bims-celmim 2026-05-17 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–05–17
23 papers selected by
Marc Segarra Mondejar, AINA

Intracellular lactic acidosis reprograms glycolysis and mitochondrial anaplerosis in cancer cells.
MitoSafe hypothesis: safeguarding mitochondrial morphology and innate immunity.
Whole-blood NAD+ levels do not reflect healthy ageing.
AMPK: a master regulator of mitochondrial quality and quantity.
mTOR-NAA10-C7orf50 axis senses nutritional status to coordinate ribosome biogenesis and autophagy.
Single-cell lipidomic analysis of the epithelial-mesenchymal transition using mass spectrometry imaging.
MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.
Chaperone-mediated autophagy protects against retinal photoreceptor degeneration by modulating proteostasis of glucose metabolism enzymes.
The dual function of mitophagy in ferroptosis.
Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.
Quantitative proteomic profiling of neural cells-specific metabolic reprogramming in response to mitochondrial dysfunction using iMPAQT2.
Advances in near-infrared fluorescent probes for the tumor microenvironment.
Intra-mitochondrial glycolysis maintains mitochondrial function and underlies the pathogenesis of retinitis pigmentosa.
Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
Cellular mechanometabolism: stimuli and implications.
Brain metabolomic profiling reveals ischemia-dominant disruption of metabolic pathways and tissue homeostasis in neonatal hypoxic-ischemic brain injury.
Intravital calcium imaging of meningeal macrophages reveals niche-specific dynamics and aberrant responses to brain hyperexcitability.
Ascites protects against ferroptosis and enables the peritoneal growth of ovarian cancer.
Selective targeting of kinesin on lipid droplets in the liver reduces plasma lipids.
The pentose phosphate pathway contributes to excess lactate production in radiation-induced fibroblast to myofibroblast transdifferentiation.
The role of ATP synthase subunit e (ATP5I) in mediating the metabolic and antiproliferative effects of metformin in cancer cells.
PI(3)P regulates mitochondrial dynamics through EXC-5-dependent actin remodeling.
NAD+ supply and redox state limit developmental speed in the Drosophila eye.

J Biol Chem. 2026 May 14. pii: S0021-9258(26)02022-3. [Epub ahead of print] 113150

Intracellular lactic acidosis reprograms glycolysis and mitochondrial anaplerosis in cancer cells.

Chengmeng Jin, Siying Zeng, Hao Wu, Xun Hu.

  Intracellular lactic acidosis, a metabolic state newly defined in this study, is characterized by a coupled increase in intracellular lactate and proton concentrations, resulting in higher levels inside cancer cells than outside. This finding expands the Warburg paradigm: lactic acidosis is not merely extracellular but intracellular, reshaping metabolism through direct biochemical mechanisms. Acidic pH and elevated lactate jointly suppress glycolysis by inhibiting HK, PFK1 and GAPDH, enforcing a low-flux, energy-efficient state. Meanwhile, pyruvate enters the TCA cycle through a pyruvate - lactate -export - reimport - lactate - pyruvate cycle that both fuels mitochondrial metabolism and maintains lactic acidosis intracellularly and extracellularly. Lactic acidosis also reprograms anaplerosis by promoting lactate-derived oxaloacetate formation and reducing glutamine dependence. Together, these findings establish lactic acidosis as an active regulator of cancer metabolism, revealing a distinct metabolic state. This coupled lactate-proton state drives coordinated metabolic reprogramming across glycolysis and mitochondrial metabolism. representing a fundamental tumor adaptation that may be exploited to disrupt cancer metabolic resilience.

Keywords:  TCA cycle; Warburg effect; glycolysis; lactic acidosis; tumor microenvironment

DOI:  https://doi.org/10.1016/j.jbc.2026.113150
Trends Cell Biol. 2026 May 13. pii: S0962-8924(26)00065-6. [Epub ahead of print]

MitoSafe hypothesis: safeguarding mitochondrial morphology and innate immunity.

Nora Haggerty, Kentaro Nakamura, Hiromi Sesaki, Miho Iijima.

  Mitochondria divide and fuse, and the balance between these processes maintains mitochondrial morphology and function. Although the core fusion and division machinery is well established, how cells sense mitochondrial morphology and actively adjust it remains unclear. In this Opinion article, we propose a new conceptual framework, termed 'Mitochondrial Safeguard (MitoSafe)', in which cells monitor mitochondrial size and rebalance division and fusion through four branches: activation of fusion or inhibition of division in small mitochondria and activation of division or inhibition of fusion in enlarged mitochondria. Recent findings show that fusion is suppressed once mitochondria exceed a healthy size threshold. Dysregulation of this branch of MitoSafe, involving Parkin, PINK1, SLC25A3, SOD1, and cytochrome-c oxidase, causes mitochondrial enlargement, mitochondrial DNA release, and stimulator of interferon genes (STING)-mediated inflammation.

