bims-medebr 2026-01-25 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–01–25
eighteen papers selected by
Regina F. Fernández, Johns Hopkins University

Loss of Fatty Acid Oxidation by Neural Stem and Progenitor Cells Increases Proliferation but Does Not Improve Long-Term Neurogenesis After Mild Traumatic Brain Injury.
Functional 17O-MRI of cerebral oxygen consumption in the activated rat brain.
Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I Function.
Cholesterol depletion activates trafficking-coupled sphingolipid synthesis.
Inducible deletion of DGAT1 and 2 from microglia exacerbates neurodegeneration and endolysosomal lipid accumulation in male PS19 mice.
Tregs Promote Astrocyte-Neuron Lactate Shuttle via Inhibiting STING Pathway to Improve Neurological Recovery After Ischemic Stroke.
Metabolic reprogramming during human neuron differentiation indicates glutaminase as a key determinant in Fragile X syndrome.
Metabolome Atlas of Brain Reveals Regional Shared and Unique Metabolic Drifts in Response to Type 2 Diabetes in Male Mice.
The 2025 Sir David Cuthbertson Lecture: Energy metabolism: Beyond calories, feeding the mitochondria.
Elevated cerebral oxygen extraction fraction in Parkinson's disease correlates with motor impairment severity.
Comprehensive metabolic profiling across five lifespan stages in murine hippocampus and cortex reveals sex-related variation in age-related cognitive decline.
The Antiseizure Medication Stiripentol Inhibits Mitochondrial Complex I by Blocking Early-Stage Electron Transfer.
The molecular mechanism of lipid uptake by membrane-anchored bridge-like lipid transfer proteins.
Cholesterol Promotes Lung Adenocarcinoma Brain Metastasis by Stabilizing EGFR Protein to Drive EMT, Metabolic Reprogramming, and Premetastatic Niche Formation.
NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
Effect of enteral arachidonic acid and docosahexaenoic acid supplementation on brain volumes at term in preterm infants: a secondary outcome analysis of a randomised controlled trial.
UBA52 Overexpression Ameliorates Intracerebral Hemorrhage-Associated Neuronal Apoptosis and Mitochondrial Dysfunction: A Protective Role in Neurons.
The Interplay Between Nurr1 and Mitochondrial Biogenesis: Implications for Neurodegenerative Therapy.

ASN Neuro. 2026 ;18(1): 2610198

Loss of Fatty Acid Oxidation by Neural Stem and Progenitor Cells Increases Proliferation but Does Not Improve Long-Term Neurogenesis After Mild Traumatic Brain Injury.

Javier Allende Labastida, Regina F Fernandez, Tiffany Chu, Noelle Puleo, Maria Shishikura, Michael J Wolfgang, Joseph Scafidi, Susanna Scafidi.

  Neurogenesis in the dentate gyrus of the hippocampus is a conserved and highly regulated process throughout the lifespan. Hippocampal neural stem and progenitor cells (NSPCs) can either transition into an activated proliferative state or remain quiescent. Accumulating data suggests that mitochondrial fatty acid β-oxidation is important in maintaining NSPCs quiescence under normal physiological conditions; however, the contribution of this pathway in NSPCs following brain injury remains unknown. While severe traumatic brain injury (TBI) is characterized by increased NSPCs proliferation in the hippocampus, the extent of this proliferative response after mild TBI, the most prevalent form of TBI, has not been fully delineated. Using closed head injury as a model of mild TBI and a brain-specific knockout mouse of carnitine palmitoyltransferase 2 (CPT2; an obligate gene in mitochondrial fatty acid β-oxidation), we investigated the role of fatty acid oxidation in hippocampal NSPCs proliferation in naïve and injured male and female mice. Our results show that loss of CPT2 in the brain does not affect hippocampal proliferation in naïve mice. Furthermore, mild TBI upregulates proliferation at day 3 post-injury, and is further increased only in male CPT2-deficient mice. Despite the post-injury increase in hippocampal NSPCs proliferation in CPT2B-/- mice, long-term neurogenesis remained unchanged. Together, these data provides a new insight into the metabolic regulation of NSPCs neurogenesis in the hippocampus following mild traumatic brain injury.

Keywords:  Fatty acid oxidation; hippocampus; mild traumatic brain injury; neural stem and progenitor cells; proliferation

DOI:  https://doi.org/10.1080/17590914.2025.2610198
J Cereb Blood Flow Metab. 2026 Jan 19. 271678X251405668

Functional 17O-MRI of cerebral oxygen consumption in the activated rat brain.

