bims-medebr 2026-09-13 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–09–13
fourteen papers selected by
Regina F. Fernández, Johns Hopkins University

Lactate as a metabolic-epigenetic hub in neurological disorders.
A Novel Reporter Mouse for Astrocyte-Derived Extracellular Vesicles Reveals Enrichment of Cargo at Neuronal Mitochondria.
Anesthesia, perimortem conditions, and brain harvest method govern the measured metabolome: analysis of substandard samples generates flawed metabolite levels.
From physiological homeostasis to pathological injury: Cell-specific functions, imbalance mechanisms, and disease biomarker value of brain lipid droplets.
Apolipoprotein E in spinal cord injury: mechanisms of lipid dysregulation, neuroinflammation, and opportunities for repair.
Astrocyte-microglia lactate shuttle restrains microglial phenotypic transition during myelin phagocytosis in radiation-induced brain injury.
Maternal Diet Enrichment in n-3 Long-Chain Polyunsaturated Fatty Acids during Pregnancy and Lactation Improves Their Transfer from the Mother to the Offspring and Counterbalances High-Fat Diet-Induced Alterations in a Sex-Dependent Manner in Rats.
Acetyl-CoA-dependent processes are preferentially supported by local metabolite synthesis.
Distinct Urea Cycle Dysfunction Profiles Differentiate Acute Metabolic Decompensation in TMEM70 and MT-ATP6-Related Mitochondrial ATP Synthase Defects.
ENT1 inhibition links oligodendrocyte lipid metabolism to connectivity in tauopathy.
The effect of ketamine on mitochondrial bioenergetics, viability, and function: A systematic review.
A Lactate-H4K12la-HDAC1 epigenetic axis governs microglial state transitions during experimental autoimmune encephalomyelitis in female mice.
Neuronal monocarboxylate transporter 2 is downregulated and aggravates seizures in a rat model of infantile epileptic spasms.
Rotenone-induced oxidative stress triggers peroxisomal alterations in BV-2 microglial cells.

Metab Brain Dis. 2026 Sep 10. pii: 213. [Epub ahead of print]41(1):

Lactate as a metabolic-epigenetic hub in neurological disorders.

Yu Gu, Potao Zhang, Chunyan Lei.

  Lactate, once considered merely a metabolic waste product of glycolysis, has emerged as a pivotal signaling molecule that bridges cellular metabolism and epigenetic regulation in the central nervous system. The discovery of protein lactylation in 2019 revealed a novel post-translational modification that directly linked lactate accumulation to changes in gene expression, fundamentally reshaping our understanding of how metabolic states influenced neural function and dysfunction. This comprehensive review synthesizes recent advances in lactate biology, encompassing the expanding enzymatic landscape of lactylation-including newly identified writers, erasers, and readers-and their roles in neurodegenerative diseases. We critically re-examine metabolic coupling models beyond the classical astrocyte-neuron lactate shuttle (ANLS), incorporating neuronal glycolytic capacity, oligodendrocyte-specific relay mechanisms, and cell type-specific monocarboxylate transporter (MCT) expression patterns. Furthermore, we explore the concentration-dependent duality of lactate effects through G protein-coupled receptor 81 (GPR81)/hydroxycarboxylic acid receptor 1 (HCAR1) signaling, the functional significance of non-histone lactylation in neural cells, and the interplay between lactylation and mitochondrial quality control, ferroptosis, and adult hippocampal neurogenesis. Finally, we discuss emerging therapeutic strategies targeting lactate metabolism and lactylation modifications -ranging from lactate dehydrogenase (LDH) inhibitors and MCT modulators to exercise-induced neuroprotection-and identify critical challenges for clinical translation. By integrating these cutting-edge findings, we provide an updated theoretical framework that positions lactate as a central node connecting metabolic reprogramming with epigenetic dysregulation in neurodegeneration.

Keywords:  Epigenetic regulation; Lactate; Metabolic reprogramming; Neurodegenerative diseases; Protein lactylation

DOI:  https://doi.org/10.1007/s11011-026-01984-9
FASEB J. 2026 Sep 30. 40(18): e72260

A Novel Reporter Mouse for Astrocyte-Derived Extracellular Vesicles Reveals Enrichment of Cargo at Neuronal Mitochondria.

