bims-medebr 2026-08-23 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–08–23
25 papers selected by
Regina F. Fernández, Johns Hopkins University

Cross-species neural co-culture uncovers metabolic signatures of cellular crosstalk.
Distinct spatiotemporal immunometabolic remodeling following acute traumatic brain injury.
Hyperpolarized 13C MRI uncovers early and progressive metabolic dysfunction in the hAPP-J20 mouse model of Alzheimer's disease.
MARK4 regulates GLUT3 surface expression and neuronal glucose uptake.
Lipid droplets as redox-active organelles after spinal cord injury: lipid peroxidation, mitochondrial dysfunction, and neuroinflammation.
Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.
Modulation of the brain lipids after long-term exposure to diets varying in their ratio and content in omega-6 and omega-3 polyunsaturated fatty acids in mice.
Progranulin deficiency perturbs lipid metabolism in white matter microglia.
Recombinant sialylated ApoE2 suppresses ApoE4 and sex-specifically strengthens brain metabolism and cognition in ApoE4 mice.
Written in the Stars: Astrocyte Biology From Evolution to Disease.
Restoration of Neuronal Metabolism and Memory in Alzheimer's Disease by Reprogramming the Exosomal microRNA Network.
Small-Scale Cell Biological Analysis of Lipid Rafts of Blood Platelets and Cerebellar Neurons.
Serotonin deficiency caused by inactivation of Tph2 in mice leads to widespread sex-dependent changes in cerebral oxidative metabolic activity.
When Powerhouses Fail and Rust Takes Over: Primary Mitochondrial and Lipid Metabolism Failure with Secondary Iron Accumulation and Lipid Peroxidation in Neurodegeneration with Brain Iron Accumulation.
Mitochondrial dysfunction in intracerebral hemorrhage: molecular mechanisms and pathological consequences.
Isoflurane and surgery aggravate APOE4-dependent lipid dysregulation and neural dysfunction, leading to neurological impairment in male mice.
Tmem117, an oligodendrocyte-enriched regulator of NCX activity, links myelin homeostasis to counterregulation and metabolic health.
Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.
The role of microglia glucose metabolism reprogramming in Alzheimer's disease treatment.
Mitochondrial dynamics in Huntington's disease.
Mitochondrial dysfunction in schizophrenia and psychotic disorders: Implications for antipsychotic drug mechanisms.
Sirtuins in mitochondrial physiology and energy homeostasis.
Adenylosuccinate acts as a novel pro-angiogenic factor.
NOTCH3 Mutations in CADASIL Alter Lipid Metabolism: Insights from Patient Plasma and In Vitro Models.
Loss of neurofibromin alters adult metabolism via effects during a developmental critical period.

bioRxiv. 2026 Jul 31. pii: 2026.07.31.741820. [Epub ahead of print]

Cross-species neural co-culture uncovers metabolic signatures of cellular crosstalk.

Katherine Rickelton, Rithvik Sandiri, Jessica Roy, Aliyah Dalier, Courtney C Babbitt.

Primates are distinguished by large brains relative to body size, with humans showing the greatest expansion. This increase in brain size evolved alongside advanced cognitive abilities as well as an elevated energetic demand. Importantly, allometric scaling alone does not explain this increased metabolic requirement, suggesting that other cellular mechanisms may be driving the unique energetic capacity of the human brain. Brain metabolism is critical for neurological function by providing the energy necessary for neuron firing. Much of metabolism in the brain is carried out by astrocytes: a type of glial cell that have long been viewed as passive support cells for neurons. More recent research has highlighted the unique roles of astrocytes in many critical neurological processes; however, it is less understood how astrocytes differ among species. To better characterize this, we developed a cross-species co-culture model of astrocytes and neurons from human or chimpanzee-derived iPSCs. This co-culture system allowed us to assess cell-type specific effects as well as species-specific differences in cellular interactions that may be driving overall differences in brain metabolism. We conducted single-cell RNA-sequencing as well as Seahorse XF Mitochondrial Stress tests and observed that human neural co-cultures are more metabolically active than chimpanzee neural co-cultures. Cross-species co-culture systems also highlight that astrocytes are driving major species differences in metabolism, whereas neurons are highly responsive to astrocytic activity. We conclude that both neurons and astrocytes have evolved differently across primates, and that metabolic interactions between these cell types are key contributors in primate brain evolution.

DOI: https://doi.org/10.64898/2026.07.31.741820
bioRxiv. 2026 Jul 29. pii: 2026.07.28.740519. [Epub ahead of print]

Distinct spatiotemporal immunometabolic remodeling following acute traumatic brain injury.

Zohreh Erfani, Erin H Seeley, Erik J Plautz, Brenda L Bartnik-Olson, Jae Mo Park.

Traumatic brain injury induces profound metabolic reprogramming across neurons, astrocytes, and microglia, yet the spatiotemporal organization of these metabolic responses remains poorly understood. Because pyruvate is uniquely positioned in cerebral metabolism by connecting glycolysis, lactate metabolism, and the tricarboxylic acid cycle, we combined matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging with in vivo administration of isotopically labeled pyruvate and immunohistochemistry to characterize cell-type-wise metabolic remodeling in a controlled cortical impact rat model during the acute and subacute phases of injury. TBI induced distinct spatiotemporal immunometabolic remodeling across neuroglial compartments. Microglia- and macrophage-enriched regions exhibited selective accumulation of citrate, succinate, and itaconate, consistent with inflammatory metabolic rewiring. In contrast, astrocyte enriched regions showed increased glutamine and malate abundance, indicative of altered neuron-astrocyte metabolic coupling such as remodeling of the glutamate-glutamine cycle and enhanced anaplerotic metabolism. These metabolic signatures evolved with distinct regional and temporal distributions, identifying compartmentalized metabolic responses. Notably, labeled isotopologues of selected metabolites, including glutamate and citrate derived from administered pyruvate, changed before the corresponding metabolite pools. Together, these findings describe the spatiotemporal landscape of immunometabolic remodeling following acute TBI, uncover metabolically distinct microglial/macrophage and astrocytic responses during secondary brain injury, and identify candidate metabolic pathways for therapeutic intervention and metabolic imaging.

