bims-medebr 2026-01-11 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–01–11
sixteen papers selected by
Regina F. Fernández, Johns Hopkins University

Signaling roles for astrocytic lipid metabolism in brain function.
Brain aerobic glycolysis is stable during adulthood: Direct evidence from cross-brain blood sampling in 239 healthy adults.
Brain lipid metabolism and transport: implications for neurodegeneration and therapeutic strategies: a comprehensive review.
Evolution of the lipidome uncovers early changes in adrenoleukodystrophy human cortical and spinal organoids.
Lactate Dehydrogenase Inhibition Reverts the Fatty Acid-Induced Neurotoxic Phenotype of Astrocytes.
Lipidomic Comparison of Detergent-Soluble and Detergent-Resistant Lipid Domains Isolated From Rat Cerebellum and the Effect of Hypoxia-Ischemia Using UPLC-HDMSE.
Microglia Mitochondrial Metabolism in Neurological Diseases.
Mitochondrial transfer from glia to neurons protects against peripheral neuropathy.
Comparative lipidomics of iPSC-derived microglia protocols reveal lipid droplet and immune differences mediated by media composition.
LPLAT11/MBOAT7-driven phosphatidylinositol remodeling ensures radial glial cell integrity in developing neocortex.
Quantitative optical nanoscopy of mitochondrial-derived vesicles in neurons classifies pre-peroxisomal and clearing organelles.
A glycolytic shunt via the pentose phosphate pathway is a metabolic checkpoint for nervous system sensory homeostasis and axonal regeneration.
Diacylglycerol kinases: Molecular mechanism of cellular and physiological functions.
p53 increases phospholipid headgroup scavenging in senescence.
ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration.
LipoID profiles lipid droplet interactions and identifies interorganelle regulators.

EMBO Rep. 2026 Jan 03.

Signaling roles for astrocytic lipid metabolism in brain function.

Juan P Bolaños, Angeles Almeida.

  Astrocytes, the most abundant glial cell type in the central nervous system, have traditionally been viewed from the perspective of metabolic support, particularly supplying neurons with lactate via glycolysis. This view has focused heavily on glucose metabolism as the primary mode of sustaining neuronal function. However, recent research challenges this paradigm by positioning astrocytes as dynamic metabolic hubs that actively engage in lipid metabolism, especially mitochondrial fatty acid β-oxidation. Far from serving solely as an energy source, fatty acid ß-oxidation in astrocytes orchestrates reactive oxygen species-mediated signaling pathways that modulate neuron-glia communication and cognitive outcomes. This review integrates recent advances on astrocytic fatty acid ß-oxidation and ketogenesis, alongside other metabolic pathways converging on reactive oxygen species dynamics, including cholesterol metabolism and peroxisomal β-oxidation. In reframing astrocytic metabolism from energy provision to signaling, we propose new directions for understanding central nervous system function and dysfunction.

Keywords:  Astrocytes; Fatty Acid β-Oxidation; Ketogenesis; Neuron-glia Metabolic Coupling; Reactive Oxygen Species Signaling

DOI:  https://doi.org/10.1038/s44319-025-00683-3
J Cereb Blood Flow Metab. 2026 Jan 08. 271678X251399122

Brain aerobic glycolysis is stable during adulthood: Direct evidence from cross-brain blood sampling in 239 healthy adults.

Jennifer S Duffy, Philip N Ainslie, Peter Rasmussen, David B MacLeod, Travis D Gibbons.

  The brain is a highly metabolic organ primarily fueled by glucose, and it is well established that a decline in cerebral glucose metabolism accompanies neurodegenerative disease. Recent work using positron emission tomography (PET) has demonstrated that cerebral glucose metabolism is also reduced in healthy aging which commences as early as 20 years of age, driven almost exclusively by reductions in non-oxidative glucose metabolism, that is, aerobic glycolysis. Given the historical variability and assumptions in PET-based interpretations regarding cerebral glucose metabolism with aging, we aimed to establish whether a drop in global aerobic glycolysis is truly a component of healthy aging in adulthood using direct measures of carbohydrates and oxygen across the human brain via invasive cross-brain blood sampling. We accumulated resting data from 17 studies comprising 239 healthy adults aged 19-45 years and show that aerobic glycolysis remains stable during aging based on a regression analysis of the arteriovenous differences for oxygen, glucose, and lactate, and their resultant ratios (oxygen glucose/carbohydrate indices). The direct cross-brain data presented here indicate that declining brain aerobic glycolysis is not a feature of normal brain aging during early-mid adulthood.