Xiaojia Ren, Zainuddin Quadri, Zhihui Zhu, Xu Fu, Liping Zhang, Erhard Bieberich.

  Extracellular vesicles (EVs) mediate intercellular transfer of lipids, proteins, and nucleic acids between cell types. We previously showed that astrocyte-derived EVs modulate neuronal mitochondria in vitro. Whether endogenous astrocytic EVs associate with neuronal mitochondria in vivo remained unknown. To address this, we generated an EV reporter mouse, Aldh1l1-Cre; CD9-tGFPfl/fl, which resulted in fluorescent labeling of astrocyte-derived CD9-positive EVs. Astrocyte-specific expression of CD9-tGFP was verified in brain tissue, where CD9-tGFP-positive particles comprised 13.2% ± 1.6% of total isolated EVs. In primary glial cultures, CD9-tGFP was restricted to astrocytes, localizing to vesicular compartments and cell protrusions (filopodia and cilia); 89.3% ± 2.2% of astrocyte-derived EVs were CD9-tGFP positive. In cortex, hippocampus, and cerebellum, CD9-tGFP was predominantly detected in astrocytic processes co-labeled with glutamate aspartate transporter 1 (GLAST1) and glial fibrillary acidic protein (GFAP), forming contacts with laminin-positive capillaries and parvalbumin-positive neurons. CD9-tGFP-labeled EVs were detected at capillaries and inside neurons, and STED microscopy revealed partial co-localization with neuronal mitochondria. Live-cell spinning disk confocal imaging and AI-assisted proximity analysis confirmed uptake of CD9-tGFP EVs by neuronal cells and cargo enrichment at mitochondria in vitro. Immunoblotting and imaging of isolated mitochondria established physical association with EV-derived CD9-tGFP in vivo, with 3-fold higher CD9-tGFP puncta density on synaptic mitochondria. Together, these findings validate the Aldh1l1-Cre; CD9-tGFPfl/fl reporter mouse as a tool for tracking astrocyte-derived EVs in vivo and provide evidence of preferential cargo enrichment at synaptic mitochondria.

Keywords:  CD9‐turboGFP; EV reporter mice; astrocyte; extracellular vesicles (EVs); mitochondria; tetraspanins

DOI:  https://doi.org/10.1096/fj.202602265R
Oxf Open Neurosci. 2026 ;5 kvag011

Anesthesia, perimortem conditions, and brain harvest method govern the measured metabolome: analysis of substandard samples generates flawed metabolite levels.

Gerald A Dienel.

  Metabolism and energetics are closely integrated with brain function, and understanding how metabolic dysfunction contributes to neurological disease may help improve therapeutic approaches. Characterization of in situ metabolite levels, spatial distributions, and metabolomes requires special attention to anesthesia use, perimortem conditions, and tissue harvest. Anesthesia, CO2 asphyxiation, vascular perfusion, and decapitation alter metabolism, thereby substantially changing the metabolome, lipidome, and neurotransmitter profile. Analysis of flawed samples produces artifactual data, raising concerns about conclusions regarding the cellular basis of metabolism, metabolite shuttling, pathway activities, labeled metabolite profiling and imaging, and relationships between metabolism, function, and neurological disorders. Appropriate procedures for in vivo metabolic assays and tissue harvest are widely-unrecognized but essential components of metabolic and metabolomic studies.

Keywords:  Alzheimer’s disease; Postmortem ischemia; [13c]glucose metabolite profiling; brain harvest; metabolome; neuronal glycolytic upregulation

DOI:  https://doi.org/10.1093/oons/kvag011
Int Immunopharmacol. 2026 Sep 10. pii: S1567-5769(26)01210-5. [Epub ahead of print]189 117363

From physiological homeostasis to pathological injury: Cell-specific functions, imbalance mechanisms, and disease biomarker value of brain lipid droplets.

Qing Zhang, Xiaolin Liu, Le Shi, Yanyu Xu, Xinran Zhang, Jingjing Liu, Qiaoqiao Li, Qinglu Wang, Lijiao Fang.