Keywords:  OMA1; PINK1; Parkin; dynamin-related GTPase; inflammation; mitochondria

DOI:  https://doi.org/10.1016/j.tcb.2026.04.007
Nat Metab. 2026 May 14.

Whole-blood NAD+ levels do not reflect healthy ageing.

DOI: https://doi.org/10.1038/s42255-026-01540-w
Trends Cell Biol. 2026 May 12. pii: S0962-8924(26)00066-8. [Epub ahead of print]

AMPK: a master regulator of mitochondrial quality and quantity.

Reuben J Shaw, Ian G Ganley, Julien Prudent, D Grahame Hardie.

  The AMP-activated protein kinase (AMPK) may have arisen soon after the endosymbiosis event that generated eukaryotes, perhaps to allow the archaeal host to communicate its requirements for ATP to the bacterial endosymbionts that became mitochondria. Consistent with this, AMPK is now known to regulate most aspects of the mitochondrial life cycle. It drives fragmentation of the network by promoting fission and inhibiting fusion, increasing mitochondrial number while allowing isolation of dysfunctional fragments from the network. It promotes the biogenesis of new mitochondrial components while also regulating mitophagy, promoting the degradation of dysfunctional mitochondria and inhibiting the removal of functional mitochondria. We will discuss these new findings and propose that the regulation of mitochondria was an ancient function of AMPK originating in the early eukaryote.

Keywords:  endosymbiosis; mitochondrial biogenesis; mitochondrial fission; mitochondrial fusion; mitophagy; origin of eukaryotes

DOI:  https://doi.org/10.1016/j.tcb.2026.04.008
Sci Adv. 2026 May 15. 12(20): eadz3835

mTOR-NAA10-C7orf50 axis senses nutritional status to coordinate ribosome biogenesis and autophagy.

Jingyu Sun, Mei Yang, Qian Li, Jiawei Liang, Haiping Feng, Lijie Gao, Yun Wang, Hongmei Liu, Caixia Guo, Tie-Shan Tang.

Cellular metabolism is precisely regulated in response to nutrient availability. As an extremely energy-consuming anabolic process, ribosome biogenesis should be tightly controlled in response to nutrient supply. However, how the nucleolus responds to different nutrient statuses remains poorly understood. Here, we show that C7orf50 is a nucleolus-localized protein and functions as a coordinator between ribosome biogenesis and autophagy, acting as what we term a "nutrient-responding nucleolar factor." C7orf50 undergoes reversible nucleolus-nucleoplasm translocation in response to nutrient deprivation and supply, with its nucleolus and nucleoplasm location dictating ribosome biogenesis and autophagic augmentation, respectively. The location-dependent function of C7orf50 is determined by acetylation at the lysine-71/lysine-72/lysine-76 residues by N-alpha-acetyltransferase 10, a substrate of mammalian target of rapamycin and a nutritional status-responsive acetyltransferase. In vivo and in vitro assays show that C7orf50 acts as an oncoprotein that promotes tumor growth. Our findings reveal a nucleolus-localized coordinating mechanism for the regulation of anabolism and catabolism transition by nutrient status.

DOI: https://doi.org/10.1126/sciadv.adz3835
iScience. 2026 Jun 19. 29(6): 115847

Single-cell lipidomic analysis of the epithelial-mesenchymal transition using mass spectrometry imaging.

Ellen Marie Botne Quinsgaard, Marco Giampà, Veronica With Andreassen, Sebastian Krossa, Anna Nordborg, Jakub Idkowiak, Johannes V Swinnen, Siver Andreas Moestue.

  The epithelial-mesenchymal transition (EMT) is a metastasis-promoting process whose heterogeneity has been extensively studied at a gene expression level. EMT involves reprogramming of lipid metabolism; however, there has been little focus lipid level heterogeneity. Here, we use mass spectrometry imaging (MSI) to measure glycerophospholipids at the single-cell level during EGF-induced EMT in MDA-MB-468 breast cancer cells. Cells undergoing EMT had reduced levels of PA, PS, PE, and PI-species and increased levels of PG-species and LPI (18:0). Multivariate analysis on the spatially resolved MSI-data revealed a heterogeneous metabolic response. Lipid levels were particularly affected by cell organization, as dispersed cells were more "EMT-like" than cohesive cells. The fraction of dispersed cells increased during EMT, indicating that pathways regulating adhesion and motility also regulate lipid metabolism. Gene expression analysis verified that EMT affected genes involved in glycerophospholipid biosynthesis. This work demonstrates heterogeneous regulation of glycerophospholipids in cancer cell populations undergoing EMT.

Keywords:  Biological sciences; Cell biology; Lipidomics

DOI:  https://doi.org/10.1016/j.isci.2026.115847
Nat Metab. 2026 May 13.

MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.