Amélie Tourais, Cameron Hery, Sophie Malaquin, Martine Guillermier, Julien Valette, Celine Baligand.

  Assessing CMRO2 during neuronal activation is essential to understanding brain energy metabolism and neurovascular coupling. Over the past decades, preclinical studies have yielded variable results, likely due to differences in techniques, models, and stimulation paradigms. Here, we present the first study using 17O-MRI to directly quantify CMRO2 during paw electrical stimulation in rats at 11.7 T. CMRO2 was significantly higher in the activated cortex (3.28 ± 0.27 µmol/g/min) than in the control cortex (2.89 ± 0.32 µmol/g/min), corresponding to a 13.8% ± 7.9% increase. A strong negative correlation was found between ΔCMRO2 and resting CMRO2, suggesting that baseline oxidative metabolism influences the evoked response. Flow-related parameters (KG, KL, kW) and cerebral blood flow (CBF) were also estimated, revealing a significant 22% increase in CBF in the activated cortex. These findings demonstrate that 17O-MRI is a robust, noninvasive tool for direct CMRO2 quantification during functional activation, with strong potential as a new standard for studying oxidative brain metabolism.

Keywords:  Oxygen-17; brain activation; cerebral metabolic rate of oxygen; functional MRI; neurometabolic coupling

DOI:  https://doi.org/10.1177/0271678X251405668
Aging Cell. 2026 Feb;25(2): e70378

Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I Function.

Meiling Wang, Yumin Chang, Aojie He, Jing Yang, Ang Li, Hongqin Wang, Kah-Leong Lim, Xing Guo, Chengwu Zhang, Li Lu.

  Age-related memory decline is a hallmark of brain aging and a primary risk factor for neurodegenerative disorders. Microglia play a crucial role in preserving memory function by maintaining brain homeostasis through phagocytosis, yet the specific mechanisms governing this protective function remain elusive. In the present study, we identified a population of Secreted Phosphoprotein 1 (Spp1)-positive microglia in both aged mouse and human brains. To investigate the role of microglial Spp1 in aging, we generated microglia-specific Spp1 knockout (Spp1-cKO) mice. We demonstrate that Spp1 deficiency selectively precipitates memory deficits in aged mice, without affecting memory function in young mice, indicating an age-dependent reliance on Spp1 signaling. Microglial phagocytic capacity positively correlates with Spp1 levels and is diminished by Spp1 deficiency. Mechanistically, Spp1 deficiency leads to the downregulation of the AKT/mitochondrial complex I pathway, thereby compromising microglial oxidative phosphorylation and function. Notably, microglia-specific overexpression of Spp1 partially ameliorates the age-related phenotypes induced by Spp1 deficiency. In conclusion, this study is the first to reveal the crucial role of microglial Spp1 in brain aging and to uncover its underlying mechanism, providing novel insights into age-related memory decline.

Keywords:  ATP; Spp1; age‐related memory decline; microglia; mitochondrial complex I

DOI:  https://doi.org/10.1111/acel.70378
J Cell Biol. 2026 Apr 06. pii: e202502083. [Epub ahead of print]225(4):

Cholesterol depletion activates trafficking-coupled sphingolipid synthesis.

Yeongho Kim, Jan Parolek, Christopher G Burd.

Homeostatic pathways maintain the lipid composition of organelle membranes, and mechanistic links between lipid sensing, synthesis, and trafficking are lacking. Acute depletion of cell cholesterol elicits an increase in the rate of very-long-chain (VLC) sphingomyelin synthesis in the Golgi apparatus, thereby promoting cholesterol retention in the plasma membrane. Stable isotope metabolic analyses and lipid trafficking assays showed that the increase in VLC-sphingomyelin results from an increase in the rate of coatomer II-dependent trafficking of VLC-ceramide from the endoplasmic reticulum to the Golgi apparatus. An integral membrane protein of the coatomer II network, cTAGE5, is required for endoplasmic reticulum-to-Golgi trafficking of ceramide and cTAGE5 overexpression caused herniations of the endoplasmic reticulum network that entrapped a synthetic ceramide analog to which cTAGE5 could be photochemically cross-linked. We propose that cTAGE5 is a ceramide sensor for export of VLC-ceramide from the endoplasmic reticulum exit site.