  Lipid droplets (LDs) are versatile cellular structures that consist of a core made of neutral lipids, surrounded by a monolayer of phospholipid membrane. Beyond energy storage, LDs serve as critical immunometabolic platforms that govern microglial activation states and neuroinflammatory cascades. Their formation and function are regulated by specific proteins, making them key carriers for maintaining brain energy metabolism and lipid homeostasis. This article systematically reviews the research progress in the field of brain LDs: it clarifies the core biogenesis mechanisms, including endoplasmic reticulum (ER) membrane curvature and sequentially coordinated independent functions of ER-localized Berardinelli-Seip congenital lipodystrophy type 2 protein (Seipin) and fat storage-inducing transmembrane protein 2 (FIT2), as well as their dual physiological roles as energy reserves and lipid buffers; it systematically characterizes widespread LD distribution across nearly all physiological central nervous system(CNS) cell populations, with prominent cell-type heterogeneity in LD abundance, neutral lipid composition and metabolic turnover dynamics noting that the formation, metabolic state, and stress response of LDs are closely related to different cell types; it analyzes how the imbalance between LD synthesis and turnover drives microglia-mediated neuroinflammation and lipotoxicity across neurodegenerative diseases (NDDs), ischemic stroke, gliomas, and CNS infections. We specifically highlight the cell-type-specific and disease-stage-dependent pharmacological modulation of LD pathways-such as Adipose triglyceride lipase (ATGL)/diacylglycerol acyltransferase (DGAT)-directed lipolysis/lipogenesis and TREM2-mediated immunometabolic reprogramming-as a stratified strategy to suppress pathological neuroinflammation while preserving physiological lipid buffering, confirming that abnormal LDs are important triggers and markers of brain diseases. Abnormal LDs trigger microglia-mediated neuroinflammation, which serves as a key link in the progression of brain diseases such as Alzheimer's disease (AD). Finally, it points out core unresolved issues such as the interaction between LDs and cellular signaling networks, and the functional heterogeneity of brain regions. This review integrates 2024-2026 in vivo imaging and multi-omic data, taking lineage-unified quantitative comparison of cell-type LD heterogeneity as the core analytical framework. On this basis, it systematically elaborates the closed-loop metabolic network of LD synthesis, lipolysis and lipophagy, summarizes the load-dependent biphasic regulatory mechanism of LDs across multiple CNS disorders, and further constructs an immunopharmacology-centered translational system: we clarify how dysregulated lipid metabolism drives microglial innate neuroinflammation, and sort out cell- and stage-selective ATGL/DGAT druggable targets together with cell-specific LD pathological biomarkers, which fills the fragmented discussion gap of existing neuro-lipid reviews.

Keywords:  Brain lipid droplets; Lipid homeostasis; Microglia; Neuroinflammation; Pharmacological targets

DOI:  https://doi.org/10.1016/j.intimp.2026.117363
Pharmacol Ther. 2026 Sep 09. pii: S0163-7258(26)00149-X. [Epub ahead of print] 109122

Apolipoprotein E in spinal cord injury: mechanisms of lipid dysregulation, neuroinflammation, and opportunities for repair.

Ciara M Walsh, Maria S Ioannou, Faith H Brennan.

