bims-celmim 2025-10-26 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–10–26
35 papers selected by
Marc Segarra Mondejar, AINA

Targeting mitochondrial structure and dynamics for therapeutic intervention in cancer.
Glycolytic reprogramming during microglial polarization in neurological diseases.
Organellar pH as an emerging vulnerability to exploit in cancer.
Mitochondrial calcium overload is the trigger for carbon monoxide neurotoxicity.
Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia.
Formation of metabolic water by aerobic glucose oxidation.
Nanomaterial-induced mitochondrial biogenesis enhances intercellular mitochondrial transfer efficiency.
PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes.
Mitochondrial fatty acid oxidation is stimulated by red light irradiation.
Cancer Dormancy and Metabolism: From Molecular Insights to Translational Opportunities.
Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.
Kir5.1-modulated potassium flux stimulates an anabolic kidney phenotype.
ATG9 assists lipid replenishment for lysosome membrane repair.
Dietary medium-chain triacylglycerols in metabolic regulation.
TM9SF1 drives the lipophagic flux via AMPK-ULK1 signaling to sustain metabolic fitness in HER2-positive breast cancer.
SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.
Rewiring microbial metabolism through post-translational switches.
The role of fibroblast growth factors in cell and cancer metabolism.
The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism.
Mitochondrial one-carbon metabolism is required for TGF-β-induced glycine synthesis and fibrotic responses.
UHRF1-mediated HIF-1α stabilization promotes ovarian cancer through metabolic reprogramming and angiogenesis.
A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS.
Label-free robotic mitochondrial biopsy.
Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection against intestinal inflammation.
A lactate-acetate interaction between macrophages and cancer cells drives metastasis.
Rapamycin alleviates hypothalamic injury in exertional heat stroke rats by activating mitophagy through the mTOR/Pink1/Parkin pathway.
Fenofibrate differentially activates PPARα-mediated lipid metabolism in rat kidney and liver.
IL-11 exacerbates cisplatin-induced acute kidney injury by facilitating apoptosis in renal tubular epithelial cells via ERK1/2-Drp1/TFEB-mediated defective autophagy.
TCA-cycle metabolites in the nucleus: drivers of chromatin and epigenetic control.
PMP2 Enhances Schwann Cell Metabolism and Promotes Myelination.
Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis.
Mitochondrial homeostasis collapse to cardiac remodeling: From mechanisms to novel targeted therapeutic avenues.
Mitochondrial ROS Drive Adipogenic Differentiation in Osteoporosis by Suppressing Protein Synthesis.
Structural basis for transport and inhibition of the human glucose-6-phosphate transporter G6PT.
The combination of venetoclax with dimethyl fumarate synergistically induces apoptosis in AML cells by disrupting mitochondrial integrity through ROS accumulation.

PLoS Biol. 2025 Oct;23(10): e3003453

Targeting mitochondrial structure and dynamics for therapeutic intervention in cancer.

Wakiko Iwata, Nora Haggerty, Hiromi Sesaki, Miho Iijima.

Mitochondrial division and fusion are critical regulators of cancer cell metabolism, proliferation, survival, metastasis, and drug resistance. Division promotes tumor development by reprogramming energy metabolism, whereas its inhibition can suppress tumor growth and metastasis. The mechanochemical GTPase DRP1, a key mediator of mitochondrial division, has emerged as a promising therapeutic target. Mitochondrial cristae also contribute to cancer progression by modulating metabolic reprogramming and oncogenic signaling. Targeting these processes may stimulate anti-tumor innate immune responses through the release of mitochondrial DNA into the cytoplasm. A deeper understanding of tumor-specific mitochondrial membrane structures and dynamics could therefore reveal novel intervention strategies and guide precision cancer therapies.

DOI: https://doi.org/10.1371/journal.pbio.3003453
Front Immunol. 2025 ;16 1648887

Glycolytic reprogramming during microglial polarization in neurological diseases.

Xiaoting Li, Congcong Fang, Yina Li, Xiaoxing Xiong, Xu Xu, Lijuan Gu.

   Background: Microglia, the resident immune cells of the central nervous system (CNS), play pivotal roles in the onset and progression of various neurological disorders. Owing to their remarkable plasticity, microglia can adopt diverse phenotypic states in response to distinct microenvironmental cues. Over the past decades, accumulating evidence has demonstrated that immune cell metabolism critically regulates their polarization and effector functions through a process termed metabolic reprogramming, in which glucose metabolism is particularly central. Glycolytic reprogramming underlies the entire polarization process, and elucidating its mechanisms may enable targeted modulation of microglial activity to mitigate their deleterious effects in CNS pathologies, thereby offering novel therapeutic avenues for these diseases.
Aim of the Review: This paper summarizes what is known about microglial polarization and glycolytic reprogramming and explores their important roles in the development of neurological diseases. The link between microglial metabolomics and epigenetics in neurological disorders requires further study.
Key Scientific Concepts of the Review: Microglia exhibit distinct phenotypic states at different stages of central nervous system (CNS) disorders, and these polarization processes are closely coupled with glucose metabolic reprogramming. Proinflammatory microglia predominantly rely on glycolysis, whereas reparative or anti-inflammatory phenotypes primarily utilize oxidative phosphorylation. Targeting glycolytic pathways to limit the polarization of microglia toward proinflammatory states has emerged as a promising therapeutic strategy for CNS diseases.

Keywords:  Warburg effect; glycolysis; lactylation; metabolic reprogramming; microglia; nervous system diseases

DOI:  https://doi.org/10.3389/fimmu.2025.1648887
Trends Cancer. 2025 Oct 23. pii: S2405-8033(25)00234-1. [Epub ahead of print]

Organellar pH as an emerging vulnerability to exploit in cancer.

Cheska Marie Galapate, Cosimo Commisso.

  Cancer cells undergo metabolic reprogramming to sustain their energy demands, and favor glycolysis despite the presence of functional mitochondria. This metabolic shift leads to the rapid production of lactate and protons. If not managed, this accumulation of acidic byproducts would lower the intracellular pH (pHi). To counteract this, cancer cells employ diverse mechanisms to extrude excess protons through membrane transporters, and also sequester them within acidic organelles. Consequently, an alkaline pHi provides cancer cells with a survival advantage by promoting their proliferation, migration, and resistance to cell death. Given the role of organellar acidification in sustaining this altered pH balance, targeting this process represents a potential therapeutic vulnerability in cancer. We explore the mechanisms by which cancer cells maintain pH homeostasis, with a particular focus on organellar pH and its impact on tumor progression. In addition, we assess inhibitors of the key transporters involved in organellar acidification and discuss their therapeutic potential in cancer.

Keywords:  cancer metabolism; organelle acidification; pH homeostasis

DOI:  https://doi.org/10.1016/j.trecan.2025.09.006
Cell Death Dis. 2025 Oct 21. 16(1): 747

Mitochondrial calcium overload is the trigger for carbon monoxide neurotoxicity.

Plamena R Angelova, Artyom Y Baev, Sergey O Bachurin, Isabella Myers, Andrey Y Abramov.