DOI: https://doi.org/10.64898/2026.07.28.740519
Res Sq. 2026 Jul 27. pii: rs.3.rs-10437814. [Epub ahead of print]

Hyperpolarized 13C MRI uncovers early and progressive metabolic dysfunction in the hAPP-J20 mouse model of Alzheimer's disease.

Tamara Vasilkovska, Lydia M Le Page, Caroline Guglielmetti, Marina Radoul, Huihui Li, Xiao Ji, Jeremy W Gordon, Ken Nakamura, Myriam M Chaumeil.

Impaired brain energy metabolism is an early feature of Alzheimer's disease (AD), but the standard metabolic imaging tool, [ 18 F]FDG-PET, reports only glucose uptake and cannot resolve downstream metabolic flux nor inform on overall metabolic profile of the brain. In this study, we used [ 18 F]FDG-PET, hyperpolarized (HP) [1- 13 C]pyruvate 13 C magnetic resonance spectroscopic imaging (MRSI), and ex vivo ¹H-NMR metabolomics to characterize how amyloid-β (Aβ) associated pathology reshapes brain energy metabolism in the hAPP-J20 mouse model, from glucose uptake to metabolic fluxes and steady-state metabolite concentrations. HP 13 C MRSI was performed in male and female wild-type (WT) and hAPP-J20 mice at 2 and 14 months of age, with FDG-PET and metabolomics acquired at the final timepoint. HP 13 C MRSI revealed a progressive, region-specific increase in glycolytic flux in hAPP-J20 mice, with increased apparent HP [1- 13 C]Lactate/Pyruvate conversion (relative to vascular delivery) localized to the hippocampus in females and to the cortex in males; HP 13 C urea perfusion measures confirmed comparable substrate delivery between genotypes. In contrast, [ 18 F]FDG-PET showed no genotype difference in regional glucose uptake, although the sex- and weight-dependent scaling of FDG uptake observed in the WT controls was lost in hAPP-J20 mice. Ex vivo metabolomics uncovered sex-divergent metabolic rewiring: a succinate-centered strengthening of the TCA cycle and propanoate metabolism in females, versus altered tyrosine and ubiquinone metabolism in males. These data show that HP 13 C MRSI detects an Aβ-associated increase in glycolytic flux before FDG-PET registers a change, and position HP 13 C pyruvate MRS imaging as a sensitive, radiation-free, flux-based biomarker that complements glucose-uptake imaging in AD.

DOI: https://doi.org/10.21203/rs.3.rs-10437814/v1
J Biochem. 2026 Aug 19. pii: mvag061. [Epub ahead of print]

MARK4 regulates GLUT3 surface expression and neuronal glucose uptake.

Sophia Jobien M Limlingan, Ambika Krishnankutty, Akiko Asada, Kanae Ando, Taro Saito.

  Brain neurons rely predominantly on glucose as an energy source and express glucose transporter 3 (GLUT3) as their principal glucose transporter. Unlike GLUT4, which undergoes insulin-stimulated membrane translocation in peripheral tissues, GLUT3 mediates largely constitutive and relatively insulin-independent glucose uptake in neurons. Although GLUT3 is essential for neuronal functions, its regulatory mechanisms are not fully understood. Microtubule affinity-regulating kinase 4 (MARK4), a member of the AMP-activated protein kinase-related kinase family, has been implicated in Alzheimer's disease and metabolic regulation in peripheral tissues. Here, we show that MARK4 knockdown in primary neurons reduces GLUT3 surface expression and consequently decreases glucose uptake. While MARK4 knockdown did not alter the intracellular distribution of GLUT3 or mitochondria, it reduced mitochondrial abundance. We further found that MARK4 activity is negatively regulated by the insulin/IGF-1-GSK3β signaling axis in primary neurons. Despite these acute metabolic effects in cultured neurons, Mark4-null mice exhibited no overt morphological abnormalities in the brain. Together, these findings identify MARK4 as a regulator of neuronal glucose uptake by modulating GLUT3 surface expression and suggest that MARK4 functions as a modulatory rather than essential component of neuronal metabolic homeostasis.

Keywords:  GLUT3; GSK3beta; IGF-1; MARK4; glucose uptake; insulin; mitochondria

DOI:  https://doi.org/10.1093/jb/mvag061
Redox Rep. 2026 Dec 31. 31(1): 2720356

Lipid droplets as redox-active organelles after spinal cord injury: lipid peroxidation, mitochondrial dysfunction, and neuroinflammation.

Yichen Zhang, Jie Li, Yinan Liu, Dong Guo.

   OBJECTIVES: Spinal cord injury (SCI) causes myelin breakdown and membrane disruption, leading to the release and redistribution of cholesterol, fatty acids, and other lipids within the lesion. The resulting disruption of lipid homeostasis can promote sustained lipid peroxidation, neuroinflammation, and repair failure. In recent years, lipid droplets (LDs) have been recognized as highly dynamic organelles that coordinate lipid storage, mobilization, energy metabolism, and stress responses. However, the stage- and cell-specific roles of LDs in lipid-redox dysregulation after SCI remain poorly understood.
METHODS: This review summarizes the basic mechanisms of LD formation, lipolysis, and lipophagy, examines the regulation of lipid peroxidation by LDs, and discusses bidirectional LD-mitochondria crosstalk. We further integrate evidence on LD remodeling across microglia/macrophages, astrocytes, neurons, oligodendrocyte-lineage cells, and microvascular endothelial cells. We also consider how these cell-specific changes relate to lipid detoxification and transfer, neuronal oxidative injury, blood-spinal cord barrier dysfunction, and remyelination.
RESULTS: We propose that LDs are not passive markers of lipid deposition after SCI but stage- and cell-type-dependent redox-metabolic regulators. Early LD formation may buffer acute lipid overload, whereas persistent oxidative stress, mitochondrial dysfunction, and impaired LD turnover may convert LDs into pathological lipid reservoirs that amplify lipid peroxidation and neuroinflammation. Finally, we discuss therapeutic strategies aimed at limiting pathological lipid accumulation, restoring LD turnover and cholesterol efflux, suppressing lipid peroxidation, and preserving mitochondrial redox homeostasis.
DISCUSSION: Together, this review provides an integrated framework for understanding how LD remodeling links lipid metabolic imbalance to secondary injury and neural repair after SCI.