  Traumatic spinal cord injury (SCI) is a devastating condition that affects millions of people worldwide and remains without effective pharmacological therapies that substantially improve neurological recovery. A major barrier to repair is the persistent secondary neuroinflammatory response that evolves over weeks to months after injury. Although neuroinflammation represents an attractive therapeutic target, broadly acting immunosuppressive approaches have yielded limited clinical benefit, highlighting the need to identify mechanisms that drive detrimental inflammation while preserving beneficial immune functions that support repair. Emerging evidence identifies dysregulated lipid handling as one such mechanism. SCI generates a substantial lipid burden through myelin and cellular breakdown, while lipidomic and metabolomic studies reveal persistent, dynamic alterations in lipid processing, storage, and transport. The capacity of resident glia and infiltrating immune cells to manage this lipid burden has important consequences for inflammatory state and tissue repair. Apolipoprotein E (ApoE), a major regulator of lipid transport and redistribution in the central nervous system, lies at the intersection of these processes, linking lipid metabolism with neuroinflammation and recovery after SCI. Here, we critically evaluate ApoE biology and its relationship to lipid dysregulation after SCI, together with preclinical evidence targeting ApoE-associated and broader lipid-regulatory pathways, including ApoE mimetics, LXR/RXR and PPARγ signaling, and statins. We distinguish demonstrated therapeutic mechanisms from proposed ApoE-dependent effects and evaluate emerging clinical evidence for lipid-modifying interventions in SCI. Finally, we consider key barriers to translation, including injury heterogeneity, sex, age and ApoE genotype, therapeutic timing and delivery, and the integration of lipid-directed interventions into multimodal strategies for SCI repair. Together, current evidence positions lipid dysregulation as an important and potentially tractable component of SCI pathogenesis, while defining the studies needed to establish the contribution of ApoE-directed and broader lipid-modifying strategies to neurological repair.

Keywords:  ApoE; Apolipoprotein E; Demyelination; Lipid metabolism; Macrophage; Microglia; Neurodegeneration; Neuroinflammation; Neurotrauma; Spinal cord injury

DOI:  https://doi.org/10.1016/j.pharmthera.2026.109122
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag215

Astrocyte-microglia lactate shuttle restrains microglial phenotypic transition during myelin phagocytosis in radiation-induced brain injury.

Rong Li, Anbang Ren, Weirui Chen, Anan Xu, Haifeng Jian, Weilan Zeng, Guixiang Liao, Jie Lin, Yuchao Wu, Ronghui Zheng, Laiji Huang, Kai Liao, Guo Yin, Yawei Yuan.

   Background: Radiation-induced brain injury (RBI) is a serious sequela in long-term survivals of patients with brain tumors or nasopharyngeal carcinoma after receiving radiotherapy. The role of multiple glial cell types in driving major RBI pathologies remains largely unclear.
Methods: The late-phase radiation response in mouse brain was profiled and analyzed using bulk tissue RNA-sequencing and single-nucleus mRNA sequencing (snRNA-seq). Glia crosstalk was investigated by using primary culture and co-culture.
Results: We found substantial loss of mature oligodendrocytes and microglia-derived neuroinflammation as 2 major features in late phase of RBI. Loss of oligodendrocytes coincides with the emergence of a radiation-induced reactive microglial subpopulation (RRM_1) characterized by enhanced phagocytosis activity, specialized for myelin debris clearance. Myelin debris phagocytosis induces a M2-to-M1 phenotypic transition in irradiated microglia. Astrocyte-microglia lactate shuttle (AMLS), mediated by monocarboxylate transporters (MCT4/MCT1), suppresses M1-like polarization of microglia. M2-like phenotype could be enhanced by secreted secreted phosphoprotein 1 (SPP1) via boosting AMLS.
Conclusions: Taken together, we found demyelination and neuroinflammation are two intimately related features in irradiated brain. Microglia and astrocyte collectively contribute to tissue homeostasis by stably scavenging myelin/cellular debris. Our data reveal a correlative glial metabolic cascade (oligodendrocytes, microglia, and astrocytes) linked to chronic neuroinflammation. These findings provide new insights into therapeutic strategies for RBI.

Keywords:  lactate; monocarboxylate transporter; myelin; phenotype transformation; radiation-induced brain injury

DOI:  https://doi.org/10.1093/noajnl/vdag215
Curr Dev Nutr. 2026 Sep;10(9): 109508

Maternal Diet Enrichment in n-3 Long-Chain Polyunsaturated Fatty Acids during Pregnancy and Lactation Improves Their Transfer from the Mother to the Offspring and Counterbalances High-Fat Diet-Induced Alterations in a Sex-Dependent Manner in Rats.

Valentine S Moullé, Agnès David-Sochard, Blandine Castellano, Isabelle Grit, Alexis Gandon, Jean-Charles Martin, Patricia Parnet.