Carbon monoxide is an important gasotransmitter and regulator of cell function in different tissues, including the central nervous system. However, in large doses, it is a poisonous gas that causes mortality and morbidity. Moreover, the majority of survivors of high-dose exposures develop serious neurological conditions. Here, we studied the effect of toxic concentrations of carbon monoxide released from the compound CORM-401 and its removal (re-oxygenation) on calcium signalling in primary cortical neurons and astrocytes. We found that CO induces changes in intracellular Ca2+ concentration in both neurons and astrocytes. The mechanism of these signals was different-in neurons, it was activated by NMDA and AMPA receptors, while in astrocytes, CO-induced fusion of VNUT2-positive vesicles followed by activation of P2Y receptors. Calcium signal in neurons and astrocytes promotes mitochondrial calcium uptake, which dramatically increases after the removal of CO from the medium, which, in combination with higher rates of production of ROS, induces mitochondrial permeability transition and cell death. CO-induced death of neurons and astrocytes could be prevented with partial inhibition of mitochondrial calcium uptake by Tg2112x and/or inhibition of ROS production in the phase of re-oxygenation. Thus, the bidirectional interaction between mitochondrial calcium overload and production of reactive oxygen species is crucial for CO-induced death of neurons and astrocytes.

DOI: https://doi.org/10.1038/s41419-025-08012-1
Nat Commun. 2025 Oct 21. 16(1): 9312

Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia.

Jacquelyne Ka-Li Sun, Ronald P Hart, Karl Herrup, Amy Zexuan Peng, Genper Chi-Ngai Wong, Deng Wu, Kin-Ming Kwan, Kim Hei-Man Chow.

The maintenance of metabolic homeostasis relies on the ability to flexibly transit between catabolic and anabolic states in response to insulin signaling. Here we show insulin-activated ATM is a critical mediator of this process, facilitating the swift transition between catabolic-and-anabolic fates of glucose by regulating the functional status of PKM2 and HIF1α. In Ataxia-Telangiectasia (A-T), these mechanisms are disrupted, resulting in intrinsic insulin resistance and glucose intolerance. Consequently, cells exhibit a compensatory dependence on glutamine as an alternative metabolite for energy metabolism. Cerebellar degeneration, a hallmark of A-T, is characterized by the pronounced vulnerability of Purkinje cells, attributed to their unexpected sensitivity to insulin. Supplementation with α-ketoglutarate, the α-keto acid backbone of glutamine, has demonstrated potentials in alleviating glutamine dependence and attenuating Purkinje cell degeneration. These findings suggest that peripheral metabolic deficiencies may contribute to sustained neurodegenerative changes in A-T, underscoring the importance of screening, monitoring and addressing these metabolic disruptions in patients.

DOI: https://doi.org/10.1038/s41467-025-64360-8
Fluids Barriers CNS. 2025 Oct 23. 22(1): 104

Formation of metabolic water by aerobic glucose oxidation.

Bjørn Quistorff.

A recent paper suggests that the water originating from the ATP production coupled to aerobic glucose oxidation causes more than a 6 fold increase in the production of metabolic water, compared with the standard textbook description of the oxidation process. However, the authors seem to have forgotten that the simultaneous processes of ATP utilization takes up the same amount of water, which was liberated during the ATP synthesis. Thus, at steady state, there is no net increase in the production of metabolic water.

DOI: https://doi.org/10.1186/s12987-025-00712-2
Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2505237122

Nanomaterial-induced mitochondrial biogenesis enhances intercellular mitochondrial transfer efficiency.

John Soukar, Kanwar Abhay Singh, Ari Aviles, Sarah Hargett, Harman Kaur, Samantha Foster, Shounak Roy, Feng Zhao, Vishal M Gohil, Irtisha Singh, Akhilesh K Gaharwar.

  Intercellular mitochondrial transfer, the spontaneous exchange of mitochondria between cells, is a recently described phenomenon crucial for cellular repair, regeneration, and disease management. Enhancing this natural process holds promise for developing novel therapies targeting diseases associated with mitochondrial dysfunction. Here, we introduce a nanomaterial-based approach employing molybdenum disulfide (MoS2) nanoflowers with atomic-scale vacancies to stimulate mitochondrial biogenesis in cells to make them mitochondrial biofactories. Upon cellular uptake, these nanoflowers result in a two-fold increase in mitochondrial mass and enhancing mitochondrial transfer to recipient cells by several-fold. This enhanced efficiency of transfer significantly improves mitochondrial respiratory capacity and adenosine triphosphate production in recipient cells under physiological conditions. In cellular models of mitochondrial and cellular damage, MoS2 enhanced mitochondrial transfer achieved remarkable restoration of cell function. This proof-of-concept study demonstrates that nanomaterial-boosted intercellular mitochondrial transfer can enhance cell survivability and function under diseased conditions, offering a promising strategy for treating mitochondrial dysfunction-related diseases.

Keywords:  biomaterials; cellular medicine; mitochondria; nanomaterials; regenerative medicine

DOI:  https://doi.org/10.1073/pnas.2505237122
JCI Insight. 2025 Oct 21. pii: e193805. [Epub ahead of print]

PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes.

Rodrigo M Florentino, Olamide Animasahun, Nils Haep, Minal Nenwani, Kehinde Omoloja, Leyla Nurcihan Altay, Abhinav Achreja, Kazutoyo Morita, Takashi Motomura, Ricardo Diaz-Aragon, Lanuza Ap Faccioli, Yiyue Sun, Zhenghao Liu, Zhiping Hu, Bo Yang, Fulei Wuchu, Ajay Shankaran, Miya Paserba, Annalisa M Baratta, Shohrat Arazov, Zehra N Kocas-Kilicarslan, Noah Meurs, Jaideep Behari, Edgar N Tafaleng, Jonathan Franks, Alina Ostrowska, Takahiro Tomiyama, Kyohei Yugawa, Akinari Morinaga, Zi Wang, Kazuki Takeishi, Dillon C Gavlock, Mark Miedel, D Lansing Taylor, Ira J Fox, Tomoharu Yoshizumi, Deepak Nagrath, Alejandro Soto-Gutierrez.

  Genetic variants in lipid metabolism influence the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and end-stage liver disease (ESLD). The mechanisms by which these variants drive disease are poorly understood. Because of the PNPLA3-I148M variant's strong correlation with all stages of the MASLD spectrum and the lack of tractable therapeutic targets, we sought to understand its impact on cellular function and liver metabolism. Primary human hepatocytes (HAH) and iPSC-derived hepatocytes (iHeps) from healthy individuals possessing the PNPLA3-I148M mutation were characterized for changes in lipid metabolism, cellular stress, and survival. Using lipidomics, metabolomics, stable isotope tracing, and flux propensity analysis, we created a comprehensive metabolic profile of the changes associated with the PNPLA3-I148M variant. Functional analysis showed that the presence of the PNPLA3-I148M variant increased endoplasmic reticulum stress, mitochondrial dysfunction, and peroxisomal β-oxidation, ultimately leading to cell death via ferroptosis. Nutritional interventions, ferroptosis-specific inhibitors, and genetic approaches modulating GPX4 activity in PNPLA3-I148M HAH and iHeps decreased programmed cell death. Our findings indicate that therapies targeting ferroptosis in patients carrying the PNPLA3-I148M variant could affect the development of MASLD and ESLD and highlight the utility of iPSC-based models for the study of genetic contributions to hepatic disorders.

Keywords:  Cell stress; Fatty acid oxidation; Gastroenterology; Hepatology; Lipidomics

DOI:  https://doi.org/10.1172/jci.insight.193805
FEBS Lett. 2025 Oct 18.