Keywords:  Spinal cord injury; cholesterol efflux; lipid droplets; lipid peroxidation; lipophagy; mitochondrial dysfunction; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.1080/13510002.2026.2720356
Am J Physiol Cell Physiol. 2026 Aug 21.

Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.

Yewon Chang, Hee-Joo Kim, Yeongmin Kim, Aron Park, Seungyoon Nam, Deveena R Banerjee, Clinton M Hasenour, Jamey D Young, George A Brooks, Robert R Wolfe, Il-Young Kim.

  A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As the glucose utilization declines in AD patients, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (A) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under A-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of AD patients. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by A aggregates. Using a 13C stable isotope tracer, we verified cellular lactate uptake and its incorporation into TCA cycle in neurons under the neurotoxic condition. ¹³C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.

Keywords:  Alzheimer's disease; lactate shuttle; metabolic flux; neuronal metabolism

DOI:  https://doi.org/10.1152/ajpcell.00268.2026
Food Res Int. 2026 Oct 31. pii: S0963-9969(26)01478-X. [Epub ahead of print]242(Pt 1): 119794

Modulation of the brain lipids after long-term exposure to diets varying in their ratio and content in omega-6 and omega-3 polyunsaturated fatty acids in mice.

Jean-Baptiste Bizeau, Lucy Martine, Caroline Peltier, Stéphane Grégoire, Bénédicte Loriot, Alain M Bron, Niyazi Acar, Marie-Agnès Bringer.

  Lipids are essential for brain physiology. Although dietary lipids, including polyunsaturated fatty acids (PUFAs), are known to influence brain lipid composition, few studies have been conducted under conditions that reflect realistic societal challenges and long-term dietary exposure patterns. The primary objective of this study was to assess the effect of long-term dietary exposure to two n-6/n-3 PUFA precursor ratios reflecting health recommendations versus a Western diet, on the lipid composition of different brain structures (cortex, cerebellum, striatum, hippocampus and hypothalamus) in mice, as well as on cortical oxidative stress and inflammation. For this purpose, we used diets containing 5% fat by weight with two n-6/n-3 PUFA precursor ratios: LA/ALA = 5:1 (recommended ratio) and LA/ALA = 15:1 (Western diet-like ratio). We also studied the impact of supplementing a Western diet with fish oil rich in DHA and EPA. Lipid classes, as well as the fatty acid composition -including PUFAs- of brain structures were differentially affected by the diets. At an equivalent dietary n-6/n-3 PUFA ratio (5:1), fish oil rich in EPA and DHA as the main source of dietary n-3 PUFAs did not increase brain DHA levels compared with intake derived solely from ALA in vegetable oils. Supplementation in EPA- and DHA-rich fish oil exerted a greater effect on cortical oxidative and inflammatory status than a high LA/ALA ratio. Further studies are needed to determine how these PUFA-associated alterations affect brain structure function and/or homeostasis.

Keywords:  Brain; Diet; Docosahexaenoic acid; Fatty acids; Lipids; Omega-3 PUFA; Omega-6 PUFA

DOI:  https://doi.org/10.1016/j.foodres.2026.119794
bioRxiv. 2026 Jul 28. pii: 2026.07.27.740601. [Epub ahead of print]

Progranulin deficiency perturbs lipid metabolism in white matter microglia.

Dahyun Yu, Ellen Armour, Sonnet Davis, Jung Suh, Matthew Simon, Jimei Tong, Gilbert Di Paolo, Leonard Petrucelli.

Progranulin (PGRN) deficiency is a common hallmark in frontotemporal dementia (FTD) patients with granulin ( GRN ) mutations (FTD- GRN ). Previous studies by our group and others have observed that reduced PGRN perturbs lysosomal function and microglial activation, which is believed to accelerate neurodegeneration in FTD- GRN patients. Lysosomal function is intrinsically linked to lipid metabolism, and evidence suggests that GRN deficiency can alter lipid profiles in the brain. Unfortunately, studies to date have focused on whole brain or cortical extracts, limiting our ability to assess cell type-dependent changes in lipid metabolism under disease conditions. Here, we employed lipidomic analysis specifically within the pontine microglia of Grn knock-out (KO) mice, a cell population that was previously linked to disease phenotypes in this model. We observed a significant reduction in the endolysosomal lipid bis(monoacylglycero)phosphate (BMP) and the lipid metabolite phosphatidylethanolamine (PE); these microglial-specific lipid alterations mirror previous whole-brain findings, suggesting that similar changes may occur across multiple cell types in the brain. We also detected a significant increase in the myelin-composing factor galactosylceramide (GalCer), which may reflect an aberrant accumulation of myelin debris within microglia that arises due to defective lysosomal clearance. Notably, lipid perturbations were exacerbated with age within Grn KO microglia, suggesting that changes in lipid metabolism are both age- and genotype-dependent in this model. Together, our results support our hypothesis that PGRN acts as a master regulator of critical microglial processes - including lysosomal function, lipid metabolism, and the regulation of myelination - in an age-dependent manner.

DOI: https://doi.org/10.64898/2026.07.27.740601
bioRxiv. 2026 Aug 04. pii: 2026.07.30.741628. [Epub ahead of print]

Recombinant sialylated ApoE2 suppresses ApoE4 and sex-specifically strengthens brain metabolism and cognition in ApoE4 mice.

Xin Zhang, Hee-Jung Moon, Teruna Siahaan, Liqin Zhao.

Human APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), whereas the relatively rare APOE2 confers exceptional protection. This study examines whether recombinant ApoE2 protein can therapeutically leverage this genetic advantage to strengthen aging brains at risk for AD. We produced recombinant human ApoE2 (rhApoE2) using the FreeStyle 293-F system, yielding rhApoE2 with extensive sialylation that closely resembles its natural form in the human brain. In ApoE4-knockin mouse primary neurons, exposure to rhApoE2 induced significant increases in hexokinase 2 expression and decreases in endogenous ApoE4 protein levels. rhApoE2 also protected ApoE4 neurons from oligomeric amyloid-β toxicity and oxidative stress. We further developed a cadherin-derived peptide (ADTC5) that transiently increases paracellular porosity of the blood-brain barrier, enabling safe, non-invasive delivery of rhApoE2 into the mouse brain. When co-administered with ADTC5, weekly intravenous doses of rhApoE2 for 4-8 weeks in middle-aged and aged ApoE4 mice enhanced synaptosomal glycolytic and exocytotic activities, promoted cortical lipid metabolic dynamics and DHA utilization, and improved learning and memory, with sex differences observed in some outcomes. These findings offer preliminary evidence supporting the therapeutic potential of human brain-like rhApoE2 sialoprotein, which enhances metabolic robustness and cognitive strength in aging ApoE4 brains, possibly modulated by sex.