Keywords:  Aerobic glycolysis; aging brain; arteriovenous difference; cerebral metabolism; neurodegeneration

DOI:  https://doi.org/10.1177/0271678X251399122
Metab Brain Dis. 2026 Jan 03. 41(1): 14

Brain lipid metabolism and transport: implications for neurodegeneration and therapeutic strategies: a comprehensive review.

Amjad Mahmood Qadir, Rebaz Anwar Omar, Seerwan Hamadameen Sulaiman, Hemn A H Barzani.

  This 2024comprehensive review examines the crucial functions of lipids in neurological health, highlighting their vital contributions to brain structure, function, and pathology. The intricate lipid composition of the brain, comprising phospholipids, sphingolipids, cholesterol, glycolipids, and polyunsaturated fatty acids, supports membrane integrity, synaptic transmission, and myelination. Lipid production, metabolism, and transport in the central nervous system are meticulously controlled, necessitating specialised interactions among neurones, glial cells, and the blood-brain barrier. Lipid homeostasis dysregulation is widely acknowledged as playing a critical role in the aetiology of neurodegenerative diseases such as Alzheimer's and Parkinson's, multiple sclerosis, and neuropsychiatric disorders like schizophrenia and depression. These disruptions result in compromised synapse function, neuroinflammation, oxidative stress, and neuronal injury. The review emphasises bioactive lipids, particularly specialised pro-resolving mediators originating from polyunsaturated fatty acids, which regulate neuroinflammation and enhance neuroprotection. Progress in lipidomics has enabled the discovery of new lipid biomarkers and therapeutic targets, presenting intriguing opportunities for disease diagnosis, prognosis, and therapy. This paper highlights the significance of lipid biology in maintaining brain health and the therapeutic potential of targeting lipid pathways to mitigate the progression of neurological diseases, integrating contemporary lipidomic discoveries and mechanistic knowledge.

Keywords:  Brain lipid metabolism; Central nervous system (CNS); Neurodegenerative disorders; Neuroinflammation; Polyunsaturated fatty acids (PUFAs)

DOI:  https://doi.org/10.1007/s11011-025-01778-5
iScience. 2026 Jan 16. 29(1): 114339

Evolution of the lipidome uncovers early changes in adrenoleukodystrophy human cortical and spinal organoids.

Roberto Montoro Ferrer, Yorrick R J Jaspers, Nicki Coveña, Nicole Breeuwsma, Inge M E Dijkstra, Julia Kempff, Jan-Bert van Klinken, Joke Wortel, Jan R T van Weering, Marc Engelen, Stephan Kemp, Vivi M Heine.

  Lipids are critical for the structure, signaling, and metabolism of the central nervous system (CNS), yet their roles during human brain development remain underexplored due to limited tissue availability. X-linked adrenoleukodystrophy (ALD), a peroxisomal disorder caused by ABCD1 mutations, disrupts very long-chain fatty acid (VLCFA) degradation, leading to axonal degeneration and demyelination. To investigate lipid dynamics in CNS development and ALD pathogenesis, we generated human induced pluripotent stem cell (hiPSC)-derived cortical and spinal cord organoids and performed lipidomics over 200 days. Lipidomic analysis revealed a dynamic lipidome, with changes in lipid abundance, saturation, and chain length reflecting neurodevelopment. ALD hiPSC-derived organoids exhibited significant lipid alterations over time, including elevated VLCFA levels and reductions in brain-relevant lipids, such as sulfatides and gangliosides, in cortical organoids. These findings provide a foundational resource for studying lipid dynamics in CNS development and emphasize the value of organoids for understanding ALD and other CNS diseases.