Mitochondrial fatty acid oxidation is stimulated by red light irradiation.

Manuel Alejandro Herrera, Camille C Caldeira da Silva, Maiza Von Denz, Mauricio S Baptista, Alicia J Kowaltowski.

  Keratinocytes are the primary constituents of sunlight-exposed epidermis. In these cells, ultraviolet (UV) A light completely inhibited oxidative phosphorylation, while equivalent doses of blue and green light preserved metabolic fluxes but reduced viability. In contrast, red light enhanced proliferation and elevated basal and maximal oxygen consumption rates for 48 h without altering protein levels of the electron transport chain. Targeted flux analysis revealed that red light specifically activates AMP-activating protein kinase (AMPK)-dependent mitochondrial fatty acid oxidation. This was accompanied by reduced levels of free fatty acids and increased acetyl-CoA carboxylase phosphorylation. Together, our results characterize wavelength-selective regulation of keratinocyte metabolism: UV/visible wavelengths induce damage, while red light triggers AMPK-dependent fatty acid oxidation, providing a mechanistic explanation for photobiomodulation in epidermal cells. Impact statement Sunlight impacts skin cells in surprising ways. While UVA harms energy production and blue/green light reduces survival, red light boosts keratinocyte metabolism. We show that red light activates AMPK-dependent fatty acid oxidation, enhancing proliferation and energy use. These findings reveal how specific wavelengths can damage or stimulate skin cells.

Keywords:  AMPK; beta oxidation; light; metabolism; mitochondria; skin

DOI:  https://doi.org/10.1002/1873-3468.70195
Cancer Lett. 2025 Oct 22. pii: S0304-3835(25)00669-X. [Epub ahead of print] 218097

Cancer Dormancy and Metabolism: From Molecular Insights to Translational Opportunities.

Yashi Wang, Lingyue Liu, Xiaozhen Zhang, Tingbo Liang, Xueli Bai.

  Cancer dormancy refers to a reversible state where cancer cells enter a quiescent phase, allowing them to evade therapeutic interventions and remain undetected. This state can lead to potential reactivation years later, resulting in relapse and metastasis. This phenomenon presents a significant challenge in cancer treatment, as dormant cells often exhibit resistance to conventional therapies. Recent studies emphasize the crucial role of metabolic reprogramming in regulating cancer dormancy, closely interacting with the tumor microenvironment. Dormant cancer cells undergo metabolic adaptations that enable their survival in a hostile tumor microenvironment. These adaptations include a decreased reliance on glycolysis and an increased dependence on oxidative phosphorylation and fatty acid oxidation. Exosomes, extracellular matrix, and cancer-associated fibroblasts dynamically regulate these metabolic states by mediating intercellular communication and modulating the biochemical and mechanical properties of the tumor microenvironment. In parallel, epigenetic regulation fine-tunes metabolic gene expression, reinforcing the dormant phenotype and enabling plastic transitions between dormancy and proliferation. Additionally, these cells utilize autophagy to recover nutrients and manage microenvironmental stress. These metabolic changes help dormant cells maintain a low metabolic state while preserving their ability to reactivate when conditions become favorable. Understanding the relationship between dormancy and metabolism offers new therapeutic opportunities aimed at targeting metabolic pathways to prevent relapse and metastasis. This review explores the mechanisms of metabolic reprogramming in dormancy induction, maintenance, and escape, providing insights into potential therapeutic strategies.

Keywords:  Autophagy; Cancer dormancy; Fatty acid oxidation; Metabolic reprogramming; Oxidative phosphorylation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.218097
Sci Rep. 2025 Oct 23. 15(1): 37028

Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.

Martina Spada, Cristina Piras, Vera Piera Leoni, Mattia Casula, Gabriella Simbula, Antonio Noto, Katia Lilliu, Karolina Krystyna Kopeć, Gabriele Serreli, Federica Murgia, Federica Etzi, Tinuccia Dettori, Luigi Atzori, Paola Caria.

  Colorectal cancer (CRC) cells are 'addicted' to glutamine to satisfy energy and biosynthetic needs. Inhibiting glutamine metabolism enzymes, like glutaminase, is a potential cancer therapy strategy. Although the GLS inhibitor CB-839 is being evaluated in clinical trials, a comprehensive assessment of its antitumor activity in CRC cells is crucial. The present study aimed to evaluate the impact of CB-839 treatment on different CRC cell lines in terms of survival and proliferation. Furthermore, metabolic adaptations resulting from CB-839 treatment, particularly in energetic pathways, were investigated. Three CRC cell lines (HCT116, HT29, and SW480) were treated with different CB-839 concentrations. Cytotoxicity was assessed via MTT assay, proliferation capacity by flow cytometry, and ATP production rates by Seahorse XF analysis. Moreover, metabolomic profile was explored with untargeted GC-MS and 1H-NMR, and targeted analysis of the Krebs cycle was conducted using GC-MS/MS. HT29 cells exhibited the highest sensitivity to CB-839. Subsequent experiments focused on HT29 and SW480 cells. CB-839 treatment altered cell cycle progression and increased glycolytic ATP production in HT29 cells. Metabolomic analysis revealed changes in Krebs cycle and glutaminolysis in both cell lines, along with alterations in amino acids, sugars, antioxidants, and organic acid levels. This study highlighted glutamine's key role in CRC cells and provided a foundation for elucidating the mechanisms of response and resistance to CB-839.

Keywords:  CB-839; Colorectal cancer; Energetic metabolism; Glutaminase-1 inhibition; Glutamine metabolism; Glutaminolysis

DOI:  https://doi.org/10.1038/s41598-025-20528-2
iScience. 2025 Oct 17. 28(10): 113601

Kir5.1-modulated potassium flux stimulates an anabolic kidney phenotype.

Aihua Wu, Masa-Ki Inoue, Yahua Zhang, Clinton M Hasenour, Juan Pablo Arroyo, Fabian Bock, Alina Yu, Mohammed Z Ferdaus, Yvette Blackwell, Roman M Lazarenko, Jamey D Young, Jerod S Denton, Eric Delpire, Ming-Zhi Zhang, Raymond C Harris, Andrew S Terker.

  The kidney maintains systemic potassium (K+) balance through energy-intensive epithelial transport processes. Under K+-restricted conditions, kidney epithelial cells proliferate to accommodate profound increases in transport. Tissue reorganization to minimize systemic K+ loss is essential for survival, yet metabolic details remain obscure. Here, we demonstrate that the most-activated kidney pathways under low K+ conditions are those governing metabolism, including carbohydrate- and glutamine-based processes and fatty acid synthesis. We identify that reduced K+ intake stimulates glycolytic flux in the renal cortex to increase amino acid abundance, de novo fatty acid synthesis, and organ expansion. Using a novel mouse model harboring a dominant-negative Kir5.1 channel, we show that each of these steps is dependent on intact basolateral Kir channel flux to initiate rapid kidney growth. Results identify details of a low K+-simulated anabolic kidney program requiring Kir channel function and highlight a therapeutic role for targeting Kir channels to modulate cell physiology and metabolism.

Keywords:  Cellular physiology; Metabolic flux analysis; Technical aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.113601
Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00570-2. [Epub ahead of print]60(20): 2701-2702

ATG9 assists lipid replenishment for lysosome membrane repair.

Hemmo Meyer, Bojana Kravic.