DOI: https://doi.org/10.1083/jcb.202502083
Cell Rep. 2026 Jan 16. pii: S2211-1247(25)01613-4. [Epub ahead of print]45(1): 116841

Inducible deletion of DGAT1 and 2 from microglia exacerbates neurodegeneration and endolysosomal lipid accumulation in male PS19 mice.

G Travis Tabor, Alexandra Litvinchuk, Yun Chen, Austin Allison, Elizabeth W Sun, Bettina van Lengerich, Sonnet S Davis, Elizabeth West, Johannes C M Schlachetzki, Carisa Zeng, Hao Hu, Peter B Lin, Prabal Sharma, Xiaoying Chen, Samira Parhizkar, Sihui Song, Xin Bao, Lakshita Senthil, Abhirami K Iyer, Shih Feng You, Javier Remolina Serrano, Melissa Manis, Emily Franke, Anil G Cashikar, Carla M Yuede, Jung H Suh, Celeste M Karch, Andrew Folick, Suneil K Koliwad, Robert V Farese, Tobias Walther, Eric J Huang, Maxim Artyomov, Christopher K Glass, Gilbert Di Paolo, Jason D Ulrich, David M Holtzman.

  Brain myeloid cells accumulate neutral lipids in multiple human neurodegenerative disorders and relevant mouse models. These lipids are often assumed to be contained in lipid droplets (LDs). While studies have been performed in cell culture and Drosophila models to characterize glial LDs, the roles of microglial LD biogenesis in mammalian tauopathy are unclear. To address this issue, we induced the deletion of diacylglycerol acyltransferases (DGATs) 1 and 2, enzymes critical for LD formation, from microglia in the PS19 mouse model of tauopathy. Microglial DGAT double knockout (KO) exacerbated neurodegeneration and increased the abundance of brain cholesteryl esters in male PS19 mice. Myeloid cell lipid accumulations appeared to largely localize to endosomes/lysosomes, not LDs, at baseline and were exacerbated upon DGAT KO. Our results suggest that microglial DGAT-dependent TAG/LD biogenesis is adaptive in advanced tauopathy. Most lipid accumulation in brain myeloid cells does not appear to correspond to LDs in this tauopathy model, which has implications for the development of lipid-modulating therapies for neurodegenerative diseases.

Keywords:  CD68; CP: metabolism; CP: neuroscience; PS19; cholesteryl ester; diacylglycerol acyltransferase; lipid droplet; lysosome; microglia; neurodegeneration; tauopathy; triglyceride

DOI:  https://doi.org/10.1016/j.celrep.2025.116841
CNS Neurosci Ther. 2026 Jan;32(1): e70753

Tregs Promote Astrocyte-Neuron Lactate Shuttle via Inhibiting STING Pathway to Improve Neurological Recovery After Ischemic Stroke.

Yao Meng, Xiaoyan Li, Yonghong Bi, Pengyu Duan, Zhehao Jin, Lan Luo, Weiyu Feng, Hangbing Li, Xiangcheng Zhao, Kun Zuo, Jiali Chen, Longfei Li, Yuling Xing, Miao Yu, Muyan Cui, Yang Yu, Bing Zhang.

   BACKGROUND: Excessive immune response following ischemic stroke is closely associated with poor clinical prognosis. Although regulatory T cell (Treg) is recognized as pivotal immunomodulator, its potential mechanisms in post-stroke neurological recovery and immunotherapy remain unclear.
METHODS: Neurological recovery and neuronal remodeling were investigated by behavior tests, HE staining, Nissl staining, and LFB staining. Monocarboxylate transporter (MCT) was detected to evaluate the role of astrocyte-neuron lactate shuttle (ANLS) in Tregs-mediated neuroprotection by immunofluorescence and western blot, lactate assay, ATP assay, and cell viability assay experiments. The expression of stimulator of interferon gene (STING) and phosphorylation of downstream factors were examined by western blot.
RESULTS: Tregs significantly attenuated neuronal injury, upregulated the expression of synaptic plasticity-related proteins, promoted myelin reconstruction, and improved spatial cognition, memory function, and motor coordination. Mechanistically, Tregs enhanced MCT-mediated lactate transfer to neurons, providing energy supply for neuronal remodeling, whereas the MCT inhibitor 4-CIN reversed Tregs-mediated neuroprotection. In addition, Tregs suppressed the activation of the STING pathway, and activation of STING by DMXAA abolished the Tregs-induced potentiation of ANLS.
CONCLUSIONS: This study clarifies a novel mechanism by which Tregs promote ANLS and provide energy supply for neuronal remodeling by inhibiting the STING pathway, thereby improving the long-term neurological recovery after stroke.