DOI: https://doi.org/10.64898/2026.07.30.741628
Acta Physiol (Oxf). 2026 Sep;242(9): e70289

Written in the Stars: Astrocyte Biology From Evolution to Disease.

Carmen Falcone, Lutgarde Arckens, Monica Baiula, Andrea Bedini, Riccardo Bocchi, Matthew J Broadhead, Marco Caprini, Fabio Cavaliere, Fabrizia Cesca, Helena H Chowdhury, Katarzyna Ciuba, Laura Civiero, Carole Escartin, Stefano Ferroni, Francesco Formaggio, Angelisa Frasca, Rossella Gratton, Matthew Holt, Nunzio Iraci, Marko Kreft, Loredana Leggio, Annamaria Lia, Anna R Malik, Rogier Min, Franziska E Müller, Cahuê Murat, Maria João Pereira, Aleksandra Pekowska, Francesco Petrelli, Paula Ramos-Gonzalez, Maria V Sanchez-Mico, Zala Smole, Dimitra Sokolova, Maite Solas, Alessia Soldano, Lukasz Mateusz Szewczyk, Carola Torazza, Francesco Paolo Ulloa Severino, Nerea Urrestizala-Arenaza, Andre Zeug, Jiafeng Zhou, Micaela Zonta, Robert Zorec, Alexei Verkhratsky, Nilhan Gunhanlar.

  In the 21st century, neuroglial research has entered a period of Renaissance, extending the views of prominent neuroanatomists and neurologists of the 19th and early 20th centuries, who assigned to glial cells numerous physiological functions and highlighted their fundamental role in the pathophysiology of nervous system diseases. Astrocytes are highly diversified in structure and function; they control brain homeostasis, support synaptic connectivity, and enable information processing in neural networks. Evolutionary diversification of astrocytes, initially emerging as supportive cells of primitive sensory organs, drove a continuous expansion of astroglial complexity and functional versatility, ultimately making them indispensable neuroprotectors and homeostatic regulators. The large, morphologically elaborate astrocytes of the human brain arguably reflect an evolutionary response to increased neuronal homeostatic demands. Astrocytes are indispensable for synaptic function, serving as the principal regulators of neurotransmitter turnover and neuronal excitability. Astrocytes also govern brain energy metabolism, mitochondrial dynamics, and calcium signaling, thereby actively shaping cortical plasticity and circuits. Astrocytes are fundamental elements of the pathophysiology of neurological, neuropsychiatric, and neurodegenerative diseases, including Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, Rett syndrome, genetic astrocytopathies, and neurotrauma, where they demonstrate complex reactive changes directed at tissue preservation and regeneration, but which can also contribute to disease progression. Advances in single-cell transcriptomics, calcium imaging, chemogenetics, and iPSC-based models have transformed our understanding of astrocyte diversity and disease-specific dysfunction, opening new avenues of investigation. Given that no CNS disorder is known to occur without astrocyte involvement, multiple astrocyte-specific molecules represent compelling targets for cell-directed therapeutic strategies.

Keywords:  Alzheimer's disease; Parkinson's disease; Rett syndrome; amyotrophic lateral sclerosis; astrocytes; evolution; neurodegeneration; neuropathology; synaptic transmission

DOI:  https://doi.org/10.1111/apha.70289
J Mol Neurosci. 2026 Aug 15. pii: 130. [Epub ahead of print]76(3):

Restoration of Neuronal Metabolism and Memory in Alzheimer's Disease by Reprogramming the Exosomal microRNA Network.

Tarique Anwer, Ankit Verma, Abdulaziz Asiri, Mubarak Alaklobie, Abdullah Albaqami, Fahad Alshahrani, Khaled Aly, Manju Sharma, Shadma Siddiqui, Nawazish Alam, Mohammad Firoz Alam.

  Historically the development of amyloid-β plaques and tau neurofibrillary tangles have been used as the hallmarks of Alzheimer's disease (AD). However, there is increasing evidence suggests that these pathological hallmarks are secondary to deeper metabolic defect in the brain. AD is progressively being recognized as a metabolic synaptic disorder characterized by insulin resistance, impaired cellular energy homeostasis, mitochondrial dysfunction, and synaptic degeneration. Synaptic plasticity is closely linked to the insulin-sensitive system of glucose utilization, mitochondrial activity, and local protein synthesis that render the synapses highly sensitive to the malfunction of the metabolic system. Recent discoveries highlight the important role of exosomes in mediating communication between neural cells by transferring regulatory miRNAs across neuronal networks. Exosomal miRNAs regulate insulin signaling, synaptic gene expression, mitochondrial function, and neuroinflammation. In AD, exosomal miRNA profiles are significantly altered, with enrichment of miR-29, miR-34a, miR-146a, and miR-21, alongside depletion of synapse-supporting miR-132. These changes contribute to insulin resistance, impaired glucose transporter trafficking, dendritic spine destabilization, and reduced expression of synaptic proteins such as PSD-95 and synaptophysin, ultimately leading to cognitive decline. Importantly, neuron-derived exosomes can cross the blood-brain barrier, making their miRNA cargo promising biomarkers and therapeutic targets for early AD diagnosis and precision treatment.

Keywords:  Alzheimer’s disease; Exosomes; MicroRNAs; Neuronal insulin resistance; Synaptic plasticity

DOI:  https://doi.org/10.1007/s12031-026-02587-w
Methods Mol Biol. 2026 ;3035 263-368

Small-Scale Cell Biological Analysis of Lipid Rafts of Blood Platelets and Cerebellar Neurons.

Keisuke Komatsuya, Norihito Kikuchi, Tetsuya Hirabayashi, Kohji Kasahara.

  Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and proteins that can be stabilized into platforms involved in the regulation of various vital cellular processes. Here, we describe small-scale isolation methods of lipid rafts. Detergent-resistant membrane raft fraction is isolated by a volume of 0.8 mL sucrose density gradient centrifugation from blood platelets. Raft fraction is also isolated from cerebellar neurons by co-immunoprecipitation using anti-glycosphingolipid monoclonal antibodies.

Keywords:  Cerebellar neurons; Detergent-resistant membrane; Glycosphingolipids; Immunoprecipitation; Lipid rafts; Mass spectrometry; Platelets; Signal transduction; Sphingomyelin; Sucrose density gradient

DOI:  https://doi.org/10.1007/978-1-0716-5288-6_22
J Neural Transm (Vienna). 2026 Aug 17.

Serotonin deficiency caused by inactivation of Tph2 in mice leads to widespread sex-dependent changes in cerebral oxidative metabolic activity.

Pilleriin Kupper, Margus Kanarik, Marianna Norden, Angelika G Schmitt-Böhrer, Ruth Shimmo, Klaus-Peter Lesch, Jaanus Harro.

  Tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of serotonin synthesis in the CNS, has been associated with numerous behavioural traits and psychiatric disorders. Tph2 modified mice present altered sensitivity to stress, and excessively aggressive behaviour that develops even in female animals. We have measured histochemically the activity of cytochrome c oxidase (COX) in 106 brain regions in wildtype, Tph2 heterozygous and total knockout male and female mice (n=78). In addition to direct comparisons by sex and genotype, COX activity co-variation in putative aggression networks was examined. Overall, female mice have higher COX activity than males. In regions affected by Tph2 inactivation a consistent pattern emerged, where Tph2± mice had the lowest, Tph2-/- mice had the highest COX activities, and Tph2+/+ in-between. Tph2 inactivation induced broad changes and an extensive reorganisation of neural activity as revealed by regional activity co-variation matrices of COX. These patterns of inter-regional correlations differed between sexes. Co-variation of COX activity also differed between males and females in the proposed networks for aggressiveness. In male mice, Tph2 inactivation disrupted co-variation of COX activity of the dorsal raphe and the periaqueductal grey matter with limbic regions. The septum appears as a hub of altered connectivity in females but not in males. Serotonin deficiency is associated with altered regional neural activity patterns as revealed by COX histochemistry. These alterations are profoundly different in male and female mice, and suggest that serotonin plays a partly sex-dependent role in the regulation of behaviour.

Keywords:  Aggressive behaviour; Cytochrome oxidase histochemistry; KO mice; Oxidative metabolism; Serotonin deficiency; Sex differences; Tryptophan hydroxylase 2

DOI:  https://doi.org/10.1007/s00702-026-03265-2
ASN Neuro. 2026 ;18(1): 2717255

When Powerhouses Fail and Rust Takes Over: Primary Mitochondrial and Lipid Metabolism Failure with Secondary Iron Accumulation and Lipid Peroxidation in Neurodegeneration with Brain Iron Accumulation.

Aradhika Vijeev, Shaik Basha, Spandana S Nadig, Kripa Agarwal, Vibhuti Meharchandani, Aparna Ramakrishna Pai, Krishna Kishore Mahato.

  Neurodegeneration with brain iron accumulation (NBIA) comprises a genetically heterogeneous group of rare movement disorders characterized by progressive neurodegeneration and selective basal ganglia iron deposition. Recent discoveries have fundamentally reshaped the understanding of NBIA, indicating that defects in coenzyme A metabolism, mitochondrial bioenergetics, lipid remodeling, autophagy-lysosomal pathways, and ferroptosis precede and promote secondary iron dyshomeostasis rather than resulting from primary abnormalities in iron metabolism. This review integrates recent mechanistic and translational evidence (2020-2026) across both common and underrepresented NBIA subtypes, including pantothenate kinase-associated neurodegeneration, phospholipase A2-associated neurodegeneration, COASY protein-associated neurodegeneration, mitochondrial enoyl-CoA reductase protein-associated neurodegeneration, mitochondrial membrane protein-associated neurodegeneration, β-propeller protein-associated neurodegeneration, fatty acid hydroxylase-associated neurodegeneration, neuroferritinopathy, and mitochondrial DNA-associated forms. Unlike previous reviews, this synthesis consolidates findings from patient-derived induced pluripotent stem cell neuronal and glial models, compartment-specific iron localization, advanced neuroimaging biomarkers, and emerging therapeutic strategies within a unified mechanistic framework. Collectively, the evidence supports a paradigm in which mitochondrial dysfunction and lipid metabolic failure initiate disease progression, whereas iron accumulation amplifies oxidative injury and lipid peroxidation, thereby increasing ferroptotic cell death and neuronal degeneration, providing an updated foundation for biomarker discovery, mechanistically informed therapeutic development, and precision medicine approaches in NBIA.

Keywords:  Coenzyme A metabolism; ferroptosis; mitochondrial dysfunction; neurodegeneration with brain iron accumulation (NBIA); precision medicine

DOI:  https://doi.org/10.1080/17590914.2026.2717255
Front Cell Neurosci. 2026 ;20 1913984

Mitochondrial dysfunction in intracerebral hemorrhage: molecular mechanisms and pathological consequences.

Tong Chen, Xu Gao, Yuhao Chang, Bin Wang, Zhouying Shi, Haiyue Xu, Yue Yuan, Fan Li, Ping Li.

  Intracerebral hemorrhage (ICH) carries high rates of disability and mortality, with a poor prognosis largely attributable to secondary brain injury (SBI). Mitochondria, a central hub for cellular redox regulation and energy metabolism, are not only affected by SBI but can also, once dysfunctional, initiate and exacerbate SBI. In this review, we classify post-ICH mitochondrial dysfunction into three major categories: excessive accumulation of mitochondrial reactive oxygen species, dysregulation of energy metabolism, and dysregulation of mitochondrial quantity and quality control. We delineate the molecular mechanisms and pathological consequences of each. Furthermore, given the extensive crosstalk between mitochondrial dysfunction and diverse forms of cell death in ICH (e.g., apoptosis, necrosis, necroptosis, ferroptosis, and pyroptosis), we discuss their mechanistic links. Overall, this review proposes a mitochondria-centered framework and emphasizes crosstalk between different types of dysfunction, thereby advancing our understanding of SBI pathophysiology after ICH and providing a systematic perspective on therapeutic strategies aimed at restoring mitochondrial homeostasis.