Lysosomal membranes can be permeabilized under various conditions with detrimental consequences for the cell. In this issue, de Tito et al. report that the lipid scramblase ATG9, best known for its role in autophagosome formation, helps distribute lipids from the ER to reseal the limiting membrane and restore lysosomal function.

DOI: https://doi.org/10.1016/j.devcel.2025.09.010
Trends Endocrinol Metab. 2025 Oct 19. pii: S1043-2760(25)00216-4. [Epub ahead of print]

Dietary medium-chain triacylglycerols in metabolic regulation.

Ye Cao, Josephine M Kanta, Christopher A Bishop, Bente Kiens, Andreas M Fritzen, Maximilian Kleinert.

  Dietary medium-chain triacylglycerols (MCTs; C8:0-C12:0) are absorbed and utilized differently compared with long-chain fats. They directly enter the portal vein as free medium-chain fatty acids, most of which are converted to ketone bodies in the liver, with a significant proportion entering the circulation. Accumulating evidence links MCT intake to improved glucose homeostasis; increased energy expenditure and satiety with concomitant modest weight loss; and chain length-dependent modulation of circulating lipoprotein profiles and liver metabolism. Emerging data also suggest direct benefits for cardiac contractility, hinting at a broader cardiometabolic advantage. Here, we synthesize the current evidence, outlining how MCTs influence cardiometabolic health. We further discuss mechanistic insights, from cellular substrate partitioning and mitochondrial dynamics to gut-liver signaling to propose mechanisms of MCT action.

Keywords:  energy balance, cardiometabolic health, ketone bodies; glucose homeostasis; medium-chain fatty acids; medium-chain triacylglycerols

DOI:  https://doi.org/10.1016/j.tem.2025.09.010
Cell Death Dis. 2025 Oct 24. 16(1): 755

TM9SF1 drives the lipophagic flux via AMPK-ULK1 signaling to sustain metabolic fitness in HER2-positive breast cancer.

Xiaofen Li, Xiaoqin Yu, Kaiyan Huang, Xin Yu, Shiping Luo, Xiewei Huang, Chuangui Song.

Therapeutic resistance and recurrence in human epidermal growth factor receptor 2-positive breast cancer (HER2 + BC) remain critical challenges that portend poor patient outcomes. Dysregulated autophagy and lipid metabolism contribute to tumor progression, yet the crosstalk between these pathways is poorly understood. This study investigates the role of transmembrane 9 superfamily member 1 (TM9SF1) in lipophagy and lipid metabolic reprogramming in HER2 + BC under metabolic stress. Clinically, TM9SF1 was significantly upregulated in HER2 + BC tissues and correlated with poor prognosis. Functionally, its expression correlated with markers of enhanced autophagy and lysosomal lipid catabolism, and it promoted tumor cell proliferation in vitro and in vivo. Conversely, TM9SF1 knockdown suppressed lipophagy under both basal and starvation conditions, inhibiting lipid droplet (LD) hydrolysis and the conversion of triglycerides to free fatty acids. This suppression was phenotypically characterized by LD accumulation, reduced autophagosomes and lipophagosomes, and altered enzymatic and lipidomic profiles. Mechanistically, TM9SF1 sustained lipophagy by promoting the phosphorylation of AMP-activated protein kinase at Thr172 and UNC-51-like kinase 1 at Ser555. Consequently, TM9SF1 was pivotal for lipid metabolic reprogramming, maintaining energy homeostasis and enhancing adaptation to nutrient deprivation through lipophagy. Overall, our findings identify TM9SF1 as a key HER2 + BC-associated regulator that drives lipophagy via the AMP-activated protein kinase-UNC-51-like kinase 1 pathway, facilitating LD turnover and free fatty acids utilization to sustain energy homeostasis in HER2 + BC. This work establishes a critical link between malignant phenotypes and metabolic resilience. Targeting this regulatory network represents a promising strategy to dismantle the metabolic scaffolds underlying HER2 + BC aggressiveness and therapeutic resistance.

DOI: https://doi.org/10.1038/s41419-025-08093-y
Commun Biol. 2025 Oct 20. 8(1): 1485

SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.

Zhang Xianhong, Gao Yue, Zhang Yu, Zhang Yichen, Chen Yufei, Pei Xinke, Zhang Jinhui, Wang Yiqi, Du Yitian, Hao Shuailin, Ni Ting.

Protein lysine succinylation is a crucial post-translational modification that regulates nearly all aspects of eukaryotic and prokaryotic cell, including gene transcription, cell metabolism and redox homeostasis. Among them, metabolic disorders caused by dysfunctional post-translational modifications induce aging and aged-related diseases, including cancer. This study quantified the dynamic changes in protein succinylation in response to DNA damage stress induced by etoposide (ETOP) in tumor cells. A total of 4354 lysine succinylation sites on 1259 proteins were identified, many of which have not been previously reported. Bioinformatics analysis revealed that many proteins are involved in the metabolism of nicotinamide adenine dinucleotide phosphate (NADPH) in mitochondria (including MTHFD2). We further found that low activity or depletion of MTHFD2 enhances the degree of TIS in breast cancer cells and decreases their resistance to chemotherapeutic agents. Interestingly, we also found that SIRT5-mediated desuccinylation of MTHFD2 was able to reduce the senescence of breast cancer cells, thereby enhancing their resistance to chemotherapeutic drugs. This effect may explain the poorer prognosis observed in breast cancer patients with high expression levels of SIRT5 or MTHFD2. These systematic analyses provide new insights into targeting succinylation-modified metabolic proteins to enhance TIS, and their combination with senolytics for breast cancer therapy.

DOI: https://doi.org/10.1038/s42003-025-08878-z
Trends Biotechnol. 2025 Oct 23. pii: S0167-7799(25)00409-3. [Epub ahead of print]

Rewiring microbial metabolism through post-translational switches.

Xianhao Xu, Yang Li, Jiaheng Liu, Xueqin Lv, Long Liu.

  Recent advances in post-translational regulatory tools have enabled precise and rapid control of metabolic flux in microbial cell factories. In this review, we systematically summarize current post-translational regulatory tools for modulating the abundance, localization, and activity of key metabolic enzymes. We first discuss protein degradation tags for tunable control of enzyme levels. Then, we discuss spatial regulation through natural and synthetic subcellular compartments. We also highlight emerging approaches for engineering allosteric switches, including computational and de novo design methods. Finally, we outline future directions toward orthogonal, efficient, and cross-species compatible systems. This review provides conceptual and technical insights to guide the development of next-generation post-translational regulatory tools for dynamic metabolic control in microbial cell factories.

Keywords:  allosteric regulation; metabolic flux control; post-translational regulation; protein degradation tags; subcellular compartmentalization

DOI:  https://doi.org/10.1016/j.tibtech.2025.10.002
FEBS Lett. 2025 Oct 23.

The role of fibroblast growth factors in cell and cancer metabolism.

Jessica Price, Chiara Francavilla.