   Background: Low birth weight (LBW) increases the risk of developing metabolic disorders in adulthood and reduces fatty acid (FA) brain accretion in offspring in rodent models. As milk composition is partially influenced by maternal diet, it is conceivable to act on maternal diet to improve FA brain accretion and development in offspring.
Objectives: The study aimed to evaluate the impact of n-3 long-chain polyunsaturated FA (LCPUFA) deficiency or enrichment in the maternal diet during gestation and lactation on maternal diet on milk composition, offspring brain lipids, and the potential to counterbalance the effects of a high-fat diet (HFD).
Methods: We investigated the influence of n-3 LCPUFA-deficient and -enriched maternal diets, as well as HFD challenge, on key aspects of offspring development, including birth weight, milk and brain FA composition, glucose and lipid metabolism outcomes, and general behavior in male and female offspring from a rat model of maternal protein restriction.
Results: Maternal n-3 LCPUFA-deficient diet leads to discernible alterations both in mother red blood cell (RBC) membranes, milk, and offspring brain, impacting critical FAs such as α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). The exact opposite effect is observed with a maternal EPA-, DHA-, and arachidonic acid (AA)-enriched diet. DHA, n-3 LCPUFA, and the n-6/n-3 ratio in maternal RBC membrane are identified as offspring-predicting brain FA composition. An n-3-deficient maternal diet clearly impacts metabolic health, in particular hepatic lipid metabolism, and general motor activity of the offspring later in life in a sex-dependent manner. Providing an EPA-DHA-AA-enriched diet during gestation and lactation partially normalized these parameters.
Conclusions: Our findings demonstrate that maternal n-3 LCPUFA deficiency disrupts offspring brain FA composition and metabolic health, whereas an EPA-DHA-AA-enriched diet during gestation and lactation partially restores these alterations, highlighting the potential of maternal dietary intervention to mitigate long-term developmental and metabolic risks in LBW offspring, in particular after HFD challenge.

Keywords:  brain; metabolic programming; milk; n–3 long-chain polyunsaturated fatty acid; perinatal

DOI:  https://doi.org/10.1016/j.cdnut.2026.109508
Sci Adv. 2026 Sep 11. 12(37): eaee4935

Acetyl-CoA-dependent processes are preferentially supported by local metabolite synthesis.

Julianna G Supplee, Pedro Costa-Pinheiro, Karl Wessendorf-Rodriguez, Stephanie Stransky, Qihua Yang, Christina Demetriadou, Nivitha Murali, Joy Li, Jennifer L Pennise, Mariola M Marcinkiewicz, Simone Sidoli, Nathaniel W Snyder, Christian M Metallo, Ronen Marmorstein, Kathryn E Wellen.

The cell nucleus is an active metabolic site. Numerous enzymes best known for their roles in cytosolic or mitochondrial pathways also function in the nucleus, where they contribute to gene regulation and DNA replication and repair. Although metabolites can diffuse through nuclear pores, it remains unclear the extent to which the nucleus and cytosol operate as continuous versus distinct metabolic spaces. Both compartments require acetyl-CoA-for example, for histone acetylation and lipid synthesis-and the acetyl-CoA generating enzyme ATP-citrate lyase (ACLY) resides in both locations, but the significance of its dual localization is incompletely understood. Using cell lines in which ACLY is localized to either compartment, we find that ACLY in either location supports fatty acid synthesis and histone acetylation, yet compartment-localized ACLY enables finer control. Nuclear ACLY preserves histone H3K23 acetylation under glucose limitation and modulates specific transcriptional programs, whereas cytosolic ACLY most efficiently supports lipid biosynthetic fluxes. Thus, local synthesis defines a preferential metabolic fate, providing more precise regulation.

DOI: https://doi.org/10.1126/sciadv.aee4935
J Inherit Metab Dis. 2026 Sep;49(5): e70244

Distinct Urea Cycle Dysfunction Profiles Differentiate Acute Metabolic Decompensation in TMEM70 and MT-ATP6-Related Mitochondrial ATP Synthase Defects.

Barbara Siri, Diego Martinelli, Rosalba Carrozzo, Sara Boenzi, Sara Cairoli, Cristiano Rizzo, Teresa Giovanniello, Johannes Häberle, Carlo Dionisi-Vici.