Keywords:  cell death; intracerebral hemorrhage; mitochondrial dysfunction; mitochondrial quality control; mitochondrial reactive oxygen species; secondary brain injury; stroke

DOI:  https://doi.org/10.3389/fncel.2026.1913984
bioRxiv. 2026 Aug 05. pii: 2026.07.31.742028. [Epub ahead of print]

Isoflurane and surgery aggravate APOE4-dependent lipid dysregulation and neural dysfunction, leading to neurological impairment in male mice.

Yun Li, Yuanyuan Ji, Cosar Uzun, Syed Taufiqul Islam, Meigeng Hu, Dan Zhao, Yaping Li, Hangnoh Lee, Zihui Wang, Hui Li, Jace W Jones, Shaolin Liu, Junfang Wu.

Purpose: Perioperative exposure to the volatile anesthetic isoflurane (ISO) has been associated with cognitive and olfactory deficits and may increase the risk of Alzheimer's disease (AD). Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, contributes to disease pathogenesis through disrupted lipid homeostasis. However, whether and how isoflurane interacts with APOE genotype to influence neurological vulnerability remains unclear.
Methods: Young adult, presymptomatic humanized APOE4 and APOE3 knock-in mice underwent laparotomy under 2 h of isoflurane anesthesia. Microglia and astrocytes were isolated from the olfactory bulb (OB) and hippocampus (HI) by magnetic-activated cell sorting. Lipid composition, transcriptional responses, and functional outcomes were assessed using lipidomic, bulk RNA-seq, and longitudinal behavioral testing. In vivo and ex vivo electrophysiological recordings evaluated neuronal excitability and synaptic transmission in both regions.
Results: By day 7 post-anesthesia, cell type-specific lipidomic profiling of both OB and HI revealed more pronounced lipid perturbations in microglia and astrocytes from APOE4/ISO mice than from APOE3 mice, characterized by elevated free fatty acids, increased lipid peroxidation, triglyceride depletion, and reduced hippocampal hexosylceramides and cardiolipins. Electrophysiological recordings showed greater olfactory circuit dysfunction in APOE4/ISO mice, accompanied by persistent odor memory deficits, transient olfactory sensitivity loss, early motor coordination impairments, and delayed cognitive deficits. RNA sequencing of the OB identified downregulated lipid metabolism and atherosclerosis-related pathways.
Conclusion: These findings establish a mechanistic link between APOE4-dependent glial lipid dysregulation, olfactory circuit dysfunction, and delayed cognitive impairment following isoflurane anesthesia and surgery, highlighting lipid homeostasis as a potential therapeutic target.

DOI: https://doi.org/10.64898/2026.07.31.742028
Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2530122123

Tmem117, an oligodendrocyte-enriched regulator of NCX activity, links myelin homeostasis to counterregulation and metabolic health.

Melvin Alappat, Marta Anna Mazurkiewicz, Iris Zambounis, Alice Mastrangelo, Vicente Mario Algaba Martínez, Thomas Grampp, Francesco Prisco, Anja Kipar, Alexandre Picard, Musadiq A Bhat, Dietmar Benke, Hanns Ulrich Zeilhofer, Bernard Thorens, Sevasti Gaspari.

  The counterregulatory response (CRR) to hypoglycemia-critically depending on pancreatic glucagon secretion-is a fundamental, evolutionarily conserved homeostatic mechanism orchestrated by the central nervous system (CNS) to ensure survival during glucose scarcity. Tmem117 was previously identified in a genetic screen as a potential hypothalamic regulator of CRR. Here, we reveal that Tmem117 is enriched in cells of the oligodendrocytic lineage and we characterize the contribution of oligodendrocytic Tmem117 in CRR. We show that depletion of Tmem117 from either all oligodendrocyte lineage cells or only mature oligodendrocytes leads to myelin deficits and male-specific defects in CRR. Furthermore, we reveal that transient, adult-onset depletion of Tmem117 in mature oligodendrocytes is sufficient to induce long-lasting metabolic imbalances in male mice, suggesting that defects in oligodendrocytes and myelin can affect peripheral glucose homeostasis. Mechanistically, we provide insights on the molecular mechanism of action of Tmem117 showing that it regulates intracellular calcium dynamics through its interaction with the sodium-calcium exchanger NCX1. Together, these results redefine our understanding of the cellular contributors to the CRR, highlight the importance of oligodendrocytes in systemic glucose regulation, and position Tmem117 as a promising molecular target for cell-specific manipulation of sodium-calcium exchanger (NCX) activity.

Keywords:  counterregulatory response; myelin; ncx1; oligodendrocytes; tmem117

DOI:  https://doi.org/10.1073/pnas.2530122123
J Lipid Res. 2026 Aug 20. pii: S0022-2275(26)00156-2. [Epub ahead of print] 101126

Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.

Pieter R Norden, Riley J Wedan, Abigail E Ellis, Madeleine L Hart, Megan R Gendjar, Morgan T Canfield, Ryan D Sheldon, Sara M Nowinski.

α-Lipoic acid (LA) is widely included in "mitochondrial cocktails" recommended to patients with primary mitochondrial disorders, yet its mechanism of action remains unclear. Here, we define the intracellular availability and functional utilization of LA in mammalian cells. We show that under typical culture conditions, free LA is near-completely absent in cells. Rather, any LA generated through mitochondrial fatty acid synthesis (mtFAS) remains in a protein-bound pool, as disruption of the mtFAS pathway does not alter free LA levels despite strong loss of protein lipoylation. Conversely, supplementation with exogenous LA markedly increases free intracellular LA in both control and mtFAS-deficient cells, but is incapable of restoring protein lipoylation, mitochondrial respiration, or cell proliferation in the absence of mtFAS. Instead, the cellular effects of LA supplementation resemble those of the antioxidant N-acetylcysteine. These findings clarify the mechanism of action of a widely used mitochondrial supplement and identify a fundamental disconnect between cellular LA abundance and mitochondrial utilization, challenging the rationale for using LA supplementation to restore mitochondrial function.