Keywords:  Developmental neuroscience; Lipidomics; Nervous system anatomy

DOI:  https://doi.org/10.1016/j.isci.2025.114339
Glia. 2026 Mar;74(3): e70136

Lactate Dehydrogenase Inhibition Reverts the Fatty Acid-Induced Neurotoxic Phenotype of Astrocytes.

Daniel Esteve, Mariana Bresque, Daniel Okhuevbie, Sandhya Ramachandran, Mariana Pehar, Marcelo R Vargas.

  Astrocytes are central to lipid metabolism in the central nervous system. Due to their morphological and functional characteristics, astrocytes can uptake fatty acids (FAs) from the bloodstream and extracellular space and store them in lipid droplets (LD). LD are dynamic organelles, whose accumulation in astrocytes has been shown to occur upon exposure to various stress stimuli. Different hypotheses proposed to explain motor neuron degeneration in amyotrophic lateral sclerosis (ALS) implicate mitochondrial dysfunction and oxidative stress. Mitochondrial dysfunction in astrocytes is associated with elevation of cytoplasmic lipids and lipid-binding proteins. We observed increased LD in the spinal cord of symptomatic ALS mice, as well as in human transdifferentiated astrocytes obtained from ALS patients. Using a co-culture model, we examined the effect of FA overload and its impact on astrocyte-motor neuron interaction. LD accumulation was tightly coupled with an NF-κB-driven proinflammatory response in nontransgenic astrocytes, correlating with motor neuron toxicity. These results provide additional evidence to the notion that altered energy balance may contribute to neuronal death in ALS. Furthermore, pharmacological inhibition of lactate dehydrogenase (LDH) reversed LD accumulation in mouse and human astrocytes expressing ALS-linked mutations. Genetic ablation of LDHA similarly reduced LD accumulation in response to FA treatment. Collectively, our data underscore the role of lipid metabolism in astrocyte-neuron interactions in ALS models and suggest that LD accumulation, rather than serving solely as a protective mechanism, reflects a metabolic stress state linked to a detrimental phenotypic transformation in astrocytes.

Keywords:  LDH; NF‐κB; astrocytes; inflammation; lipid droplets

DOI:  https://doi.org/10.1002/glia.70136
J Mass Spectrom. 2026 Jan;61(1): e70000

Lipidomic Comparison of Detergent-Soluble and Detergent-Resistant Lipid Domains Isolated From Rat Cerebellum and the Effect of Hypoxia-Ischemia Using UPLC-HDMSE.

Samuel A Krug, Min He, Ningfeng Tang, Cynthia Bearer, Maureen A Kane.

  Hypoxic ischemic encephalopathy (HIE) due to insufficient oxygen or blood flow to the brain can result in inflammation, impaired neurodevelopment, or death. Changes to microdomain lipid composition may contribute to altered structure and function of key regulatory processes; however, knowledge regarding changes to membrane lipid composition after HIE is incomplete. Here, we describe the application of untargeted lipidomics to investigate the impact of hypoxia-ischemia on detergent-resistant membrane (DRM) and detergent-soluble membrane (DSM) domains fractionated from the cerebellum in a rat model of HIE. Lipidomics utilized ultra performance liquid chromatography coupled to data independent tandem mass spectrometry with traveling wave ion mobility. Lipid alterations specific to the DRM domains after hypoxia-ischemia included lysophospholipids, sphingomyelins, ceramides, triglycerides, and phosphatidylethanolamines, which are lipid species that have been linked to cognitive and neuronal impairment. The advances in lipidomics have enabled the tools available to study lipid composition. These data may provide insight into membrane disruption after HIE in relation to lipid composition and concentration.

Keywords:  hypoxic ischemia; lipid membrane; lipidomics; liquid chromatography–tandem mass spectrometry; membrane domains

DOI:  https://doi.org/10.1002/jms.70000
Mol Neurobiol. 2026 Jan 03. 63(1): 337

Microglia Mitochondrial Metabolism in Neurological Diseases.