Henry M Cohen, Benjamin Gottschalk, Carmen Choya-Foces, Adam Chatoff, Anya Wilkinson, Elena Berezhnaya, Joanne F Garbincius, Adyson Johnson, Tyler L Stevens, Jordan E Howe, Hailey Lesniak, Anna Schmidt, Jennyfer Ngo, Emily Megill, Dhanendra Tomar, Nathaniel W Snyder, Wolfgang F Graier, John W Elrod.

Mitochondrial matrix Ca2+ concentration ([Ca2+]m) is theorized to be an essential regulator of mitochondrial metabolism by positively regulating key mitochondrial dehydrogenases. However, ablation or functional inhibition of the mitochondrial calcium uniporter channel (mtCU) fails to significantly perturb basal metabolism and is largely phenotypically silent in the absence of stress. Here we demonstrate that MICU proteins, the reported gatekeepers of mtCU, function in coordination to impart calcium-dependent regulation to FADH2-dependent mitochondrial dehydrogenases through metabolon formation independently of the mtCU and [Ca2+]m. Our results demonstrate that MICU proteins differentially localize to mitochondrial microdomains and form heterodimers and interactomes in response to intermembrane space Ca2+ binding their respective EF-hand domains. Using an equimolar expression platform coupled with unbiased proteomics, we reveal unique interactomes for MICU1/MICU2 versus MICU1/MICU3 heterodimers and demonstrate that MICU proteins control coupling of mitochondrial glycerol-3-phosphate dehydrogenase and succinate dehydrogenase/complex II and impart calcium-dependent changes in activity. We propose that MICU-mediated mitochondrial metabolons are a fundamental system facilitating matching of mitochondrial energy production with cellular demand and is the primary physiological calcium signaling mechanism regulating homeostatic energetics, not mtCU-dependent changes in [Ca2+]m.

DOI: https://doi.org/10.1038/s42255-026-01513-z
Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2527503123

Chaperone-mediated autophagy protects against retinal photoreceptor degeneration by modulating proteostasis of glucose metabolism enzymes.

Raquel Gómez-Sintes, Inmaculada Tasset, Ignacio Ramírez-Pardo, Adrián Martín-Segura, Sandra Alonso-Gil, Antonio Díaz, Kristen Lindenau, Concepción Lillo, Pedro de la Villa, Simone Sidoli, Evripidis Gavathiotis, Ana María Cuervo, Patricia Boya.

  Defective proteostasis is a hallmark of aging cells and tissues. Among the different components of the proteostasis network, in this study, we focus on a selective form of autophagy known as chaperone-mediated autophagy (CMA), and we set out to understand its physiological role in the retina. Using mice deficient for CMA [knockout for lysosome-associated membrane protein type 2A (Lamp2A)], we have found that CMA blockade leads to impaired visual function, altered retinal proteostasis, and photoreceptor cell death. Conversely, mice that overexpress human LAMP2A show higher resistance to chemically induced photoreceptor degeneration and slower visual function decline. We found a similar protective effect against retinal degeneration upon pharmacological activation of CMA. To start elucidating the mechanisms behind CMA's protective role in the retina, we used comparative proteomics and found elevated levels of enzymes related with glucose metabolism in CMA-deficient retinas that phenocopy those observed in old mice retinas. Overall, our results highlight a cytoprotective role for CMA in retina, in part through proteostatic regulation of enzymes involved in glucose metabolism, and support the feasibility of pharmacologically upregulating CMA against retinal degeneration.

Keywords:  aging; autophagy; metabolism; retina; small-molecules

DOI:  https://doi.org/10.1073/pnas.2527503123
Biophys Rep. 2026 Apr 30. 12(2): 116-125

The dual function of mitophagy in ferroptosis.

Xiaoxuan Zeng, Xushan Ma, Yueping Bai, Jiaqi Li, Fan Yu.

  Ferroptosis is a new form of cell death driven by iron-dependent lipid peroxidation. Thus, it is closely related to the lipid and iron metabolism. Accumulating evidence has suggested mitochondria, the center of cell metabolism, are important regulators of ferroptosis. This is not surprising as mitochondria are also the center for lipid metabolism and iron metabolism, as well as redox balance. As the essential way of mitochondrial quality control, mitophagy may alleviate ferroptosis. On the other hand, the digestion of iron-rich mitochondria may provide ample sources for the activation of ferroptosis. This review describes these new findings about the interplay of mitophagy and ferroptosis and demonstrates the dual role of mitophagy in ferroptosis.

Keywords:  Ferroptosis; Iron; Mitophagy; ROS

DOI:  https://doi.org/10.52601/bpr.2025.240071
Mitochondrion. 2026 May 12. pii: S1567-7249(26)00057-7. [Epub ahead of print]90 102167

Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.

Ayumu Sugiura, Kohta Nakamura, Heidi M McBride, Yasushi Okazaki.