  The fibroblast growth factor (FGF) family and the FGF receptors are ubiquitously expressed and regulate a plethora of cell signaling cascades during development, tissue and cell homeostasis, and metabolism. Dysregulated FGF signaling is associated with cancer and several genetic and metabolic disorders. As FGF signaling regulates all the key metabolic processes to maintain whole-body homeostasis, there is an increasing focus on engineering FGFs as potential treatments for dysregulated metabolism. Within cancer, reprogramming of energy metabolism is a crucial step leading to tumorigenesis, metastasis formation, and resistance to therapy. FGF signaling dysregulation in cancer enables uncontrolled proliferation and survival and promotes therapy resistance and metastasis. However, the role of FGF signaling within cancer metabolism is not well understood. A better understanding of how FGF signaling affects the rewiring of cancer metabolism as well as tumorigenesis would provide novel avenues for discovering potential drug targets and biomarkers. Here, we discuss the role of paracrine, endocrine, and intracellular FGFs within metabolism as well as the current understanding of how FGF signaling contributes to rewired cancer metabolism.

Keywords:  FGF; cancer; cell signaling; fibroblast growth factor receptor; homeostasis; metabolism; metastasis; receptor tyrosine kinase; therapy resistance

DOI:  https://doi.org/10.1002/1873-3468.70199
Sci Adv. 2025 Oct 24. 11(43): eadt3879

The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism.

Ying Yang, Da Eun Kang, Qi Fan, Eric A Hanse, Hosung Bae, Rocio A Barahona, Xiyu Shen, Bryan I Ruiz, Shelly H Lee, Katherine R Pasterczyk, Nainpriya Babbar, Katherine G Waldvogel, Roberto Tinoco, Kim N Green, Qin Yang, Cholsoon Jang, Mei Kong.

Aging is characterized by disruptions in metabolic homeostasis, yet the mechanisms that regulate these metabolic changes remain poorly understood. We show that the serine/threonine-protein phosphatase 6 (PP6) regulatory subunit 3, SAPS3, is a critical regulator of metabolism during aging. SAPS3 deletion significantly extends lifespan in mice and counteracts age-related impairments in metabolic health. SAPS3 deficiency improves the effects of aging on the affective behaviors, cognition, and motor functions in aged mice. We find that SAPS3 expression is increased during aging to inhibit adenosine monophosphate-activated kinase (AMPK) activity. Deletion of SAPS3 leads to AMPK activation and reverses cellular senescence and aging-induced metabolic alterations. Using in vivo U-13C6-D-glucose tracing and metabolomic analysis, we find that SAPS3 deficiency restores metabolic homeostasis with increased glycolysis, tricarboxylic acid (TCA) cycle, and decreased fatty acid synthesis in aged mice. These findings highlight a critical role of the SAPS3/PP6 phosphatase complex in aging and suggest that strategies targeting SAPS3 may promote longevity and healthy aging.

DOI: https://doi.org/10.1126/sciadv.adt3879
Nat Commun. 2025 Oct 20. 16(1): 9250

Mitochondrial one-carbon metabolism is required for TGF-β-induced glycine synthesis and fibrotic responses.

Angelo Y Meliton, Kun Woo D Shin, Rengül Cetin-Atalay, M Volkan Atalay, Yufeng Tian, Jennifer C Houpy Szafran, Takugo Cho, Kaitlyn A Sun, Parker S Woods, Obada R Shamaa, Bohao Chen, Nickolai O Dulin, Aliya N Husain, Alexander Muir, Hardik Shah, Gökhan M Mutlu, Robert B Hamanaka.

TGF-β-dependent activation of lung fibroblasts is a hallmark of Idiopathic Pulmonary Fibrosis (IPF) which results in excessive collagen deposition and progressive scarring. Collagen production by lung fibroblasts is supported by de novo synthesis of glycine, the most abundant amino acid in collagen protein. SHMT2 produces glycine by transferring a one-carbon (1 C) unit from serine to tetrahydrofolate (THF), producing 5,10-methylene-THF (meTHF). meTHF is then converted back to THF in the mitochondrial 1 C pathway. It is unknown how 1 C metabolism contributes to collagen protein production and fibrosis. Here, we demonstrate that TGF-β induces the expression of mitochondrial 1 C pathway enzymes, including MTHFD2, in human lung fibroblasts. MTHFD2 was required for TGF-β-induced cellular glycine accumulation and collagen protein production in lung fibroblasts. Pharmacologic inhibition of MTHFD2 ameliorated fibrotic responses after intratracheal bleomycin instillation in vivo. Our findings suggest that mitochondrial 1 C metabolism is a therapeutic target for IPF and other fibrotic diseases.

DOI: https://doi.org/10.1038/s41467-025-64320-2
Cell Death Dis. 2025 Oct 24. 16(1): 751

UHRF1-mediated HIF-1α stabilization promotes ovarian cancer through metabolic reprogramming and angiogenesis.

Yuanna Jiang, Fang Peng, Yibo Chen, Aoyu Fu, Ruichen Yang, Ziyue Yang, Qian Wang, Lanqin Cao.

Ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) is an important epigenetic regulatory factor that is highly expressed in various cancers and participates in tumorigenesis and progression. However, the role and molecular mechanisms of UHRF1 in ovarian cancer (OC) remain unclear. Through survival analysis, cellular functional experiments, and animal studies, we identified UHRF1 as a key gene influencing OC progression and prognosis. Hypoxia-inducible factor-1 (HIF-1α), a well-known pro-cancer molecule, undergoes classic degradation via the ubiquitin-proteasome pathway. We discovered that UHRF1 interacts with HIF-1α, affecting its hydroxylation level, thereby inhibiting HIF-1α polyubiquitination and degradation. Functional experiments revealed that knocking down HIF-1α in stable UHRF1-overexpressing cell lines significantly reversed the malignant phenotype of OC cells. Furthermore, UHRF1 can also regulate the expression of key downstream molecules such as GLUT1, HK2, LDHA, and VEGFA by modulating HIF-1α, thus influencing tumor cell metabolism and angiogenesis. In summary, our findings suggest that UHRF1 plays a crucial role in the development of OC by regulating the expression of HIF-1α.

DOI: https://doi.org/10.1038/s41419-025-08033-w
Front Immunol. 2025 ;16 1652516

A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS.

Louise Nuyttens, Marah Heyerick, Maxime Roes, Elise Moens, Céline Van Dender, Charlotte Wallaeys, Tino Hochepied, Steven Timmermans, Jolien Vandewalle, Claude Libert.

  Tumor necrosis factor (TNF) causes a lethal systemic inflammatory response syndrome (SIRS) which is characterized by significant metabolic alterations. Based on liver RNA sequencing, we found that TNF impairs the malate-aspartate shuttle (MAS), an essential redox shuttle that transfers reducing equivalents across the inner mitochondrial membrane thereby recycling cytosolic NAD+. This downregulation of MAS genes in TNF-induced SIRS likely results from loss of HNF4α function, which appears to be the key transcription factor involved. Using Slc25a13-/- mice lacking citrin - a crucial MAS component - we demonstrate that MAS dysfunction exacerbates TNF-induced metabolic dysregulations and lethality. Disruptive NAD+ regeneration leads to diminished mitochondrial β-oxidation, leading to elevated levels of circulating free fatty acids (FFAs) and to hepatic lipid accumulation. Simultaneously, MAS dysfunction promotes glycolysis coupled to lactate production and reduces lactate-mediated gluconeogenesis, culminating in severe hyperlactatemia that triggers VEGF-induced vascular leakage. Overall, MAS dysfunction contributes to metabolic failure and lethality in TNF-induced SIRS, highlighting its potential as a promising, therapeutic target.