Jin Wang, Yikun Gao, Qing Chen, Xiaoxing Xiong, Sen Miao, Xuemei Chen, Youjia Tang, Lijuan Gu.

  Microglia, the resident immune cells of the central nervous system (CNS), play critical roles in maintaining brain homeostasis and responding to neurological insults. Recent advances have fundamentally reshaped our understanding of how microglial mitochondrial metabolism influences neuroinflammation and disease progression. Single-cell transcriptomics has revealed unexpected metabolic heterogeneity, identifying distinct phenotypes such as disease-associated microglia (DAM) and lipid-laden microglia (LLM) that represent not merely activated states but terminal endpoints of metabolic paralysis. These discoveries converge on a unified pathogenic mechanism: mitochondrial quality control failure leads to mitochondrial DNA release, which activates the cGAS-STING pathway to create an "epigenetic lock" that drives sustained neuroinflammation. Interestingly, we highlight that the loss of metabolic flexibility-rather than glycolysis per se-is the true driver of pathology, explaining why the same metabolic shift can be protective during acute injury but pathological when sustained chronically. We critically examine conflicting evidence across Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke, including the puzzling dual roles of glycolysis, controversies surrounding the experimental autoimmune encephalomyelitis (EAE) model in multiple sclerosis research, and the paradoxical worsening of stroke outcomes following microglial depletion. By synthesizing these mechanistic insights with lessons from failed clinical trials, we identify critical translational gaps-including the lack of longitudinal human data and validated biomarkers-and propose a precision medicine framework focused on restoring mitochondrial dynamics and metabolic flexibility in neurological diseases.

Keywords:   Metabolic reprogramming; Mitochondrial metabolism; Neuroinflammation; Microglia

DOI:  https://doi.org/10.1007/s12035-025-05640-8
Nature. 2026 Jan 07.

Mitochondrial transfer from glia to neurons protects against peripheral neuropathy.

Jing Xu, Yize Li, Charles Novak, Min Lee, Zihan Yan, Sangsu Bang, Aidan McGinnis, Sharat Chandra, Vivian Zhang, Wei He, Terry Lechler, Maria Pia Rodriguez Salazar, Cagla Eroglu, Matthew L Becker, Dmitry Velmeshev, Richard E Cheney, Ru-Rong Ji.

Primary sensory neurons in dorsal root ganglia (DRG) have long axons and a high demand for mitochondria, and mitochondrial dysfunction has been implicated in peripheral neuropathy after diabetes and chemotherapy1,2. However, the mechanisms by which primary sensory neurons maintain their mitochondrial supply remain unclear. Satellite glial cells (SGCs) in DRG encircle sensory neurons and regulate neuronal activity and pain3. Here we show that SGCs are capable of transferring mitochondria to DRG sensory neurons in vitro, ex vivo and in vivo by the formation of tunnelling nanotubes with SGC-derived myosin 10 (MYO10). Scanning and transmission electron microscopy revealed tunnelling nanotube-like ultrastructures between SGCs and sensory neurons in mouse and human DRG. Blockade of mitochondrial transfer in naive mice leads to nerve degeneration and neuropathic pain. Single-nucleus RNA sequencing and in situ hybridization revealed that MYO10 is highly expressed in human SGCs. Furthermore, SGCs from DRG of people with diabetes exhibit reduced MYO10 expression and mitochondrial transfer to neurons. Adoptive transfer of human SGCs into the mouse DRG provides MYO10-dependent protection against peripheral neuropathy. This study uncovers a previously unrecognized role of peripheral glia and provides insights into small fibre neuropathy in diabetes, offering new therapeutic strategies for the management of neuropathic pain.

DOI: https://doi.org/10.1038/s41586-025-09896-x
Stem Cell Reports. 2026 Jan 08. pii: S2213-6711(25)00383-2. [Epub ahead of print] 102779

Comparative lipidomics of iPSC-derived microglia protocols reveal lipid droplet and immune differences mediated by media composition.