  Mitochondrial-derived vesicles (MDVs) mediate selective trafficking of mitochondrial proteins and lipids to other organelles and contribute to organelle communication and mitochondrial quality control. While MDVs that deliver mitochondrial cargo to lysosomes have been extensively studied, the diversity of MDV pathways linking mitochondria to peroxisomes remains poorly understood. In particular, it is unclear how MDV pathways targeting peroxisomes relate to those delivering cargo to lysosomes, and whether cargos targeted to pre-existing peroxisomes utilize the same vesicular intermediates that participate in de novo peroxisome biogenesis. Here we examined MAPL trafficking using a peroxisome reconstitution system in PEX3-deficient fibroblasts. We found that MAPL is excluded from PEX3-positive pre-peroxisomal vesicles and instead is delivered to pre-existing peroxisomes, indicating that MAPL trafficking occurs through a pathway distinct from vesicles that initiate peroxisome formation. Structure-function analysis further revealed that a C-terminal amphipathic helix within MAPL is required for efficient targeting to peroxisomes. SNX9 depletion impaired both MAPL delivery to pre-existing peroxisomes and stress-induced lysosomal MDV pathways, whereas VPS35 depletion selectively reduced MAPL delivery without affecting lysosomal MDV pathways. In contrast, Parkin depletion impaired lysosomal MDV pathways but did not influence MAPL trafficking. Together, these findings demonstrate that mitochondria generate multiple classes of MDVs that are sorted into mechanistically distinct trafficking routes linking mitochondria with peroxisomes and lysosomes.

Keywords:  Lysosomes; Mitochondria; Mitochondrial-derived vesicles; Peroxisomes

DOI:  https://doi.org/10.1016/j.mito.2026.102167
Mitochondrion. 2026 May 14. pii: S1567-7249(26)00058-9. [Epub ahead of print] 102168

Quantitative proteomic profiling of neural cells-specific metabolic reprogramming in response to mitochondrial dysfunction using iMPAQT2.

Akito Tani, Mikako Yagi, Natsuki Horiuchi, Kento Nagata, Tomohiro Tanaka, Hiroki Kittaka, Ko Igami, Takeshi Uchiumi.

  Age-related mitochondrial dysfunction is increasingly recognized as a key contributor to neurodegenerative disease pathogenesis. In the central nervous system, neurons, oligodendrocytes, and astrocytes which derived from neural stem cells, fulfill distinct metabolic and functional roles. However, the specific vulnerabilities of these cell types to mitochondrial impairment remain unclear. In this study, we employed the iMPAQT2 proteomics platform to systematically compare the metabolic profiles of neurons, oligodendrocytes, and astrocytes, and to elucidate the molecular consequences of mitochondrial dysfunction induced by chloramphenicol and oligomycin. Our findings indicate that neurons and oligodendrocytes primarily rely on oxidative phosphorylation (OXPHOS) for ATP production, whereas astrocytes predominantly utilize glycolysis. It is noteworthy that oligodendrocytes exhibited enriched pathways for cholesterol synthesis, fatty acid degradation, and heme catabolism-processes that are critical for myelin maintenance. Treatment with the mitochondrial function inhibitors chloramphenicol or oligomycin reduced the expression of OXPHOS enzymes in all cell types. This reduction was particularly pronounced in oligodendrocytes for glycolysis, cholesterol synthesis, heme degradation, and fatty acid degradation. These results suggest that oligodendrocytes are particularly vulnerable to mitochondrial dysfunction, which may play a pivotal role in the pathogenesis of age-related neurodegenerative disorders.

Keywords:  Metabolic enzyme; Mitochondrial dysfunction; Neural cells; Proteomics; iMPAQT2

DOI:  https://doi.org/10.1016/j.mito.2026.102168
J Transl Med. 2026 May 14.

Advances in near-infrared fluorescent probes for the tumor microenvironment.

Haodong Hu, Changyue Zhang, Xiaoqi Kong, Ye Chen, Ruijiao Chen.

   BACKGROUND: Cancer remains a major threat to human health worldwide, but with progress in early diagnosis and treatment technology, the progression of cancer has been effectively slowed. Near-infrared (NIR) fluorescent probes are noninvasive imaging tools that show great promise for early tumor detection and intra-operative guidance due to their high sensitivity, deep tissue penetration, and high signal-to-noise ratio.
MAIN BODY: In recent years, the rapid development of NIR fluorescent probes has been driven by a growing understanding of the unique characteristics of the tumor microenvironment. Targeting these features, such as pH, viscosity, polarity, hypoxia, and enzymes, has become a key strategy in the rational design of sensitive small-molecule fluorescent probes for cancer diagnosis and therapy. In this review, we have summarized the recent progress in NIR fluorescent probes for the tumor microenvironment, with an emphasis on their design principles, imaging performance, potential applications, and the challenges faced in clinical translation.
CONCLUSIONS: Despite certain progress in near-infrared fluorescent probes, challenges remain, such as tumor heterogeneity and clinical translation. Future efforts should focus on multi-responsive designs, improved photostability, and multimodal imaging strategies. We hope this review can provide a valuable reference for the development of novel fluorescent probes.

