novel ubiquitin-related regulator of autophagy, specifically facilitating autophagosome-lysosome fusion via a GABARAPs-dependent mechanism. This study reveals a previously unrecognized role of G2E3 in late-stage autophagy and suggests that targeting G2E3 could provide a potential therapeutic approach for modulating autophagy-dependent cellular processes, including cancer progression.

DOI: https://doi.org/10.1038/s41420-025-02717-0
Sci Adv. 2025 Oct 10. 11(41): eadw4153

TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.

Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Biaoxin Chai, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.

Innate immune signaling is activated in immunometabolic diseases, including type 2 diabetes, yet its impact on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for pancreatic β cell function at baseline, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and mitophagy following metabolic stress in mouse and human islets. TRAF6 was critical for the recruitment and function of the ubiquitin-mediated (Parkin-dependent) mitophagy machinery. Glucose intolerance induced by TRAF6 deficiency following metabolic stress was reversed by concomitant Parkin deficiency by relieving obstructions in receptor-mediated (Parkin-independent) mitophagy. Our results establish that TRAF6 is vital for traffic through Parkin-mediated mitophagy and implicates TRAF6 in the cross-regulation of ubiquitin- and receptor-mediated mitophagy. Together, we illustrate that β cells engage innate immune signaling to adaptively respond to a diabetogenic environment.

DOI: https://doi.org/10.1126/sciadv.adw4153