Aiko Toda Robert, Amanda McQuade, Sascha J Koppes-den Hertog, Lena Erlebach, Deborah Kronenberg-Versteeg, Martin Kampmann, Martin Giera, Rik van der Kant.

  Altered microglial lipid metabolism is heavily implicated in Alzheimer's disease (AD) and aging. Recently, protocols were developed to generate human induced pluripotent stem cell-derived microglia-like cells (iMGL) to study microglial function in vitro, including embryoid body-based methods and induced transcription factor (iTF)-dependent approaches. Here, we performed comparative lipidomics on iMGL from these methods and report major differences in multiple lipid classes, including triglycerides (TGs), a storage form of fatty acids implicated in microglial reactivity. TGs are strongly increased in iTF microglia due to the absence of a media supplement (B-27). Supplementing iTF microglia with B-27, or its component L-carnitine, reduces TGs and promotes a homeostatic state. B-27 also renders iTF microglia metabolically responsive to immune stimuli. Overall, our data show that iMGL differentiation methods have a major impact on microglial lipidomes and warrant attention when studying AD and neuroinflammatory processes involving lipids.

Keywords:  iPSC; lipid droplet; lipid metabolism; lipidomics; microglia; neuroinflammation; triglycerides

DOI:  https://doi.org/10.1016/j.stemcr.2025.102779
iScience. 2026 Jan 16. 29(1): 114248

LPLAT11/MBOAT7-driven phosphatidylinositol remodeling ensures radial glial cell integrity in developing neocortex.

Yuki Ishino, Yusuke Kishi, Taiga Iwama, Naohiro Kuwayama, Hiroyuki Arai, Yukiko Gotoh, Junken Aoki, Nozomu Kono.

  Phosphatidylinositol (PI) is highly enriched in arachidonic acid, an essential polyunsaturated fatty acid for brain development. This enrichment is mediated by the phospholipid remodeling enzyme lysophospholipid acyltransferase 11 (LPLAT11), also known as membrane-bound O-acyltransferase 7 (MBOAT7), whose deficiency causes microcephaly in both humans and mice. Here, we show that Mboat7 deficiency impairs indirect neurogenesis in the developing neocortex by compromising radial glial cell (RGC) integrity, resulting in fewer layer II-V neurons. Mboat7-deficient RGCs exhibited decreased proliferation, impaired differentiation into intermediate progenitor cells, and increased apoptosis. These defects were preceded by Golgi apparatus rounding, reduced apical E-cadherin expression, and dysregulated apical detachment of RGCs. Moreover, the Mboat7-deficient cortex displayed reduced PI(4,5)P2 levels, and pharmacological inhibition of PI(4,5)P2 synthesis recapitulated the Golgi rounding observed in Mboat7-deficient RGCs. These findings suggest that compromised RGC integrity due to reduced PI(4,5)P2 levels, resulting from decreased arachidonic acid-containing PI, underlies the microcephaly associated with MBOAT7 deficiency.

Keywords:  Cellular neuroscience; Developmental neuroscience; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2025.114248
Nat Commun. 2026 Jan 08.

Quantitative optical nanoscopy of mitochondrial-derived vesicles in neurons classifies pre-peroxisomal and clearing organelles.

Giovanna Coceano, Jonatan Alvelid, Martina Damenti, Gabriella Ferretti, Johannes Mueller, Joanna Rorbach, Ilaria Testa.

Healthy mitochondria are crucial for maintaining neuronal homeostasis. Their activity depends on a dynamic lipid and protein exchange through fusion, fission, and vesicular trafficking. Studying vesicles in neurons is challenging with conventional microscopy due to their small size, heterogeneity, and dynamics. We use multicolour stimulated emission depletion nanoscopy to uncover the ultrastructure of mitochondrial-derived vesicles (MDVs) in live neurons, biosensors to define their functional state, and a pulse-chase strategy to identify their turnover in situ. We identified three populations of vesicular structures: one transporting degradation products originating from oxidative stress, one shuttling cargo and newly translated proteins for local organelle biogenesis and one consisting of small, functional mitochondria. Furthermore, we provide evidence supporting that de novo peroxisomes biogenesis occurs via the fusion of endoplasmic reticulum and MDVs at mitochondrial sites. Our data provide mechanistic insight into organelle biogenesis driven by significant diversity in MDV morphology, functional state, and molecular composition.