Keywords:  Cancer marker; NIR fluorescent probe; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-026-08240-9
Nat Commun. 2026 May 12.

Intra-mitochondrial glycolysis maintains mitochondrial function and underlies the pathogenesis of retinitis pigmentosa.

Linghui Kong, Jiajian Liang, Dan Liu, Shanshan Jia, Hui Gu, Yiwen He, Wenting Luo, Songying Cao, Yizhang Dong, Chao Yang, Minghui Liao, Guojia Wan, Bo Du, Dongxue Ding, Wei Ma, Xiaowei Wei, Anhua Wu, Zhengwei Yuan.

Glycolysis is classically defined as a cytoplasmic process. Here, in our investigation of mitochondrial dysfunction in Retinitis Pigmentosa (RP), we report the unexpected discovery of a complete and functional glycolytic pathway operating inside mitochondria. Through CoIP-MS, polysome profiling, and [U-13C] glucose isotope tracing, we demonstrate that key glycolytic enzymes are locally translated and metabolically active within the organelle. Mechanistically, we show that the VWA8-PHB2-GRP75 complex is responsible for anchoring these enzymes, thereby sustaining intra-mitochondrial glycolysis and preserving mitochondrial function by regulating NAD+ levels and reactive oxygen species (ROS) homeostasis. In vivo, Vwa8 knockout in both mice and zebrafish abolishes this metabolic safeguard, leading to RP-like phenotypes that can be partially rescued by reactivating mitochondrial glycolysis. Collectively, these findings redefine the spatial compartmentalization of glucose metabolism and establish mitochondrial glycolysis as a therapeutic target for mitochondrial diseases.

DOI: https://doi.org/10.1038/s41467-026-72988-3
Nat Aging. 2026 May 14.

Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.

David E Lee, Lauren K McKay, Akshay Bareja, JiaCheng Yang, Wentao He, Demitrius A Hill, James R Bain, Shihuan Kuang, Guo-Fang Zhang, Christopher B Newgard, James P White.

Sarcopenia and the age-related decline in muscular strength and regenerative capacity contribute directly to loss of autonomy, greater risk for hospitalization and healthcare utilization. One contributing cellular phenotype associated with skeletal muscle aging is a loss in the function and number of resident muscle stem cells (MuSCs) or satellite cells. MuSC activation leads to dramatic changes in cellular architecture and metabolic reprogramming, including both mitochondrial biogenesis and increased glycolysis. Despite these changes to increase energy production, high energy demands may not be fully met during periods of MuSC activation. Here we used in vitro and in vivo approaches in mice to demonstrate the function of glutaminase for age-related changes in MuSC function. By combining fluorescence-activated cell sorting (FACS) isolation with metabolomics and stable isotope tracing, we show an age-related decline in reductive (counterclockwise) flux of glutamine through the tricarboxylic acid (TCA) cycle, a pathway by which MuSCs build cellular fatty acid stores as necessary biomass for MuSC function.

DOI: https://doi.org/10.1038/s43587-026-01120-3
EMBO Rep. 2026 May 09.

Cellular mechanometabolism: stimuli and implications.

Ismael Ortiz, Santiago Lopez, Raghu Vamsi Kondapaneni, Jose V Hernandez, Keefer Boone, Cynthia A Reinhart-King.

While much is known about the effects of the chemical microenvironment on cellular metabolism, mechanical cues have emerged as critical stimuli of intracellular metabolic pathways. Mechanical signals from the extracellular matrix (ECM), neighboring cells, and the microenvironment intersect with key regulators of cellular metabolism, often leading to changes in fundamental cell behaviors, including cell proliferation and migration. Here, we review recent work that has uncovered a role for mechanical cues from microenvironmental factors on cellular metabolism. We discuss how cell-ECM interactions and forces such as shear, tension, and compression affect cellular metabolic requirements and energy production. Importantly, mechanometabolism shapes both physiological homeostasis and pathological states, and further investigation has implications for understanding tissue function and disease progression and uncovering potential therapeutic strategies.

DOI: https://doi.org/10.1038/s44319-026-00795-4
Sci Rep. 2026 May 14.

Brain metabolomic profiling reveals ischemia-dominant disruption of metabolic pathways and tissue homeostasis in neonatal hypoxic-ischemic brain injury.

Nora Wolff, Maria Triantafyllou, Javid Ghaemmaghami, Georgios Sanidas, Chad Everett Byrd, Gabriele Simonti, Susan Aja, Aurelie Roux, Khyzer Aziz, Evan Goldstein, Jiangyang Zhang, Allen Dale Everett, David Graham, Panagiotis Kratimenos, Ioannis Koutroulis, Frances Northington.