DOI: https://doi.org/10.1016/j.jlr.2026.101126
J Alzheimers Dis. 2026 Aug 21. 13872877261478594

The role of microglia glucose metabolism reprogramming in Alzheimer's disease treatment.

Qingyu Cao, Mengmeng Shen, Yan Liu, Caicai Li, Lu Liu, Jidong Zhou, Rujing Yue, Dejun Niu, Yayun Ren, Lihong Pan, Jingchun Yao, Guimin Zhang.

  Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment, and there remains a lack of effective treatments capable of reversing or significantly slowing disease progression. Accumulating evidence indicates that the immune function of microglia, the resident immune cells of the central nervous system, is a critical factor in regulating AD pathogenesis. Emerging research in immunometabolism further reveals that glucose metabolic reprogramming serves as a central driver of microglial phenotypic and functional differentiation. This review systematically outlines the fundamental characteristics of microglial glucose metabolism and focuses on how the dynamic metabolic reprogramming it undergoes during AD progression regulates microglial immune behavior and inflammatory responses. Building on this, we further summarize key regulatory targets within the "metabolism-immune axis" and corresponding pharmacological intervention strategies. Finally, this article discusses current challenges and future research directions in the field of microglial immunometabolism. This review aims to provide a theoretical foundation for AD intervention strategies targeting the "metabolism-immune axis" and to offer insights for the development of novel disease-modifying therapeutics.

Keywords:  Alzheimer's disease; glucose metabolism; immune function; key targets; microglia

DOI:  https://doi.org/10.1177/13872877261478594
J Huntingtons Dis. 2026 Aug 17. 18796397261478163

Mitochondrial dynamics in Huntington's disease.

Beatriz Paiva, Ana Cristina Rego.

  Emerging evidence suggests a central and early role of mitochondrial dysfunction, including altered mitochondrial dynamics, in Huntington's disease (HD) pathogenesis. Processes such as mitochondrial fission, fusion, transport and mitophagy are vital for proper mitochondrial function and seem to be key mediators of neuronal vulnerability in HD. In this review, we summarize mechanistic insights into mitochondrial dynamics in HD, highlighting how mutant huntingtin (mHTT) impairs mitochondrial biogenesis and morphology, disrupts Drp1-dependent fission, compromises fusion, transport and organelle crosstalk with the endoplasmic reticulum, and disrupts mitochondrial quality control, ultimately leading to neuronal degeneration. Since these alterations correlate with bioenergetic deficits, calcium dysregulation and oxidative stress, we highlight how altered mitochondrial dynamics contribute to and possibly drive HD pathogenesis. Furthermore, we discuss how mitochondrial dynamics in HD can be altered based on cell type specificity, experimental model and disease stage.

Keywords:  mitochondria; mitophagy; neurotoxicity; pathogenic mechanisms; preclinical models

DOI:  https://doi.org/10.1177/18796397261478163
Psychiatr Danub. 2026 04;38(2): 147-154

Mitochondrial dysfunction in schizophrenia and psychotic disorders: Implications for antipsychotic drug mechanisms.

Svjetlana Loga-Zec, Aleksandra Klobučar, Orhan Lepara, Gorana Sulejmanpašić, Amra Memić-Serdarević, Nataša Loga-Andrijić.

   BACKGROUND: Schizophrenia (SCH) is a severe neuropsychiatric disorder associated with complex neurobiological alterations and suboptimal therapeutic outcomes. Increasing evidence indicates that mitochondrial dysfunction may contribute to SCH pathophysiology through impaired energy metabolism, oxidative stress, altered calcium homeostasis, and dysregulation of neuronal function. This review aims to summarize current knowledge regarding mitochondrial abnormalities in schizophrenia and to explore their potential involvement in the mechanisms of action of antipsychotic drugs.
SUBJECTS AND METHODS: A comprehensive review of the current literature was performed, focusing on human studies, cellular and animal models investigating mitochondrial alterations in schizophrenia, as well as studies evaluating the effects of antipsychotic medications on mitochondrial structure and function.
RESULTS: Available evidence demonstrates structural, molecular, and functional mitochondrial abnormalities in schizophrenia, including alterations in mitochondrial density, respiratory chain activity, oxidative phosphorylation, ATP production, and redox regulation. Antipsychotic drugs influence mitochondrial pathways in a complex and drug-specific manner. Some antipsychotics may impair mitochondrial respiration and increase oxidative stress, whereas others may exert compensatory or protective effects. Mitochondrial alterations may also contribute to cognitive impairment, negative symptoms, treatment response variability, and metabolic adverse effects associated with antipsychotic therapy.
CONCLUSIONS: Mitochondrial dysfunction represents an important component of schizophrenia pathophysiology and a potential therapeutic target. The interaction between mitochondrial pathways and antipsychotic drug effects highlights mitochondria as a possible pharmacodynamic interface for personalized treatment strategies. Further in vivo studies and biomarker-based approaches are required to clarify drug-mitochondria interactions and improve therapeutic outcomes in schizophrenia.

Keywords:  Schizophrenia; antipsychotic drugs; energy metabolism; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.24869/psyd.2026.147
Methods Enzymol. 2026 ;pii: S0076-6879(26)00157-6. [Epub ahead of print]733 111-142

Sirtuins in mitochondrial physiology and energy homeostasis.

Arshdeep Kaur, Ullas Kolthur Seetharam.

  Mitochondrial sirtuins integrate cellular metabolic and energetic state with post-translational regulation of mitochondrial proteins, thereby influencing bioenergetics, redox homeostasis, and metabolic flexibility. Despite extensive study of individual sirtuins, a comprehensive understanding of their function remains limited by methodological and conceptual challenges. These arise from the complex metabolic environment in which mitochondrial sirtuins act, including compartmentalized NAD+ pools, metabolite-driven non-enzymatic acylation, overlapping substrate specificities, and limited tools to accurately characterize enzyme-specific activity, particularly for SIRT4. This review aims to highlight current experimental approaches used to study mitochondrial sirtuins, and the need to integrate enzymatic measurements with metabolic and physiological readouts. We discuss the importance of considering mitochondrial spatial heterogeneity within cells, tissue-specific metabolic context, and temporal dynamics of metabolic state when interpreting sirtuin activity. Recent advances in quantitative proteomics, metabolite profiling, and mitochondria-specific analyses provide new opportunities to resolve these complexities. Moving forward, integrating these approaches with a systems-level and quantitative framework will be critical to fully understand how mitochondrial sirtuins orchestrate metabolic regulation across cellular and organismal scales.