  ATP synthase defects, including TMEM70 and MT-ATP6 deficiencies, cause severe mitochondrial encephalo-(cardio)-myopathies complicated by acute metabolic decompensations (AMDs) often associated with hyperammonaemia. However, detailed biochemical characterisation of these events remains limited. The aim of the study was to evaluate the metabolic profiles associated with TMEM70 and MT-ATP6 deficiencies during AMDs in comparison to stable metabolic conditions, assessing frequency and severity of hyperammonaemia, and exploring the mechanisms linking impaired mitochondrial ATP production to the urea cycle by in vivo ureagenesis studies, using [15N] ammonium chloride as stable isotope and assessed by high-resolution mass-spectrometry coupled with liquid chromatography. We retrospectively analysed clinical and biochemical profiles from two genetically confirmed cohorts. Patients with TMEM70 deficiency experienced more frequent AMDs, often with hyperammonaemia and requiring extracorporeal detoxification, while the MT-ATP6 cohort had more prominent neurological symptoms and a lower incidence of hyperammonaemia. Biochemically, both groups showed elevated lactate, alanine and glutamine, with orotic aciduria and abnormalities in purine/pyrimidine metabolism. Plasma citrulline levels were divergent in the two cohorts, with a consistent reduction in patients with MT-ATP6 deficiency and normal or borderline elevated levels in the TMEM70 cohort. In vivo stable isotope studies pointed to the differential impact of TMEM70 and MT-ATP6 deficiency on ureagenesis and on the enrichment of individual urea cycle-related amino acids. This study reveals that TMEM70 and MT-ATP6 deficiencies share features of mitochondrial dysfunction but present distinct metabolic profiles, highlighting a different impact on the urea cycle and its related metabolites, and providing novel insights on our understanding of mitochondrial pathophysiology.

Keywords:  ATP synthase defects; MT‐ATP6; TMEM70‐related encephalo‐(cardio)‐myopathy; acute metabolic decompensation; urea cycle

DOI:  https://doi.org/10.1002/jimd.70244
Alzheimers Dement. 2026 Sep;22(9): e71789

ENT1 inhibition links oligodendrocyte lipid metabolism to connectivity in tauopathy.

Ching-Pang Chang, Ching-Wen Chang, Ching-Wen Wu, Jian Jing Siew, David Blum, Lee-Way Jin, You-Yin Chen, Yijuang Chern.

   INTRODUCTION: Metabolic dysfunction, altered adenosine signaling, and white matter abnormalities are implicated in tauopathies, but their relationship to network disconnection remains unclear. Myelinating oligodendrocytes may represent a metabolically vulnerable hub linking these processes to circuit dysfunction.
METHODS: We assessed human hippocampal tissue by immunofluorescence and profiled THY-Tau22 mice using diffusion tensor imaging, metabolomics, lipidomics, and single-nucleus RNA sequencing. Symptomatic mice were treated with the equilibrative nucleoside transporter 1 (ENT1) inhibitor J4 to evaluate therapeutic modulation.
RESULTS: Hippocampal tissue from patients with tauopathy showed reduced oligodendrocyte- and myelin-associated CNPase signal. THY-Tau22 mice exhibited progressive reductions in hippocampal-prefrontal fractional anisotropy, myelin-associated alterations, purine and lipid metabolic remodeling, and oligodendrocyte-enriched lipid-associated transcriptional changes. J4 treatment selectively modulated purine and lipid metabolic pathways and improved myelin-associated markers and structural connectivity measures.
DISCUSSION: ENT1 inhibition links adenosine homeostasis to oligodendrocyte-associated metabolic pathways and supports further investigation as a potential therapeutic approach for tauopathy-associated network dysfunction.

Keywords:  Alzheimer's disease; ENT1; adenosine; lipid metabolism; oligodendrocytes; tauopathy; white matter

DOI:  https://doi.org/10.1002/alz.71789
J Psychopharmacol. 2026 Sep 07. 2698811261481085

The effect of ketamine on mitochondrial bioenergetics, viability, and function: A systematic review.

Sabrina Wong, Gia Han Le, Simryn Selby, Stavroula Bargiota, Diana K Orsini, Sara Di Luch, Shreya Vasudeva, Gabrielle Lovell, Joshua D Rosenblat, Roger S McIntyre.