  In neonatal hypoxic-ischemic brain injury (HIBI), a common form of perinatal brain damage associated with mortality and neurological disability, the disruption of oxygen and nutrient supply severely impacts brain metabolism. Though therapeutic hypothermia reduces cerebral metabolic rate and improves outcomes, disruption of oxidative metabolism compromising neuronal survival often persists. The complex cerebral metabolic shifts in HIBI remain poorly understood. We directly analyzed the metabolome (LC-MS) of neonatal hypoxia-ischemia (HI)-affected brain tissue to gain further insight into HIBI pathophysiology, isolate the metabolic effects of ischemia and hypoxia, and identify potential therapeutic targets. Postnatal day 10 mice were subjected to five experimental conditions: HI (n = 9) by unilateral carotid artery ligation (UCAL) and hypoxia exposure; contralateral hemispheres; ischemia (UCAL, n = 8); hypoxia (n = 12); and naive (n = 9). Cerebral hemispheres were analyzed 24h post-HI to capture their acute metabolic state. HI resulted in marked alterations in energy production, amino acid and nucleotide metabolism, and pathways governing neuronal homeostasis. Metabolites and pathways linked to NAD⁺ signaling, glutamate regulation, PI3K/AKT signaling, arginine metabolism, neuroinflammation, and vascular regulation were significantly dysregulated. Importantly, these metabolic changes were largely reproduced by ischemia alone, revealing an ischemia-dominant metabolic phenotype. Overall, brain metabolomic profiling identified ischemia as a primary driver of metabolic dysfunction in neonatal HIBI and highlighted specific metabolic pathways involved in bioenergetic deficit, imbalance of neurodegenerative-neuroprotective mechanisms, inflammation, and vascular function, as candidate targets for future therapeutic strategies aimed at limiting secondary brain injury and mitigating neurodevelopmental sequelae.

Keywords:  Arginine; Hypoxic-ischemic encephalopathy; N-acetylaspartic acid; NAD+ signaling; Neurocritical care; Perinatal arterial ischemic stroke

DOI:  https://doi.org/10.1038/s41598-026-51705-6
Elife. 2026 May 13. pii: RP109888. [Epub ahead of print]15

Intravital calcium imaging of meningeal macrophages reveals niche-specific dynamics and aberrant responses to brain hyperexcitability.

Simone Carneiro-Nascimento, Chao Wei, Anna Gutterman, Dan Levy.

  The meninges, which envelop and protect the brain, host a dense network of resident macrophages with diverse roles in regulating homeostasis and neuroinflammation. Despite their importance, we have a limited understanding of their behavior in vivo. Many dynamic cellular functions of macrophages involve intracellular Ca2+ signaling. However, virtually nothing is known about the spatiotemporal Ca2+ dynamics of meningeal macrophages in vivo. We developed a chronic intravital two-photon imaging approach and related computational analysis tools to interrogate meningeal macrophage Ca2+ dynamics, at subcellular resolution, in a novel Pf4-Cre:Ai162 conditional GCaMP6s reporter mouse model. Using imaging in awake mice, we characterized Ca2+ activity in meningeal macrophages at steady state and in response to cortical spreading depolarization (CSD), an aberrant pro-inflammatory brain hyperexcitability event implicated in migraine, traumatic brain injury, and stroke. In homeostatic meninges, macrophages in the dural perivascular niche exhibited several Ca2+ dynamic features, including event duration and signal frequency spectrum, distinct from those localized to the interstitial, non-perivascular niche. Simultaneous tracking of macrophage Ca2+ dynamics and local vasomotion revealed a subset of dural perivascular macrophages whose activity was coupled to locomotion-driven diameter fluctuations of their associated vessels. Most perivascular and non-perivascular meningeal macrophages displayed propagating intracellular Ca2+ activity and synchronized intercellular Ca2+ elevations, potentially driven by extrinsic factors. In response to CSD, the majority of perivascular and non-perivascular meningeal macrophages showed a persistent decrease in Ca2+ activity, while a smaller subset displayed Ca2+ elevations. Mechanistically, calcitonin gene-related peptide receptor signaling mediated the increase but not the decrease in CSD-mediated Ca2+ signaling. Collectively, our results highlight a previously unknown diversity of Ca2+ dynamics in meningeal macrophages at steady state and in response to an aberrant brain hyperexcitability event linked to neuroinflammation.

Keywords:  CGRP; calcitonin gene-related peptide; calcium imaging; cortical spreading depolarization; immunology; inflammation; macrophages; meninges; migraine; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.109888
Nat Commun. 2026 05 11. pii: 4190. [Epub ahead of print]17(1):

Ascites protects against ferroptosis and enables the peritoneal growth of ovarian cancer.

Yasaman Setayeshpour, Ssu-Yu Chen, Divya L Dayanidhi, Yunji Lee, Shao-Chin Wu, Juan J Aristizabal-Henao, Jianli Wu, Chao-Chieh Lin, Nazanin Setayeshpour, Chiara Federico, Alexander A Mestre, Michael A Kiebish, Andrew Berchuck, David S Hsu, Zhiqing Huang, Susan K Murphy, Jen-Tsan Chi.