Keywords:  STING; Tregs; astrocyte‐neuron lactate shuttle; ischemic stroke; neurological recovery

DOI:  https://doi.org/10.1002/cns.70753
Cell Rep. 2026 Jan 19. pii: S2211-1247(25)01629-8. [Epub ahead of print]45(1): 116857

Metabolic reprogramming during human neuron differentiation indicates glutaminase as a key determinant in Fragile X syndrome.

Sneha Shah, Daniel Barnes, Botao Liu, Tenzin Tseyang, Thang Do, Jodi L Bubenik, Suna Jung, Mina N Anadolu, Maria P Ivshina, Verónica Martínez-Cerdeño, Elizabeth Berry-Kravis, Maurice S Swanson, Jessica B Spinelli, Joel D Richter.

  Metabolic homeostasis gone awry is a contributor to, if not an underlying cause of, several neurologic disorders. Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in FMR1 and consequent loss of the encoded protein FMRP, which results in downstream molecular, neurologic, and mitochondrial deficits that are linked to cognitive impairment. In the human postmortem brain, many metabolites and solute carrier proteins are coordinately dysregulated, which also occurs during the differentiation of human induced pluripotent stem cells (iPSCs) into excitatory neurons. Metabolic tracing in FXS neurons demonstrates a dearth of glutamine deamidation to glutamate, which reduces anaplerosis into the TCA cycle, potentially hindering the bioenergetic and biosynthetic functions of mitochondria. Mechanistically, aberrant expression of glutaminase isoforms in FXS is responsible for reduced glutaminolysis, thereby altering glutamate levels, which may contribute to FXS.

Keywords:  CP: metabolism; CP: neuroscience; Fragile X syndrome; glutamate transporters; glutaminase; human neurons; iPSC; metabolomics

DOI:  https://doi.org/10.1016/j.celrep.2025.116857
FASEB J. 2026 Jan 31. 40(2): e71450

Metabolome Atlas of Brain Reveals Regional Shared and Unique Metabolic Drifts in Response to Type 2 Diabetes in Male Mice.

Yang Zhou, Yitong Lu, Zhaobao Wang, Xiaoqian Du, Bei Jiang, Qiuhui Xuan.

  Type 2 diabetes (T2D), with continuously increasing incidence worldwide, impairs not only peripheral organs but also the central nervous system. However, the brain-region-specific metabolic signature of T2D remains unknown, which is crucial for understanding T2D neurological complications' mechanism and developing intervention. In this study, we constructed a metabolome atlas of T2D and control brain in male mice from 7 anatomical regions using liquid chromatography-mass spectrometry-based metabolomic and lipidomic techniques. In total, 673 metabolites were identified, including energy substrates, amino acids, neurotransmitters, phospholipids, and signaling lipids. We found that the mouse brain displayed region-specific metabolic architecture; however, functionally connected regions (cerebrum, spinal cord, brainstem and cerebellum) exhibited metabolic similarity. Most metabolites exhibited significant differences between brain regions in T2D versus control mice, and no significantly differential metabolites were shared across all brain tissues. Metabolome of hypothalamus and olfactory bulb were the most affected by T2D. A common shift in lipid patterns was observed across brain regions in T2D mouse, like increased triacylglycerols while reduced fatty acids and diacylglycerols. This study offers the first evidence that T2D drives a marked rise in the neurotoxic lipid class of primary amides while simultaneously depleting the neuroprotective N-acylethanolamines. We observed a dramatic decrease in sphingolipids in the hippocampus under T2D, likely due to T2D-induced neurotoxicity that damages the myelin sheath, causing sphingolipid depletion and accelerating decomposition. Alterations in amino acid profiles were also detected. These results uncover the molecular mechanism of T2D-induced brain alterations and deliver an open-access, region-resolved metabolomic reference for future research.

Keywords:  brain regions; lipids; metabolome atlas; neurotoxic metabolites; type 2 diabetes (T2D)

DOI:  https://doi.org/10.1096/fj.202501739RR
Clin Nutr. 2026 Jan 09. pii: S0261-5614(26)00002-6. [Epub ahead of print]57 106575

The 2025 Sir David Cuthbertson Lecture: Energy metabolism: Beyond calories, feeding the mitochondria.

Eric Fontaine.