Keywords:  Enzyme kinetics; NAD(+) metabolism; Sirtuin activity; Spatio-temporal

DOI:  https://doi.org/10.1016/bs.mie.2026.05.029
Res Sq. 2026 Jul 27. pii: rs.3.rs-10221033. [Epub ahead of print]

Adenylosuccinate acts as a novel pro-angiogenic factor.

Brennon Schofield, Drew Seeger, Derek Besch, Peddanna Kotha, Svetlana Golovko, Bryon Grove, Anahita Mansouripour, Meredith Parmer, Shahram Solaymani-Mohammadi, Mikhail Golovko.

We recently demonstrated a dramatic 77-fold increase in brain adenylosuccinate (AdSucc) concentration during ischemia, reaching ~0.56 mM levels. Previously, the role of AdSucc induction under decreased energy charge was attributed to the activation of purine nucleotide (PNC) and the tricarboxylic acid cycle (TCA). However, careful analysis of metabolomic alterations in the ischemic brain under decreased energy charge did not confirm this role. To begin addressing the additional biological significance of the increased AdSucc under low-energy conditions associated with ischemia, we tested its angiogenic properties. Using a mouse in vivo angiogenesis assay, we discovered that AdSucc, but not its metabolites such as adenosine or AMP accumulated during the assay, promotes angiogenesis in vivo at concentrations found in ischemic tissues. Further, using in vitro angiogenesis assay with human umbilical vein endothelial cells (HUVEC), we demonstrated that AdSucc promotes the formation of capillary-like structures (tubes) on extracellular matrix support. We also report, for the first time, that AdSucc increases cAMP levels, supporting its signaling role, which may be linked to pro-angiogenic mechanisms. Together, our data indicate a novel mechanism of angiogenesis regulation, in which AdSucc may serve as a new signaling molecule under low-energy conditions. Further studies are required to confirm the role of endogenously produced AdSucc in tissue angiogenesis as an adaptation mechanism to low-energy conditions and repair after injury.

DOI: https://doi.org/10.21203/rs.3.rs-10221033/v1
Neurochem Res. 2026 Aug 21. pii: 241. [Epub ahead of print]51(5):

NOTCH3 Mutations in CADASIL Alter Lipid Metabolism: Insights from Patient Plasma and In Vitro Models.

Ruihua Sun, Xiaoyi Ji, Wenjian Hu, Wanyue Li, Ying Zhao, Wan Wang, Yaru Lu, Anqi Li, Yifan Huang, Jiewen Zhang.

  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common monogenic form of cerebral small vessel disease (CSVD), is caused by mutations in NOTCH3. However, the effects of NOTCH3 mutations on lipid metabolism remain poorly understood. In this study, plasma samples from CADASIL patients and matched healthy controls were subjected to lipidomic analysis. Stable 293T cell lines expressing an empty vector (NC), wild-type (WT) NOTCH3, or CADASIL-associated NOTCH3 mutants (R110C, R133C, R1175W, and R544C), as well as hCMEC/D3 cell lines expressing NC, WT, or R544C, were established to investigate lipid metabolic alterations. Lipid droplet (LD) accumulation, cholesterol levels, and the expression of cholesterol transport-related molecules were assessed. Lipidomic profiling revealed significant alterations in plasma lipid profiles in CADASIL patients compared with healthy controls. In 293T cells, LD accumulation was significantly increased in the R110C, R1175W, and R544C groups, but not in the R133C group, whereas cholesterol levels were elevated in all mutant groups. In hCMEC/D3 cells, expression of the R544C mutant markedly promoted cholesterol accumulation and reduced the expression of the cholesterol transporters ABCA1 and ABCG1. These findings indicate that NOTCH3 mutations are associated with disrupted cellular lipid homeostasis and suggest that lipid metabolic dysregulation may represent a potential mechanism contributing to CADASIL pathogenesis.

Keywords:   NOTCH3 ; CADASIL; Cholesterol; Lipid

DOI:  https://doi.org/10.1007/s11064-026-04866-9
bioRxiv. 2026 Jul 30. pii: 2026.07.29.741559. [Epub ahead of print]

Loss of neurofibromin alters adult metabolism via effects during a developmental critical period.

Catherine Steele, Ryan Weaver, Seth M Tomchik.

Metabolic alterations commonly accompany neurodevelopmental disorders and may contribute to their pathophysiology. Neurofibromatosis type 1 (OMIM 162200) is a genetic disorder that results from mutations in the NF1 gene and its encoded neurofibromin protein (Nf1). The disorder is multisystemic, affecting multiple aspects of development, physiology, and brain function. In addition, recent evidence suggests that Nf1 deficiency alters metabolic function in both humans and animal models. Whether the metabolic alterations result from changes in neurodevelopment is not known. Here we approach this question in Drosophila melanogaster , which expresses a conserved NF1 gene, exhibits phenotypes reminiscent of the human disease, and shares key developmental mechanisms with humans. Flies with nf1 mutations or RNAi-mediated knockdown exhibit altered metabolism in adulthood. Conditional Nf1 inactivation revealed that the adult metabolic phenotype resulted from loss of Nf1 in neurons during a developmental critical period (third instar larva/pupa), which corresponded to the period of nervous system maturation. Prior to the developmental critical period, nf1 mutants did not exhibit metabolic difference - rather, the metabolic alterations appeared only after the critical period. This suggests that the adult phenotype results from the onset of the developmental alteration during the critical period. High-resolution respirometry on adult mitochondria revealed no differences in complex I/II function or fatty acid oxidation between nf1 mutants and controls, suggesting that the metabolic alterations localize upstream of the electron transport chain at the cellular level. Overall, these data suggest that loss of Nf1 alters adult metabolism via effects during a critical period of nervous system development.

DOI: https://doi.org/10.64898/2026.07.29.741559