The peritoneum is a frequent site of metastasis in ovarian cancer (OVCA), often accompanied by the accumulation of ascites in the peritoneal cavity. Despite its prevalence, ascites and its role in the peritoneal growth of OVCA remain poorly understood. OVCA cells are vulnerable to ferroptosis, a type of cell death caused by lipid hydroperoxides, raising the question of how these ferroptosis-sensitive cells survive during metastasis. Here, we show that ascites from female donors protects OVCA cell lines, patient-derived tumor cells, and organoids against ferroptosis and enhances peritoneal tumor growth in female mice. Mechanistically, ascites downregulates 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), contributing to increased lipid droplets. Additionally, upon ferroptosis induction, ascites represses upregulation of the transferrin receptor TFRC, thereby decreasing labile iron levels. Furthermore, lipid-lowering fibrates reverse ascites-induced changes and attenuate peritoneal growth in female mice. These findings identify ascites-mediated ferroptosis protection as a key mechanism in OVCA metastasis and a potential therapeutic vulnerability.

DOI: https://doi.org/10.1038/s41467-026-72116-1
Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2528332123

Selective targeting of kinesin on lipid droplets in the liver reduces plasma lipids.

Subham Kumar Tripathy, Archisman Mahapatra, Ojal Saharan, Hindol Chatterjee, Neelanjana Sengupta, Siddhesh Kamat, Sreelaja Nair, Roop Mallik.

  The liver controls plasma lipids by secreting lipid-rich very low density lipoproteins (VLDL) into blood. Inside hepatocytes in the liver, Lipid Droplets (LDs) are transported to the Smooth Endoplasmic Reticulum by kinesin-1 motors, where they are catabolized to supply lipids for VLDL assembly. Here we find that kinesin-1 uses its tail domain to bind the monolayer phospholipid membrane of LDs, but alternative mechanisms to bind cellular organelles with bilayer membranes. A peptide corresponding to the tail domain of kinesin-1 therefore competes with and removes kinesin-1 selectively from LDs with minimal effect on other organelles. Delivery of lipids for VLDL assembly is consequently reduced, causing a remarkable reduction of ~50% of secreted lipids (triglycerides and cholesterol) in cell culture. Strikingly, the peptide causes no unwanted accumulation of lipids inside cells because it redistributes LDs across the cell, enhancing LD-to-mitochondria lipid trafficking for mitochondrial lipid utilization. Further, we show that egg-liposomes can be used to orally deliver the kinesin tail domain peptide to zebrafish. The peptide accumulates in the zebrafish liver, and reverses diet-induced hyperlipidemia to bring zebrafish back to a normolipidemic state. Reflecting its effects in cell culture, the peptide causes no unwanted hepatic accumulation of lipids, no toxicity, and no developmental or behavioral defects in zebrafish. Using a peptide to displace proteins (e.g., kinesin) selectively from LDs provides a radically different approach against lipid disorders. This monolayer-vs.-bilayer strategy can potentially be extended to target other LD-bound proteins that function as key regulators of Lipid metabolism.

Keywords:  VLDL; hyperlipidaemia; kinesin; lipid droplets; lipoproteins

DOI:  https://doi.org/10.1073/pnas.2528332123
J Biol Chem. 2026 May 13. pii: S0021-9258(26)02014-4. [Epub ahead of print] 113142

The pentose phosphate pathway contributes to excess lactate production in radiation-induced fibroblast to myofibroblast transdifferentiation.

Josly Pierre-Louis Odoom, Sarah V Camus, Mark Sfeir, Yang Yue, L Ashley Cowart, Margaret A T Freeberg, Thomas H Thatcher, Patricia J Sime.

  Thoracic radiation is an effective mainstay treatment for lung cancer, however patients risk developing an adverse side effect known as radiation-induced lung injury (RILI). RILI is dose-limiting, can be permanent, and may threaten normal lung function, but the underlying mechanism is not well characterized. RILI can include both inflammatory (radiation pneumonitis) and fibrotic (radiation-induced lung fibrosis) pathologies. Myofibroblasts are the main effector cells of fibrosis, and we and others have shown that ionizing radiation induces differentiation of normal lung fibroblasts to the myofibroblast phenotype (FMT, fibroblast to myofibroblast transdifferentiation). We previously reported that radiation induces production of excess lactate, which promotes an acidic microenvironment that activates the major profibrotic cytokine, transforming growth factor - β (TGFβ). TGFβ in turn upregulates production of lactate, creating a pro-fibrotic feed-forward loop. Here, we performed targeted metabolomics and metabolic tracer studies to determine how radiation alters cellular metabolism to promote fibrosis in cultured human lung fibroblasts and a mouse model of radiation induced lung fibrosis. Radiation upregulated both glycolysis and the pentose phosphate pathway (PPP), and we found that the PPP was a significant source of lactate production. Inhibition of glycolysis by targeting pyruvate kinase M2 prevented radiation-induced FMT and lactate production but did not affect fibronectin expression. However, when the gluconic shunt or the non-oxidative pentose phosphate pathway is blocked by targeting glucose-6-phosphate dehydrogenase, FMT, lactate production, and fibronectin are markedly reduced. Our data reveals that the PPP is an important compensatory mechanism and driver of lactate accumulation observed in RILI.