   BACKGROUND: Extant literature indicates mitochondrial dysfunction may contribute to the pathophysiology of depressive disorders. Preclinical data indicate that anesthetic doses of ketamine are associated with deficits in mitochondrial viability and function. Ketamine and esketamine have demonstrated rapid antidepressant effects in persons with difficult-to-treat depressive disorders. Herein, we aim to synthesize literature reporting on the effect of antidepressant doses of ketamine and esketamine in vivo versus in vitro on mitochondrial viability and function.
METHODS: We performed a systematic review of previous studies on PubMed, Ovid, and Scopus databases from inception to November 30, 2025. Preclinical studies reporting on the effect of antidepressant doses of ketamine and/or esketamine in mitochondrial viability, structure/morphology, bioenergetics, and metabolic function were sought for inclusion.
RESULTS: Thirteen studies were included. Lower ketamine/esketamine concentrations generally did not adversely affect membrane potential, oxidative phosphorylation, respiration, or bioenergetics, whereas higher concentrations or prolonged exposure induced mitochondrial dysfunction in some models. Additional evaluation of the safety of ketamine/esketamine on mitochondria in humans is required.
CONCLUSION: Preliminary research suggests that ketamine at lower concentrations may not adversely affect brain mitochondrial viability or bioenergetic function, but requires further validation. The reported effects on mitochondrial viability and function are preclinical, model- and dose-dependent and derived from limited heterogeneous literature. This study generates the hypothesis that ketamine's antidepressant mechanism of action may be partially mediated by insulin-sensitive metabolic pathways, energetically supporting synaptic remodeling and neurogenesis. Incorporation of mitochondrial and metabolic biomarkers into ketamine clinical trials is a current research imperative.

Keywords:  bioenergetics; esketamine; ketamine; mitochondria

DOI:  https://doi.org/10.1177/02698811261481085
Nat Commun. 2026 Aug 04. pii: 9593. [Epub ahead of print]17(1):

A Lactate-H4K12la-HDAC1 epigenetic axis governs microglial state transitions during experimental autoimmune encephalomyelitis in female mice.

Jiahong Li, Su Meng, Jiajian Li, Quanfeng Wei, Xin Hua, Jinzhou Feng, WenYu Hu, Hongxing Wang, Yinan Zhao.

Microglial functional plasticity is shaped by metabolic and epigenetic reprogramming, but how these processes regulate central nervous system autoimmunity remains unclear. We find that cerebrospinal fluid lactate levels correlate with multiple sclerosis severity. Using female mouse models of experimental autoimmune encephalomyelitis, spinal lactate accumulation drives persistent microglial histone lactylation, coupling to glycolytic activation. Microglia-specific deletion of lactate dehydrogenase A reduces this lactylation and exacerbates disease severity. Exogenous lactate ameliorates pathology without altering peripheral immune infiltration by suppressing inflammatory states and promoting reparative programs. Epigenomic profiling demonstrates direct lactylation enrichment at promoters of neurotrophic genes, linking metabolic flux to transcriptional activation. Histone deacetylase 1 acts as an epigenetic brake by erasing this modification; its inhibition restores neurotrophic signaling and mitigates pathology. In this work, we show that a lactate-driven epigenetic axis governs microglial state transitions, highlighting a tractable therapeutic target for metabolic intervention in neuroinflammatory diseases.

DOI: https://doi.org/10.1038/s41467-026-76302-z
Neurobiol Dis. 2026 Sep 09. pii: S0969-9961(26)00349-9. [Epub ahead of print] 107604

Neuronal monocarboxylate transporter 2 is downregulated and aggravates seizures in a rat model of infantile epileptic spasms.

Jiayu Liu, Jie Chen, Haohan Lin, Duan Wang, Ningning Chen, Donghui Lin, Yi Li, Chunqing Zhang, Shiyong Liu, Kaifeng Shen, Zengpeng Yu, Tingsong Li.