  In this article, I explore how energy metabolism depends on proper mitochondrial function. Adenosine triphosphate (ATP), the main source of energy for cells, is mainly produced in the mitochondria as a result of the fusion of hydrogen produced by the breakdown of nutrients with oxygen. This reaction allows protons to be pumped across the inner mitochondrial membrane, creating a gradient that powers ATP synthesis. However, ATP production is not perfectly efficient. Some oxygen is consumed without generating ATP due to proton leaks or other processes that utilize the gradient. Diet, hormones, and cellular signals can alter mitochondrial efficiency: for example, hyperthyroidism and polyunsaturated fatty acid deficiency cause uncoupling, while hypothyroidism and nitric oxide increase coupling but reduce maximum ATP production. I also point out that the use of ATP depends on its thermodynamic value, which is reflected in the Adenosine triphosphate/Adenosine diphosphate ratio ([ATP]/[ADP] ratio). A decrease in this ratio can selectively reduce certain ATP-consuming processes, as shown in studies on metformin and imeglimin. In cases of stress or nutritional deficiency, cells can consume ATP without performing useful work, leading to inefficiency or even cell death when the [ATP]/[ADP] ratio collapses. Knowing that these concepts are quite complex, I have simplified them to make clear that mitochondria are more than just passive "powerhouses of cells".

Keywords:  Efficiency; Energy metabolism; Flux–force relationship; Kinetics; Mitochondria; Thermodynamics

DOI:  https://doi.org/10.1016/j.clnu.2026.106575
Sci Rep. 2026 Jan 18.

Elevated cerebral oxygen extraction fraction in Parkinson's disease correlates with motor impairment severity.

Huseyin Enes Candan, DongKyu Lee, Hansol Lee, Jae-Hyeok Lee, Junghun Cho, HyungJoon Cho.

  Parkinson's disease (PD) is the second most common neurological disorder, but its diagnosis remains challenging. Cerebral glucose metabolism has emerged as a promising biomarker for PD based on previous studies. While these studies have established a PD-related pattern of metabolic activity of glucose in the brain, cerebral oxygen metabolism is less explored, and there is no well-established PD-related pattern of cerebral oxygen metabolism. This study investigates cerebral oxygen extraction fraction (OEF) as a measure of cerebral oxygen metabolism to monitor disease progression in early-stage PD. OEF was measured noninvasively using magnetic resonance imaging with the QSM + qBOLD technique in 50 PD patients and 30 healthy controls. Whole-brain and region-of-interest analyses were conducted, focusing on key regions within the basal ganglia. Results revealed significantly elevated OEF in the basal ganglia of PD patients compared to controls. Moreover, OEF showed a positive correlation with Unified Parkinson's Disease Rating Scale Part III scores, indicating an association between increased oxygen extraction and motor impairment severity in early PD. These findings support the potential of cerebral OEF as an early biomarker of motor symptom severity. Therefore, it can enhance our understanding of metabolic dysfunction in the basal ganglia during the early stages of PD.

Keywords:  Brain metabolism; Cerebral oxygen metabolism; Motor impairment; Oxygen extraction fraction; Parkinson’s disease

DOI:  https://doi.org/10.1038/s41598-026-36435-z
Commun Biol. 2026 Jan 19.

Comprehensive metabolic profiling across five lifespan stages in murine hippocampus and cortex reveals sex-related variation in age-related cognitive decline.

Xi Long, Wuping Liu, Changhan Chen, Qi Guo, Yidan Wang, Fang Yu, Yujin Zhang, Rodney E Kellems, Yang Xia.

This study employs Barnes maze behavioral assessments, untargeted liquid chromatography-mass spectrometry metabolomics, and 13C6-glucose isotopic tracing to systematically investigate cognitive function and metabolic profiles in hippocampal and cortical tissues of male and female mice across five distinct age-ranges. Behavioral analyses reveal significant cognitive decline in both sexes by 16-months-of-age, with females exhibiting more severe impairment by 23-months, demonstrating a sex-related variation. 13C6-glucose tracing analyses reveals that glucose is rapidly and preferentially metabolized toward the Tricarboxylic acid cycle over glycolysis and the pentose phosphate pathway (PPP), with metabolism rates increasing from juvenility to meet developmental demands and maintaining homeostasis into pre-elderly. Surprisingly, glucose metabolism continues to rise in elderly males but declines in females. Developmental shifts from purine biosynthesis to degradation display sex-related variation, highlighting sustained synthesis in elderly males versus degradation in aging females. Finally, age and sex- related differences in amino acids, neurotransmitters, histidine-derived antioxidants, and the arginine-urea cycle further underscore complex metabolic reprogramming in the CNS. Overall, our study elucidates from a metabolic perspective the molecular basis of sex-related variation in age-related cognitive decline by characterizing sex-related variation in reprogramming of glucose, purine, and amino acid metabolic networks.