DOI: https://doi.org/10.1038/s41467-025-68160-y
Cell. 2026 Jan 05. pii: S0092-8674(25)01379-0. [Epub ahead of print]

A glycolytic shunt via the pentose phosphate pathway is a metabolic checkpoint for nervous system sensory homeostasis and axonal regeneration.

Yayue Song, Lucia Luengo-Gutierrez, Virag Sagi-Kiss, Guiping Kong, Helen Huang, Moritz Steinruecke, Luming Zhou, Zhulin Yuan, Francesco De Virgiliis, Istvan Pap, Charlotte Decourt, Yuyang Yan, Hee Hwan Park, Hanqi Zhang, Jiahui Wei, Elizabeth Want, Xuemei Tong, Zoltan Takats, Simone Di Giovanni.

  Homeostasis and repair in the nervous system are thought to rely on distinct molecular programs. Here, we uncover an unexpected role for the pentose phosphate pathway (PPP) in peripheral sensory axons, where it supports both homeostatic mechanosensation and axonal regeneration after injury. We show that the PPP is enriched and active in sciatic nerve axoplasms, where it maintains redox balance via NADPH production, enabling physiological mechanical sensation. However, following sciatic nerve injury, the PPP is required for regeneration by fueling ribonucleotide synthesis through ribose-5-phosphate. In contrast, this pathway remains inactive after spinal cord injury (SCI), contributing to regenerative failure. Reactivation of the PPP, through neuronal transketolase overexpression or oral ribose supplementation, promotes metabolic reprogramming, restores sensory and motor axonal growth, and improves neurological recovery after SCI. These findings propose the PPP as a metabolic checkpoint in sensory neuron physiology and regeneration, highlighting its therapeutic potential for central nervous system repair.

Keywords:  TKT; axon regeneration; homeostasis; mechanical sensation; nerve injury; neuronal metabolism; pentose phosphate pathway; ribose; spinal cord injury; transcription

DOI:  https://doi.org/10.1016/j.cell.2025.12.003
Prog Lipid Res. 2026 Jan 06. pii: S0163-7827(25)00055-4. [Epub ahead of print] 101373

Diacylglycerol kinases: Molecular mechanism of cellular and physiological functions.

Tomohiro Kimura, Richard M Epand.

  Diacylglycerol (DAG) and phosphatidic acid (PA), being positioned in the central hub of glycerophospholipid biosynthesis pathways, are lipids vital for the structural and functional integrity of the cell. DAG kinases (DGKs) are the enzymes responsible for the conversion of DAG to PA to regulate the dynamically changing spatiotemporal levels of these lipids in various organelles and cellular structures. DAG and PA thereby function intricately in mechanistic events like cell signaling in association with the intracellular lipid profiles controlling membrane physiology. In mammalian cells, there are ten DGK isoforms, i.e., α, β, γ, δ, η, κ, ε, ι, ζ, θ, and their splice variants. Recent advancement of structural prediction algorism enables us to gain unparalleled insights into their molecular architectures, despite limited experimental data available to date. The structural information gives fundamental clues to understand pertinent cellular events that are reviewed in this work on a broad range of topics in health and disease. Upon cell stimuli, DAG is formed by hydrolysis of a phospholipid such as phosphatidylinositol (PI) 4,5-bisphosphate (PI(4,5)P2) via a phospholipase C (PLC). While relationship of the DGK activity with specific lipid acyl-chain species is being recognized, that with the sn-1 ether linkage like the vinyl ether has not yet been revealed. Importance of these relationships may be evident, considering the known regulation of the PLC activity by lipid rafts. Elucidation of molecular details of DGK functions in the context of membrane biophysics is thus essential for our understanding of cellular events in the individual tissues and organs.

