bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2026–03–01
nineteen papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Rethinking Human Energy Metabolism.
  2. Lactate receptor HCAR1 in neonatal hypoxic-ischemic seizures.
  3. Brain-derived ketone bodies can replace glucose to power neural function.
  4. Deficient de-S-acylation in aging and CLN1 contributes to lyso-mitochondrial dysfunction, lipid dyshomeostasis, and resultant lipofuscin biogenesis.
  5. Brain lipidomics for region-specific biomarker discovery in neurodegenerative diseases.
  6. Brain Ketone Bodies in Health, Evolution and Disease.
  7. SIRT1 mediates brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism.
  8. Ketogenic Strategies in Neonatal Hypoxic-Ischemic Encephalopathy-The Road to Opening Up: A Scoping Review.
  9. Modeling lipid homeostasis using stable isotope tracing and flux analysis.
  10. Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
  11. LPLAT10/LPEAT2 produces atypical phospholipids with an unsaturated fatty acid at the sn-1 position.
  12. Malonyl-CoA Decarboxylase: A Spotlight on Brain Aspects.
  13. Unraveling GDAP1: Bridging Mitochondrial Biology and Peripheral Neuropathy.
  14. Aspartate availability drives differential engagement of the malate-aspartate shuttle.
  15. Mitochondrial dysfunction and disrupted neuronal lipid homeostasis in Parkinson's disease: Potential mechanisms and therapeutic implications.
  16. Metabolomic analysis of plasma and brain tissues in fentanyl-induced conditioned place preference mice.
  17. Organelle communication networks rewire to support lipid metabolism during neuronal differentiation.
  18. The Citric Acid Cycle Modulates Neurologic Health and Is a Therapeutic Target of Dietary and Genetic Modification in Metabolic Disease.
  19. Brain Sphingolipid and Phospholipid Levels Are Altered in XK Disease.
  1. Curr Issues Mol Biol. 2026 Feb 01. pii: 159. [Epub ahead of print]48(2):
    Rethinking Human Energy Metabolism.
    Alexander Panov, Vladimir Mayorov, Sergey Dikalov, Alexandra Krasilnikova, Lev Yaguzhinsky.
      For a long time, glycolysis and mitochondrial oxidative phosphorylation were opposed to each other. Glycolysis works when there is a lack of oxygen; the mitochondria supply ATP in an oxygen environment. In recent decades, it has been discovered that glycolysis in vivo always works and the final product is lactate. Lactate can accumulate and is the transport form for pyruvate. In this review, we look at how obligate lactate formation during glycolysis affects the tricarboxylic acid (TCA) cycle and mitochondrial respiration. We conclude that fatty acid β-oxidation is a prerequisite for obligate lactate formation during glycolysis, which in turn promotes and enhances the anaplerotic functions of the TCA cycle. In this way, a supply of two types of substrates for mitochondria is formed: fatty acids as the basic energy substrates, and lactate as an emergency substrate for the heart, skeletal muscles, and brain. High steady-state levels of lactate and ATP, supported by β-oxidation, stimulate gluconeogenesis and thus support the lactate cycle. It is concluded that mitochondrial fatty acids β-oxidation and glycolysis constitute a single interdependent system of energy metabolism of the human body.
    Keywords:  beta-oxidation of fatty acids; energy metabolism; fatty acids; glycolysis; lactate; lactate cycle; mitochondria; pyruvate; respirasome; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3390/cimb48020159
  2. Epilepsia. 2026 Feb 26.
    Lactate receptor HCAR1 in neonatal hypoxic-ischemic seizures.
    Jennifer Burnsed, Angelina June, Maria Marlicz, Emmy Zucker, Ellie Kain-Kuzniewski, Hannah Mulhern, Leanne Maharaj, John Williamson, Chengsan Sun, Suchitra Joshi, Huayu Sun, Jaideep Kapur.