Keywords:  Radiation-induced pulmonary fibrosis; glycolysis; metabolic reprogramming; metabolic rewiring; metabolomics; pentose phosphate pathway; primary human lung fibroblasts; pulmonary fibrosis

DOI:  https://doi.org/10.1016/j.jbc.2026.113142
Elife. 2026 May 15. pii: RP102680. [Epub ahead of print]13

The role of ATP synthase subunit e (ATP5I) in mediating the metabolic and antiproliferative effects of metformin in cancer cells.

Guillaume Lefrançois, Emilie Lavallée, Marie-Camille Rowell, Véronique Bourdeau, Farzaneh Mohebali, Thierry Bertomeu, Ana Maria Duman, Maya Nikolova, Mike Tyers, Simon-Pierre Gravel, Andreea R Schmitzer, Gerardo Ferbeyre.

  Here, we identify the subunit e of F₁F₀-ATP synthase (ATP5I) as a target of metformin, a first-in-class antidiabetic biguanide. ATP5I maintains the stability of F₁F₀-ATP synthase dimers, which is crucial for shaping cristae morphology. We demonstrate that ATP5I interacts with a biguanide analogue in vitro, and disabling its expression by CRISPR-Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide-treated cells, including mitochondrial morphology alterations, reduction of the NAD+/NADH ratio, inhibition of oxidative phosphorylation (OXPHOS), rescue of respiration by uncouplers, and a compensatory increase in glycolysis. Notably, metformin disrupts F₁F₀-ATP synthase oligomerization, leading to the accumulation of vestigial assembly intermediates in pancreatic and osteosarcoma cancer cells, a phenotype also observed upon ATP5I inactivation in pancreatic cancer cells. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and antiproliferative effects of metformin and phenformin. Finally, a genome-wide CRISPR screening in NALM-6 lymphoma cells revealed that metformin-treated cells exhibit genetic interaction profiles similar to those observed with the F₁F₀-ATP synthase inhibitor oligomycin, but not with the complex I inhibitor rotenone. This provides unbiased support for the relevance of the newly proposed target.

Keywords:  ATP5I; F1ATPase; NAD metabolism; biguanides; biochemistry; chemical biology; human; mitochondria; pancreatic cancer

DOI:  https://doi.org/10.7554/eLife.102680
J Cell Biol. 2026 Jun 01. pii: e202603198. [Epub ahead of print]225(6):

PI(3)P regulates mitochondrial dynamics through EXC-5-dependent actin remodeling.

Sneha Hegde, Marc Germain.

Mitochondrial dynamics regulate mitochondrial activity through several pathways, but their coordination remains unclear. Zhao et al. (https://doi.org/10.1083/jcb.202508040) show that endosomal PI(3)P promotes CDC42-dependent actin polymerization on mitochondria, providing insight into the upstream signals regulating mitochondrial dynamics.

DOI: https://doi.org/10.1083/jcb.202603198
EMBO J. 2026 May 13.

NAD+ supply and redox state limit developmental speed in the Drosophila eye.

Nisha Veits, Yuting Guo, Jingjing He, Khalil Mazouni, Ivan Nemazanyy, Martin Bres, Cara Picciotto, Claire Mestdagh, Yan Yan, Francois Schweisguth.

The cellular and biochemical processes that define the speed at which embryos develop, tissues form, and cells differentiate remain largely unknown. Using the speed of progression of a differentiation front in the developing Drosophila eye to measure developmental speed, we identified genetic perturbations that slowed the progression of this front. Inhibiting the electron transport chain (ETC), and more generally energy production in mitochondria, resulted in reduced developmental speed. Defective ETC activity led to increased NADH/NAD+ ratio, whereas ATP levels remained constant due to a compensatory increase in glycolysis. Targeted perturbations showed that the metabolic state of the cells ahead of and/or at the differentiation front determined its speed. Genetic and diet-based perturbations of NAD+ metabolism indicated that developmental speed was limited by NAD+ availability. Thus, developmental speed appeared constrained by the cellular redox state and the demand for NAD+ in the developing Drosophila eye. Our findings therefore show that the NADH/NAD+ ratio is key to regulating developmental speed and highlight the importance of NAD+ availability for this regulation in Drosophila.

DOI: https://doi.org/10.1038/s44318-026-00801-4