Keywords:  Cell signaling; Diacylglycerol; Diacylglycerol kinase; Lipid rafts; Lipid–protein interactions; Membrane physiology; Phosphatidic acid; Protein–protein interactions; Structure–function relationship; Subcellular location

DOI:  https://doi.org/10.1016/j.plipres.2025.101373
Nat Cell Biol. 2026 Jan 07.

p53 increases phospholipid headgroup scavenging in senescence.

Jossie J Yashinskie, Xianbing Zhu, Grace H McGregor, Karl A Wessendorf-Rodriguez, Katrina Paras, Julia S Brunner, Benjamin T Jackson, Abigail Xie, Richard Koche, Christian M Metallo, Lydia W S Finley.

Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here we show that the transcription factor p53 increases recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases the supply of phosphoethanolamine, an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine, in part by increasing lipid turnover and transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of phosphoethanolamine conversion to phosphatidylethanolamine is well tolerated in the absence of p53 but results in dramatic organelle remodelling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR-Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism and lysosomal function. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state-specific metabolic vulnerability.

DOI: https://doi.org/10.1038/s41556-025-01853-0
Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2503834122

ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration.

Naemeh Pourshafie, Desi C Alexander, Hong Xu, Kechun Yang, Greg Donahue, Xue Lei, Shuo Zhang, Oksana Shcherbakova, Connor Hogan, Michael Gilbert, Kevt'her Hoxha, Lesley Chaboub, Virginia M-Y Lee, Peter D Adams, John A Dani, Nancy M Bonini, Shelley L Berger.

  Epigenetic mechanisms, including histone acetylation, regulate learning and memory and underlie Alzheimer's disease and related dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme generating acetyl-CoA, locally regulates histone acetylation and gene expression in neuronal nuclei. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously, we showed that systemic ACSS2 knockout mice, although largely normal in physiology, exhibit memory deficits. Here, we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Additionally, boosting histone acetylation through ACSS2 countered age-related memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. These findings position ACSS2 as a key epigenetic regulator of cognitive aging and ADRD, highlighting its potential for targeted therapeutics to enhance brain resilience and function.

Keywords:  ACSS2; Alzheimer’s Disease; Epigenetics; aging; metabolism

DOI:  https://doi.org/10.1073/pnas.2503834122
Nat Chem Biol. 2026 Jan 09.

LipoID profiles lipid droplet interactions and identifies interorganelle regulators.

Hengke Guo, Wang Wan, Yanan Huang, Nan Zhao, Ci Wu, Bowen Zhong, Rui Sun, Huan Feng, Jing Yan, Di Shen, Xuepeng Dong, Qun Zhao, Xin Zhang, Lihua Zhang, Yu Liu.

Lipid droplets (LDs) dynamically interact with other organelles, such as mitochondria, in surveillance of cellular metabolic homeostasis. The transient nature of LDs, however, poses technical challenges to snapshot molecular information underlying these interactions. Herein, we present a small-molecule-based photocatalytic protein proximity labeling method (named LipoID) to enable in situ labeling, capturing and profiling of the LD-interacting proteome. This method is enabled by a set of LD-targeting probes designed to catalyze protein modifications nearby LDs using nucleophilic substrates. Profiled by liquid chromatography-tandem mass spectrometry, LipoID identifies tethered interorganellar interactions, particularly with mitochondria, in addition to reliable capture of validated LD biomarkers (for example, perilipins (PLINs)). Coupled with comparative proteomics, LipoID discovers mitochondrial voltage-dependent anion channel 3 as a potential regulator of LD-mitochondria proximity through interacting with PLIN3 on LDs. Further metabolomics analysis suggested remodeled lipid metabolism in line with the LD-mitochondria interaction. Together, LipoID enables in situ profiling of the LD interactome and reveals interorganellar regulation.

DOI: https://doi.org/10.1038/s41589-025-02127-4