Keywords:  TNF-induced SIRS; carbohydrate metabolism; citrin; lipid metabolism; malate aspartate shuttle

DOI:  https://doi.org/10.3389/fimmu.2025.1652516
Sci Adv. 2025 Oct 24. 11(43): eadx4289

Label-free robotic mitochondrial biopsy.

Yanmei Ma, Weikang Hu, Muyang Ruan, Feixiang Bao, Xingguo Liu, Dong Sun, Hongri Gu, Chengzhi Hu.

Robotic micromanipulation has advanced cellular probing, yet achieving precise, minimally invasive intracellular operations without fluorescent labeling remains challenging. Fluorescent techniques often cause photodamage and cytotoxicity and interfere with downstream analyses. Here, we introduce an automated, multifunctional nanoprobing platform capable of label-free extraction of mitochondria from living cells with high spatiotemporal resolution. The nanoprobe integrates two individually addressable nanoelectrodes that perform electrochemical detection of reactive oxygen and nitrogen species, produced by mitochondrial metabolism, followed by dielectrophoretic trapping, manipulation, and extraction of mitochondria. We successfully demonstrated the extraction of mitochondria from living cells, which is validated through fluorescence labeling before and after extraction. Subsequent quantitative polymerase chain reaction further confirmed that the extracted sample contained mitochondria. The fusion of the transplanted mitochondria within the recipient cell's mitochondrial network confirms their activity. This automated, label-free, in situ organelle extraction micromanipulation system offers a powerful tool for understanding disease mechanisms linked to dysfunctional organelles and enables single-cell surgeries for organelle transplantation.

DOI: https://doi.org/10.1126/sciadv.adx4289
Nat Metab. 2025 Oct 21.

Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection against intestinal inflammation.

Qing Li, Rodrigo de Oliveira Formiga, Virginie Puchois, Laura Creusot, Ahmad Haidar Ahmad, Salomé Amouyal, Márcio Augusto Campos-Ribeiro, Yining Zhao, Danielle M M Harris, Frederic Lasserre, Sandrine Ellero-Simatos, Hervé Guillou, Zhan Huang, Loic Brot, Yuhang Hu, Loic Chollet, Camille Danne, Cyril Scandola, Tatiana Ledent, Guillaume Chevreux, Rafael J Argüello, Marcelo De Carvalho Bittencourt, Jessica Bettinger, Maud D'Aveni-Piney, David Moulin, Stefan Schreiber, Konrad Aden, Nathalie Rolhion, Marie-Laure Michel, Timothy Wai, Harry Sokol.

The gut microbiota and its metabolites critically regulate immune cell phenotype, function and energy metabolism. We screened a collection of gut microbiota-related metabolites to identify modulators of mitochondrial metabolism in T cells. Here we show that indole-3-propionic acid (IPA) stimulates mitochondrial respiration of CD4+ T cells by increasing fatty acid oxidation (FAO) and amino acid oxidation (AAO), while inhibiting glycolytic capacity. IPA also impacts CD4+ T cell behaviour by inhibiting their differentiation to type 1 and type 17 helper T cell phenotypes. Mechanistically, the metabolic and immune effects of IPA are mediated by peroxisome proliferator-activated receptor-β/δ. The administration of IPA rescues mitochondria respiration in mice with gut bacteria depletion or colitis by enhancing FAO and AAO in colonic CD4+ T cells. Adoptive transfer experiments show that IPA acts on CD4+ T cells to exert its protective effect against inflammation. Collectively, our study reveals that the anti-inflammatory effects of IPA are mediated by metabolic reprogramming of CD4+ T cells toward the enhancement of mitochondrial respiration.

DOI: https://doi.org/10.1038/s42255-025-01396-6
Nat Metab. 2025 Oct 20.

A lactate-acetate interaction between macrophages and cancer cells drives metastasis.

DOI: https://doi.org/10.1038/s42255-025-01398-4
Sci Rep. 2025 Oct 23. 15(1): 37031

Rapamycin alleviates hypothalamic injury in exertional heat stroke rats by activating mitophagy through the mTOR/Pink1/Parkin pathway.

Ruxue Chi, Yan Gu, Ran Meng, Lv Xuan, Zhengzhong Sun, Yuxiang Zhang, Jiaxing Wang.

  Exertional heat stroke (EHS) causes severe central nervous system damage, with mitochondrial dysfunction and oxidative stress playing major roles. Mitophagy, regulated by the Pink1/Parkin pathway, removes damaged mitochondria. Here, we investigated the potential of rapamycin (RAPA) to reduce hypothalamic injury in rats subjected to EHS. Forty healthy male Sprague-Dawley rats were randomly assigned to control, RAPA, EHS, and EHS + RAPA groups (10 rats each). Core temperatures were measured, and survival curves were generated. Hypothalamic tissue underwent hematoxylin-eosin and Nissl staining for histopathological assessment. Hypothalamic mitochondrial membrane potential, reactive oxygen species (ROS), and malonaldehyde (MDA) levels were measured. Western blotting assessed mammalian target of RAPA (mTOR), phosphorylated mTOR, Pink1, Parkin, P62, and microtubule-associated protein 1 Light chain 3 (LC3) expression, and calculated the LC3II/LC3I ratio. Immunofluorescence evaluated Pink1-Parkin and LC3-Tom20 co-localization in hypothalamic tissue. EHS and EHS + RAPA groups showed markedly increased core temperatures. RAPA mitigated pathological injury and apoptosis, reduced ROS and MDA levels, and enhanced mitochondrial membrane potential. It downregulated mTOR and p62 levels, upregulated Pink1 and Parkin, increased LC3II/LC3I ratio, and promoted LC3-Tom20 and Pink1-Parkin interactions in the hypothalamic tissue of rats treated with EHS, thereby alleviating hypothalamic injury and preserving hypothalamic function.

Keywords:  Heat stroke; Hypothalamus; Mitophagy; Parkin; Pink1; Rapamycin

DOI:  https://doi.org/10.1038/s41598-025-20313-1
Sci Rep. 2025 Oct 22. 15(1): 36842

Fenofibrate differentially activates PPARα-mediated lipid metabolism in rat kidney and liver.

Venkat R Pannala, Michele R Balik-Meisner, Deepak Mav, Dhiral P Phadke, Elizabeth H Scholl, Ruchir R Shah, Warren Casey, Scott S Auerbach, Anders Wallqvist.

  Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely prescribed to treat hyperlipidemia and has therapeutic potential in liver and kidney diseases. However, fenofibrate is also associated with adverse effects, including elevated creatinine and liver and kidney toxicity, although the underlying mechanisms remain unclear. In addition, how fenofibrate regulates lipid metabolism differently in the liver and kidney is not well understood. Therefore, in this study, we investigated the dose-dependent effects of fenofibrate on liver and kidney metabolism in rats, with a focus on PPARα activation and potential mechanisms contributing to organ-specific toxicity. We used high-throughput transcriptomic data from 5-day rat in vivo studies, where rats were exposed to fenofibrate, and performed pathway enrichment, injury module, and detailed individual gene comparison analyses to investigate how liver and kidney metabolism were differentially altered between the two organs. Fenofibrate exposure significantly increased liver but not kidney weights and caused larger perturbations in the liver compared to the kidney transcriptome, with the majority of the changes related to PPARα regulation. Interestingly, our study revealed that the PPARα and RXRα genes are differentially regulated between the liver and kidney. In addition, we identified several differences between them in cellular and mitochondrial fatty acid transport, lipoprotein metabolism, fatty acid oxidation, branched-chain amino acid degradation, and glucose metabolism pathways. Furthermore, we identified transcriptomic inflection points at which the changes in the PPARα-mediated regulation of lipid metabolism switched from beneficial to deleterious as the fenofibrate concentration increased leading to liver injury, providing potential mechanisms of toxicity.