DOI: https://doi.org/10.1038/s42003-026-09527-9
J Biol Chem. 2026 Jan 20. pii: S0021-9258(26)00049-9. [Epub ahead of print] 111179

The Antiseizure Medication Stiripentol Inhibits Mitochondrial Complex I by Blocking Early-Stage Electron Transfer.

Cyrielle L Bouchez, Thibaut Molinié, Guillaume Duranthon, Sebastian Lillo, Corinne Pellon, Nadia El Mammeri, Benjamin Dartigues, Philippe Pasdois, Benoit Pinson, Macha Nikolski, Anne Devin, Arnaud Mourier, Roland T Ullrich, Thomas Daubon.

The oxidation of NADH is essential for maintaining cellular redox balance and supporting cell metabolism. Mitochondrial complex I (NADH:ubiquinone oxidoreductase) plays a central role in this process by coupling NADH oxidation to electron transfer and proton translocation across the inner mitochondrial membrane. We previously reported that the antiseizure medication stiripentol decreases lactate production and mitochondrial respiration, suggesting an impact on NADH turnover beyond its known inhibition of lactate dehydrogenase. In this study, we identify complex I as a target of stiripentol across multiple species and cell types. Biochemical and spectroscopic analyses demonstrate that stiripentol inhibits NADH oxidation and electron transfer through a mechanism distinct from that of classical ubiquinone pocket inhibitors such as rotenone or piericidin A. Remarkably, stiripentol acts upstream of the ubiquinone reduction site, representing the first example of a complex I inhibitor with a binding site within the N-module. These findings uncover a previously unrecognized mode of complex I inhibition and link stiripentol's metabolic effects to direct modulation of mitochondrial NADH oxidation. This work broadens the understanding of stiripentol's mechanism of action and highlights its potential to modulate redox metabolism in cancer cells.

DOI: https://doi.org/10.1016/j.jbc.2026.111179
Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2520399123

The molecular mechanism of lipid uptake by membrane-anchored bridge-like lipid transfer proteins.

Daniel Álvarez, Paige Chandran Blair, Cristian Rocha-Roa, Michael Davey, Elizabeth Conibear, Stefano Vanni.

  Lipid transport by bridge-like lipid transfer proteins (BLTPs) is emerging as a key process in lipid and cellular metabolism in both physiological and pathological conditions. However, the precise mechanism of lipid transport by BLTPs has remained elusive. Here, we use extensive all-atom molecular dynamics simulations to characterize the precise mechanism of lipid transfer into the BLTP hydrophobic cavity from donor membranes. For multiple BLTPs, we observe the ability to extract and solubilize lipids without lipid selectivity, and we identify membrane destabilization as a critical parameter to achieve effective lipid desorption. We rationally design a mutant BLTP with altered ability to destabilize lipid bilayers, and we show that this abolishes lipid desorption in silico and protein function in vivo. Taken together, our data provide an atomic-level description of the mechanism of lipid transport by BLTPs, ultimately suggesting alternative strategies to interfere with their activity.

Keywords:  lipid membranes; lipid transport; membrane trafficking; molecular dynamics; organelle

DOI:  https://doi.org/10.1073/pnas.2520399123
Adv Sci (Weinh). 2026 Jan 21. e73843

Cholesterol Promotes Lung Adenocarcinoma Brain Metastasis by Stabilizing EGFR Protein to Drive EMT, Metabolic Reprogramming, and Premetastatic Niche Formation.

Ying Chen, Xiaoteng Cui, Xinyi Shi, Xu Yang, Yujing Cao, Haolin Li, Qi Zhan, Qixue Wang, Ang Li, Qihong Cheng, Yunfei Wang, Junhu Zhou, MingJie Wang, Chunsheng Kang, Xiaomin Liu.