  Infantile epileptic spasms syndrome (IESS) is an age-dependent epileptic encephalopathy of the developing brain, yet its underlying mechanisms remain unclear. Monocarboxylate transporter 2 (MCT2) maintains cerebral metabolic homeostasis via energy substrate transport, but its role in IESS epileptogenesis is unknown. We found that MCT2 was predominantly expressed in neurons and downregulated in IESS patient specimens. In contrast, in human temporal lobe epilepsy (TLE) specimens, MCT2 expression showed no statistically significant difference relative to controls. We observed this downregulation of neuronal MCT2 in an IESS rat model. Transcriptomic analysis 24 h post-spasms revealed enrichment in mitochondrial pathways and oxidative phosphorylation. Consistently, translocase of outer mitochondrial membrane 20 (TOMM20) was markedly downregulated in the cortex of IESS patients and a betamethasone/N-methyl-d-aspartate (NMDA)-induced rat model, which also displayed ultrastructural mitochondrial damage, reactive oxygen species accumulation, and an imbalanced Bax/Bcl-xL ratio. Using adeno-associated virus (AAV)-mediated MCT2 knockdown in neonatal rat somatosensory cortex, reduced MCT2 expression significantly shortened latency to spasm onset, increased spasm frequency, and exacerbated post-spasm TOMM20 loss. These findings indicate that impaired MCT2-mediated transport may compromise mitochondrial function and lower the threshold for spasm generation, a characteristic feature of this infantile-onset epilepsy. Neuronal MCT2 thus represents a promising therapeutic target for IESS.

Keywords:  Energy metabolism; Infantile epileptic spasms; Mitochondria; Monocarboxylate transporter 2; Neurons

DOI:  https://doi.org/10.1016/j.nbd.2026.107604
Front Cell Neurosci. 2026 ;20 1941513

Rotenone-induced oxidative stress triggers peroxisomal alterations in BV-2 microglial cells.

Alessio Valenza, Maurizio Muzzi, Francesca Rendina, Irene Montali, Daniele Pensabene, Anna Fracassi, Marco Segatto, Sandra Moreno.

   Introduction: Peroxisomes are highly dynamic organelles that contribute to cellular homeostasis by coordinating lipid metabolism, reactive oxygen species handling, and adaptive responses to metabolic stress. Their plasticity is particularly relevant in the nervous system, where peroxisomes cooperate with mitochondria to maintain redox and metabolic balance in neuronal and glial cells. Peroxisome proliferator-activated receptor alpha (PPARα), together with its coactivator PGC-1α, represents a major transcriptional regulator of peroxisomal and mitochondrial metabolic programs.
Methods: BV2 microglial cells were exposed to rotenone to investigate how mitochondrial oxidative stress influences the peroxisomal compartment. Mitochondrial and peroxisomal morphology, intracellular distribution, oxidative damage, and the expression of proteins involved in peroxisomal metabolism and PPARα signaling were evaluated.
Results: Rotenone induced a stress-associated microglial phenotype characterized by cytoskeletal remodeling, mitochondrial network disruption, and oxidative damage. These alterations were accompanied by a coordinated reorganization of the peroxisomal compartment, including increased abundance of peroxisomal membrane markers, redistribution of peroxisomes toward the perinuclear region, and enhanced expression of enzymes associated with peroxisomal fatty acid oxidation. An increased spatial association between peroxisomes and mitochondria was also observed, suggesting that peroxisomal remodeling forms part of a broader inter-organelle adaptation to mitochondrial dysfunction. These changes occurred together with increased nuclear phosphorylated PPARα and enhanced PGC-1α immunoreactivity, supporting the engagement of a PPARα-PGC-1α-related transcriptional response.
Discussion: Overall, our findings suggest that mitochondrial dysfunction in microglial cells activates a PPARα-associated adaptive program that promotes peroxisomal remodeling and strengthens mitochondria-peroxisome coordination. This response may represent an attempt to preserve lipid and redox homeostasis during cellular stress and identifies PPARα-regulated peroxisomal pathways as potentially relevant components of microglial metabolic adaptation in neurodegenerative conditions.

Keywords:  microglia; mitochondria; oxidative stress; peroxisomes; rotenone

DOI:  https://doi.org/10.3389/fncel.2026.1941513