Keywords:  Branched-chain amino acids; Fatty acid uptake; Fenofibrate; Gluconeogenesis; Lipid metabolism; PPARα; Peroxisome

DOI:  https://doi.org/10.1038/s41598-025-20731-1
Cell Signal. 2025 Oct 20. pii: S0898-6568(25)00597-2. [Epub ahead of print]136 112182

IL-11 exacerbates cisplatin-induced acute kidney injury by facilitating apoptosis in renal tubular epithelial cells via ERK1/2-Drp1/TFEB-mediated defective autophagy.

Danping Tao, Wenting Wu, Zerong Zheng, Hui Zhang, Yue Ji, Yiyi Zhuang, Huizhen Wang, Fenfen Peng, Xiaowen Chen, Haibo Long, Congwei Luo.

  Cisplatin-induced acute kidney injury (Cis-AKI) lacks targeted therapies. Here we identify interleukin-11 (IL-11) as a key driver of tubular injury that couples mitochondrial dynamics to autophagic flux in renal tubular epithelial cells. In a mouse Cis-AKI model, IL-11 knockdown ameliorated tubular damage and significantly improved renal function (serum creatinine, blood urea nitrogen), with concordant restoration of AQP1 and reduction of KIM-1/NGAL, indicating robust protection at the tissue and functional levels. Mechanistically, IL-11 activated ERK1/2, increased Drp1 phosphorylation and mitochondrial fission, and suppressed TFEB activity to impair lysosomal maturation and autophagic flux; ERK inhibition (SCH772984) and TFEB overexpression rescued TFEB activity, lysosomal markers, and autophagic completion, and reduced apoptosis/senscence. Tissue-level readouts (IHC for p-Drp1 and p62; immunoblots for LC3-I/II and p62) and TEM ultrastructure corroborated these pathways in vivo, linking mitochondrial fragmentation and autophagic blockade to IL-11-dependent injury. In HK-2 cells, recombinant human IL-11 (50 ng/mL) reproduced ERK-Drp1/TFEB pathway activation and phenotypes, and loss-of-function of IL-11 attenuated cisplatin-induced apoptosis and senescence. Collectively, these data define an ERK1/2-Drp1/TFEB axis by which IL-11 exacerbates Cis-AKI through mitochondrial dysfunction and autophagic flux disruption, culminating in apoptosis and cellular senescence. Targeting IL-11 or restoring TFEB activity emerges as a mechanism-based strategy to mitigate cisplatin nephrotoxicity.

Keywords:  AKI; Drp1; ERK1/2; IL-11; TFEB

DOI:  https://doi.org/10.1016/j.cellsig.2025.112182
BMC Biol. 2025 Oct 21. 23(1): 316

TCA-cycle metabolites in the nucleus: drivers of chromatin and epigenetic control.

Serena Ghisletti, Marta Russo.

  Mitochondrial enzymes are increasingly recognized for their ability to translocate to the nucleus, where they generate metabolites essential for epigenetic regulation and gene expression. Yet, whether this phenomenon broadly involves metabolic enzymes or is restricted to specific subunits remains unclear. In this review, we assess current evidence, highlight knowledge gaps, and suggest future directions on the nuclear localization and functions of metabolic enzymes, with a focus on acyl-CoA producers. Emerging studies reveal multiple mechanisms guiding these enzymes to chromatin for localized metabolite synthesis. Key questions concern nuclear import machinery, chromatin interactions, and the regulatory impact of their activity.

Keywords:  Histone modifications; Metabolism; Mitochondrial enzymes; Transcriptional regulation

DOI:  https://doi.org/10.1186/s12915-025-02423-4
J Neurochem. 2025 Oct;169(10): e70265

PMP2 Enhances Schwann Cell Metabolism and Promotes Myelination.

Gustavo Della-Flora Nunes, Jiayue Hong, Rebekah Garfolo, Acheta Jenica, Amanda S Mondschein, Olivia M Harris, Khushi Panchal, Frances L Jourd'heuil, David Jourd'heuil, Yannick Poitelon, Sophie Belin.

  Myelinating Schwann cells depend on precise metabolic regulation to support axonal function and maintain peripheral nerve integrity. Peripheral Myelin Protein 2 (PMP2), a fatty acid-binding protein enriched in myelinating Schwann cells, has been implicated in lipid metabolism and mitochondrial energy production. Here, we examine the role of PMP2 in regulating Schwann cell bioenergetics and myelination. Using both immortalized and primary Schwann cells, we show that PMP2 overexpression enhances mitochondrial ATP production. We also reveal that PMP2 alters metabolic dependencies during high metabolic demand, reducing Schwann cell reliance on glutamine while promoting greater metabolic adaptability under substrate restriction. Finally, PMP2 overexpression significantly increases myelination in vitro, indicating that PMP2-driven metabolic modulation supports the energetic demands of myelination. These findings position PMP2 as a key regulator of Schwann cell metabolism and a potential therapeutic target for demyelinating neuropathies.

Keywords:  ATP; PMP2; Schwann cell; seahorse

DOI:  https://doi.org/10.1111/jnc.70265
Nat Commun. 2025 Oct 23. 16(1): 9370

Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis.

Vikas Yadav, Sarthak Sahoo, Nitish Malhotra, Richa Mishra, Sreesa Sreedharan, Raju S Rajmani, Siva Shanmugam, Radha K Shandil, Shridhar Narayanan, Vivek V Thacker, Sunil Laxman, Mohit Kumar Jolly, Aswin Sai Narain Seshasayee, Amit Singh.

Effective clearance of Mycobacterium tuberculosis (Mtb) requires targeting drug-tolerant populations within host macrophages. Here, we show that macrophage metabolic states govern redox heterogeneity and drug response in intracellular Mtb. Using a redox-sensitive fluorescent reporter (Mrx1-roGFP2), flow cytometry, and transcriptomics, we found that macrophages with high oxidative phosphorylation (OXPHOS) and low glycolysis harbor reductive, drug-tolerant Mtb, whereas glycolytically active macrophages generate mitochondrial ROS via reverse electron transport, imposing oxidative stress on Mtb and enhancing drug efficacy. Computational and genetic analyses identified NRF2 as a key regulator linking host metabolism to bacterial redox state and drug tolerance. Pharmacological reprogramming of macrophages with the FDA-approved drug meclizine (MEC) shifted metabolism towards glycolysis, suppressed redox heterogeneity, and reduced Mtb drug tolerance in macrophages and mice. MEC exhibited no adverse interactions with frontline anti-TB drugs. These findings demonstrate the therapeutic potential of host metabolic reprogramming to overcome Mtb drug tolerance.

DOI: https://doi.org/10.1038/s41467-025-64407-w
Cell Signal. 2025 Oct 17. pii: S0898-6568(25)00585-6. [Epub ahead of print]136 112170

Mitochondrial homeostasis collapse to cardiac remodeling: From mechanisms to novel targeted therapeutic avenues.

Qi-Yun Liu, Fan-Liang Meng, Jia-Min Du, Wen-Jing Li, Si-Yuan Zhou, Ying Li.