  Brain metastasis is a major cause of mortality in advanced lung adenocarcinoma (LUAD). Accumulating evidence indicates that dysregulated lipid metabolism contributes to metastatic colonization; however, how cholesterol functions as a downstream effector within established lipid-metabolic programs to regulate key steps of the LUAD brain metastasis (LUAD-BM) cascade remains incompletely defined. Here, we demonstrate that cholesterol directly engages EGFR and stabilizes its membrane localization by blocking ubiquitin-proteasome-mediated degradation, thereby sustaining AKT/NF-κB signaling. This signaling axis promotes glycolytic reprogramming and epithelial-mesenchymal transition in LUAD cells, enhancing metastatic capacity and resistance to TKIs. Cholesterol also disrupts blood-brain barrier integrity by reducing endothelial membrane fluidity and accelerating Claudin-5 ubiquitination and degradation. Within the brain microenvironment, cholesterol directly interacts with IL-4Rα, facilitating its recruitment into lipid rafts and activation of JAK1/STAT6 signaling, which drives microglial M2 polarization and establishes a permissive pre-metastatic niche. The cholesterol-lowering drug atorvastatin reverses these tumor-intrinsic and microenvironmental effects and suppresses LUAD brain metastasis in vivo. Retrospective clinical analyses further show that hypercholesterolemia is associated with shortened survival in LUAD-BM patients, whereas statin use correlates with improved outcomes. These findings identify cholesterol as a functional mediator downstream of lipid-metabolic dysregulation and therapeutic target in LUAD-BM.

Keywords:  EGFR; brain metastasis; cholesterol; glycolytic reprogramming; lung adenocarcinoma

DOI:  https://doi.org/10.1002/advs.73843
JCI Insight. 2026 Jan 23. pii: e181812. [Epub ahead of print]11(2):

NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.

Joy Richard, Giulia Lizzo, Noélie Rochat, Adrien Jouary, Pedro Tm Silva, Alice Parisi, Stefan Christen, Sofia Moco, Michael B Orger, Philipp Gut.

  Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2-/- zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2-/- zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.

Keywords:  Cell biology; Genetic diseases; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.181812
Arch Dis Child Fetal Neonatal Ed. 2026 Jan 19. pii: fetalneonatal-2024-328292. [Epub ahead of print]

Effect of enteral arachidonic acid and docosahexaenoic acid supplementation on brain volumes at term in preterm infants: a secondary outcome analysis of a randomised controlled trial.

William Hellström, Pia Lundgren, Anders K Nilsson, Staffan Nilsson, Anna-Lena Hård, Ulrika Sjöbom, Chatarina Löfqvist, Isabella M Björkman-Burtscher, Dirk Wackernagel, Ingrid Hansen-Pupp, Lois Eh Smith, Boubou Hallberg, Karin Sävman, David Ley, Ann Hellström, Rolf A Heckemann.

   OBJECTIVE: Investigate whether enteral supplementation with arachidonic acid (AA) and docosahexaenoic acid (DHA), from birth to term-equivalent age (TEA), promotes brain maturation as a prespecified secondary outcome of a multicentre randomised controlled trial.
PARTICIPANTS: 206 infants born at 22-28 weeks gestational age (GA) were randomised into intervention or control groups from three university hospitals in Sweden.
INTERVENTION: The intervention group received an oil with AA (100 mg/kg/d) and DHA (50 mg/kg/d) starting at birth until 40 weeks postmenstrual age (PMA) in addition to standard nutrition. Standard-of-care infants received standard nutrition according to national guidelines.
MAIN OUTCOME AND MEASURES: MRI volumetrics were defined a priori as a secondary outcome of the trial and included total brain, white and cortical grey matter, central structures and cerebellum. Univariable and multivariable linear regression models were used for comparisons.
RESULTS: MRI data in 117 infants had sufficient quality for inclusion (n=58 intervention). Birth weight, GA at birth, sex distribution, and PMA at MRI were similar in the groups. Infants receiving intervention had significantly larger white-matter volume at TEA, as compared with standard of care, in models adjusted for GA at birth, sex, study centre and PMA at MRI (β=6.8 cm3, 95% CI 0.7 to 12.9, p=0.028). The contribution of the intervention to white-matter volume corresponded to 10 days of prolonged gestation.
CONCLUSION AND RELEVANCE: Our findings in this hypothesis-generating study suggest that AA+DHA promotes white matter growth, which may protect the developing brain in this vulnerable population.
TRIAL REGISTRATION NUMBER: NCT03201588.

Keywords:  Infant Development; Magnetic Resonance Imaging; Neonatology; Therapeutics

DOI:  https://doi.org/10.1136/archdischild-2024-328292
Mol Neurobiol. 2026 Jan 19. 63(1): 371

UBA52 Overexpression Ameliorates Intracerebral Hemorrhage-Associated Neuronal Apoptosis and Mitochondrial Dysfunction: A Protective Role in Neurons.