  Myocardial remodeling is a common pathological process in various cardiovascular diseases (CVDs) and represents the heart's adaptive response to pressure or volume overload. However, prolonged myocardial remodeling often leads to a progressive decline in cardiac function, ultimately resulting in heart failure (HF). This process is primarily characterized by myocardial hypertrophy and fibrosis, both of which are closely linked to mitochondrial dysfunction. Emerging research uncovers a pivotal orchestrator of this lethal transition: mitochondrial homeostasis. As the powerhouse of cardiomyocytes, dysfunctional mitochondria ignite a catastrophic cascade-energy bankruptcy, oxidative tsunamis, and apoptotic avalanches-propelling pathological hypertrophy and fibrosis. Although extensive research has explored mitochondrial homeostasis in cardiovascular diseases, a comprehensive summary of the specific mechanisms and effects of mitochondrial dysfunction in myocardial remodeling remains lacking. This review focuses on pathological myocardial remodeling associated with mitochondrial abnormalities and examines four critical factors: mitochondrial Ca2+ signaling, metabolism, dynamics, and mitophagy. Bridging molecular mechanisms to next-generation therapeutics, we systematically evaluates their roles in disease progression and discusses potential mitochondrial-targeted therapeutic strategies, offering new insights into research and treatment approaches for related conditions.

Keywords:  Ca(2+); Dynamics; Metabolism; Mitochondrial homeostasis; Mitophagy; Myocardial remodeling

DOI:  https://doi.org/10.1016/j.cellsig.2025.112170
FASEB J. 2025 Oct 31. 39(20): e71156

Mitochondrial ROS Drive Adipogenic Differentiation in Osteoporosis by Suppressing Protein Synthesis.

Yueli Zhou, Hongling Wu, Xuzheng Liu, Yuqiang Wang, Chunxiao Jin, Jiqi Zheng, Yanyang Wei, Fangfang Song, Cui Huang.

  Osteoporosis (OP) is a debilitating metabolic bone disorder, leading to disability in approximately 3.5 million individuals worldwide annually. While the bone-fat imbalance represents a hallmark of OP pathogenesis, the upstream molecular triggers remain elusive. Here, we identify mitochondrial reactive oxygen species (mtROS) as a pivotal regulator of adipogenesis in OP. We demonstrated significant accumulation of mtROS coinciding with lipid droplet formation in BMSCs isolated from osteoporotic mice. To delineate the mechanistic interplay between mtROS and lipid droplet homeostasis, four mtROS modulating cell models were developed: pharmacological induction of mtROS through Antimycin A and MitoParaquat (MitoPQ), genetic suppression of leucine-tRNA-synthetase-2 (Lars2) via siRNA-mediated knockdown, and mitochondrial antioxidant intervention using Mito-TEMPO. Complementary to these targeted approaches, we implemented intracellular ROS modulation through hydrogen peroxide (H2O2)-induced ROS elevation and glutathione (GSH) -mediated oxidative stress reduction to assess. Mechanistically, excessive mtROS disrupted global protein synthesis by suppressing phosphorylation of ribosomal protein S6, thereby restricting amino acid flux into de novo polypeptide assembly. A surplus of amino acids elevated the production of their key catabolic product, ammonia. This ammonia accumulation subsequently provoked activation of the lipogenic transcription factor SREBP1, thereby promoting lipogenesis. In ovariectomized mice, pharmacological mtROS scavenging with Mito-TEMPO not only reduced marrow adiposity but also significantly improved trabecular bone as quantified by Micro-CT and dynamic histomorphometry. Our findings demonstrated a novel mtROS-protein synthesis-ammonia-SREBP1 axis that drives pathogenic adipogenesis in osteoporosis, underscoring the translational potential of mtROS scavenging for osteoporosis treatment.

Keywords:  SREBP1; adipogenic differentiation; mitochondrial ROS; osteoporosis

DOI:  https://doi.org/10.1096/fj.202502869R
Nat Commun. 2025 Oct 24. 16(1): 9420

Structural basis for transport and inhibition of the human glucose-6-phosphate transporter G6PT.

Zhanyi Xia, Yaqi Wang, Di Wu, Cheng Chi, Chen Li, Ligong Chen, Daohua Jiang.

The human glucose-6-phosphate transporter (G6PT) moves glucose-6-phosphate (G6P) into the lumen of endoplasmic reticulum, playing a vital role in glucose homeostasis. Dysregulation of G6PT causes glycogen storage disease 1b. Despite its functional importance, the structure, G6P recognition, and inhibition mechanism of G6PT remain unclear. Here, we report the cryo-EM structures of human G6PT in apo, G6P-bound, and the specific inhibitor chlorogenic acid (CHA)-bound forms, elucidating the structural basis for G6PT transport and inhibition. The G6P pocket comprises subsite A for phosphate and subsite B for glucose. The CHA occupies the G6P site and locks G6PT in a partly-occluded state. Functional assays demonstrate that G6PT activity is enhanced by co-expression of glucose-6-phosphatase (G6PC), but G6PT does not form a complex with G6PC. Together, this study provides a solid foundation for understanding the structure‒function relationships and pathology of G6PT and sheds light on the future development of potential therapeutics targeting G6PT.

DOI: https://doi.org/10.1038/s41467-025-64464-1
Cell Death Dis. 2025 Oct 21. 16(1): 750

The combination of venetoclax with dimethyl fumarate synergistically induces apoptosis in AML cells by disrupting mitochondrial integrity through ROS accumulation.

Shin-Ichiro Kawaguchi, Kazuya Sato, Junko Izawa, Norihito Takayama, Hiroko Hayakawa, Kaoru Tominaga, Hitoshi Endo, Tom Kouki, Nobuhiko Ohno, Yoshinobu Kanda.

Leukemia cells are consistently subjected to higher oxidative stress than normal cells. To mitigate reactive oxygen species (ROS) overload, which can trigger various forms of cell death, leukemia cells employ a robust antioxidant defense system and maintain redox homeostasis. Recent evidence suggests that dimethyl fumarate (DMF), a derivative of fumarate, inactivates the antioxidant glutathione (GSH), thereby inducing oxidative stress and metabolic dysfunction, eventually leading to cell death in cancer cells. In this study, we observed that DMF decreases the GSH/oxidated GSH ratio and increases intracellular ROS levels, the extent of which is closely correlated with cell death, in acute myeloid leukemia (AML) cell lines. DMF reduced the mitochondrial membrane potential and oxidative phosphorylation (OXPHOS), effects that were almost fully restored by the antioxidant N-acetylcysteine, suggesting that these responses are ROS-dependent. Electron microscopy and inhibition assays revealed that apoptosis, rather than necroptosis or ferroptosis, is the predominant form of cell death of AML cells following DMF treatment. Notably, the combination of DMF and the BCL-2 selective BH3-mimetic venetoclax induced marked cell death in AML cells, including venetoclax-refractory　BCL-2 low expressing U937 and acquired venetoclax-resistant MOLM-14 cells. This combination also caused greater mitochondrial depolarization and a more profound reduction in OXPHOS activity than either agent alone. Collectively, our findings indicate that DMF exerts potent anti-leukemia activity in AML cells and sensitizes cells to venetoclax treatment by synergistically disrupting mitochondrial integrity through ROS accumulation.

DOI: https://doi.org/10.1038/s41419-025-08040-x