Shuainan Ma, Qi Liu, Wei Han, Zhiyi Liu, Sinan Jin, He Wu, Wei Hua.

  Intracerebral hemorrhage (ICH) incidence increases with age, and neuronal mitochondrial dysfunction and apoptosis post-ICH contribute to severe secondary brain injury. It is of paramount importance to explore molecular targets for protecting against brain injury after ICH. UBA52, a ubiquitin precursor protein, was found to be upregulated in brain tissues of ICH mice. Intracerebral injection of adeno-associated virus type 9 overexpressing UBA52 (AAV9-UBA52) alleviated neurological deficits and brain edema in ICH mice. In vitro and in vivo experiments demonstrated that UBA52 overexpression reduced hemin or ICH-induced apoptosis, reflected in decreased TUNEL-positive cells and reduced caspase-3 and caspase-9 levels. The augmentation of fluorescence intensity in Mitotracker labeling and the reduction of fluorescence intensity in JC-1 staining suggested that UBA52 overexpression mitigated hemin-induced mitochondrial damage. This was further evidenced by increased cellular ATP content and elevated cytochrome c levels located in mitochondria. In vivo findings showed that UBA52 overexpression reduced the quantity of degenerative neurons. UBA52 and NeuN co-localization verified its direct protective effect on neurons. IP-LC/MS and Co-IP assays identified Daxx as a UBA52-interacting protein, with UBA52 promoting Daxx ubiquitination and degradation. Rescue experiments showed Daxx overexpression abolished the protective effect of UBA52 against hemin-induced apoptosis and mitochondrial dysfunction. Collectively, this study demonstrated that UBA52 ameliorates ICH-induced secondary brain injury by promoting Daxx ubiquitination/degradation to inhibit neuronal apoptosis and mitochondrial damage, suggesting UBA52 as a potential protective target for ICH therapy.

Keywords:  Apoptosis; Daxx; Intracerebral hemorrhage; Mitochondrial dysfunction; UBA52

DOI:  https://doi.org/10.1007/s12035-025-05655-1
Mol Neurobiol. 2026 Jan 19. 63(1): 372

The Interplay Between Nurr1 and Mitochondrial Biogenesis: Implications for Neurodegenerative Therapy.

Simranjeet Kaur, Ashi Mannan, Thakur Gurjeet Singh.

  The transcription factor Nurr1 (NR4A2) serves as an essential element in dopaminergic neuron development since it functions predominantly in the substantia nigra, which becomes severely affected during Parkinson's disease (PD) and Alzheimer's disease (AD). Nurr1 regulates dopamine synthesis, survival-promoting, and oxidative stress genes that affect mitochondrial formation. Nurr1 binds to PGC-1α, allowing for mitochondrial activity regulation. This relationship supports mitochondrial biogenesis. Post-translational changes, including phosphorylation and acetylation, modify Nurr1 transcriptional regulation in order to enhance its ability to regulate mitochondrial genes. The assessment examines Nurr1's involvement in dopaminergic neuron development and mitochondrial formation while showing its role in reducing oxidative damage for an extensive understanding of its neurological disease functionality. Nurr1 serves as a therapeutic candidate for analysis, while the review explores obstacles and potential paths for using Nurr1-based treatments against Parkinson's disease alongside Alzheimer's disease and other neurodegenerative disorders. The extensive research utilized multiple databases, PubMed, Scopus, Medline, and EMBASE, with keywords "Nurr1," "NR4A2," "Neurodegenerative disorders," "Mitochondrial biogenesis," "Oxidative stress," "Parkinson's disease," "Alzheimer's disease," and "Therapeutic target." The analysis examined published research regarding Nurr1-mediated control of dopaminergic function and survival and mitigation of neurological and mitochondrial deficits within the past decade. Nurr1's interactions with important co-regulators like PGCα, its post-translational changes, and its effects on neuroinflammation have also received particular focus. In neurodegenerative illnesses, mitochondrial dysfunction adds to neuronal damage. Nurr1's regulation of mitochondrial biogenesis helps recover mitochondrial function, alleviate oxidative stress, and sustain neuronal survival. Dysregulation of Nurr1 expression is connected to decreased mitochondrial activity and accelerated neurodegeneration.

Keywords:  Alzheimer’s disease; Mitochondrial biogenesis; Neurodegeneration; Nurr1; Oxidative stress; PGC-1α; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-025-05633-7