      Hydroxycarboxylic acid receptor 1 (HCAR1) is a G-protein-coupled lactate receptor expressed in the brain and plays a role in neuronal excitability and repair after injury. Hypoxic-ischemic encephalopathy (HIE) is the most common cause of brain injury and seizures in term neonates. The goal of this study was to describe HCAR1 expression and function in the neonatal brain and understand its role in HIE-associated seizures. HCAR1 expression was measured using quantitative reverse transcriptase polymerase chain reaction in postnatal day (p)10-50 mice. Neuronal properties and spontaneous excitatory postsynaptic currents (sEPSCs) were measured in hippocampal principal neurons from HCAR1 knockout and wild-type mice when exposed to lactate. p10 HCAR1 knockout and wild-type mice were exposed to hypoxia-ischemia (HI) and underwent electroencephalography to compare seizure burden. HCAR1 was expressed at p10 at similar levels to adults. Lactate decreased amplitudes and sEPSC frequency in wild-type but not HCAR1 knockout mice. After HI, HCAR1 knockout mice had higher seizure burden and behavioral seizure scores than wild-type mice. HCAR1 is expressed on neurons and plays a role in neuronal excitability and seizures in the neonatal brain.
    Keywords:  HCAR1; hydroxycarboxylic acid receptor 1; hypoxia–ischemia; lactate; neonatal; seizures
    DOI:  https://doi.org/10.1002/epi.70172
  3. bioRxiv. 2026 Feb 20. pii: 2026.02.19.706813. [Epub ahead of print]
    Brain-derived ketone bodies can replace glucose to power neural function.
    Hafsa Yaseen, Karissa Cisneros, Rebecca Wright, Nikolaus Bueschke, Joseph M Santin.
      The brain is sensitive to disruptions in glucose metabolism, requiring constant delivery to support neural activity. Here, we discovered a vertebrate with the surprising capacity to abandon glucose metabolism and replace it with ketone bodies produced entirely within the brain. In frogs-animals with seemingly typical glucose demands-hibernation shifts brain bioenergetics to allow ketone bodies made within the brain to sustain neural activity without ATP from glucose metabolism. This involves, in part, the upregulation of fatty acid catabolism, ketone body synthesis, and transport from astrocytes to neurons to maintain synaptic transmission. Brain-derived ketone bodies also prevent decrements in activity that otherwise occur during hypoxia. These results provide insight into how frogs restart brain circuits following months of underwater hibernation when facing severe hypoxia and hypoglycemia that otherwise impair neural performance. Overall, these results reveal a capacity for the vertebrate brain to temporarily abandon glucose while maintaining costly functions using locally sourced ketone bodies independent from body energy stores.
    DOI:  https://doi.org/10.64898/2026.02.19.706813
  4. Res Sq. 2026 Feb 09. pii: rs.3.rs-8770768. [Epub ahead of print]
    Deficient de-S-acylation in aging and CLN1 contributes to lyso-mitochondrial dysfunction, lipid dyshomeostasis, and resultant lipofuscin biogenesis.
    Sofia Massaro Tieze, Alexander Esqueda, Rachel McAllister, Matija Lagator, Betül Yücel, Eric Sun, TuKiet T Lam, Nicholas Lockyer, Kallol Gupta, Sreeganga S Chandra.
      Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition in mouse and human brain and report the spatiotemporal dynamics of lipofuscin accumulation in aging and NCL in a murine neuroanatomical atlas. Multimodal mass spectrometry, ultrastructural analyses, and assays of metabolic flux identify a primary role of the lysosomal-mitochondrial axis in the formation of lipofuscin pathology. Dissection of implicated molecular pathways reveals protein S-acylation and unsaturated lipid homeostasis as central processes involved in lipofuscin deposition during aging and NCL.
    DOI:  https://doi.org/10.21203/rs.3.rs-8770768/v1
  5. Front Aging Neurosci. 2026 ;18 1757306
    Brain lipidomics for region-specific biomarker discovery in neurodegenerative diseases.
    Jayashankar Jayaprakash, Solomon Tebeje Gizaw, Divyavani Gowda, Hiroshi Hinou, Shin-Ichiro Nishimura, Shu-Ping Hui, Siddabasave Gowda B Gowda.
       Background: Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are progressive neurodegenerative diseases (NDs) characterized by chronic neuronal loss. The lack of effective treatments highlights the urgent need for reliable lipid biomarkers to enable diagnosis and monitor disease progression. Previous lipidomic investigations of altered lipid metabolism have focused on a single disease type, limiting cross-disease comparisons.
    Methods: We applied the untargeted liquid chromatography-mass spectrometry (LC/MS) technique to profile brain lipidome alterations and to identify disease-specific lipid biomarkers across AD, HD, and PD. Brain tissue samples were collected from four cerebral lobes of healthy volunteers (HV, n = 24) and patients diagnosed with AD (n = 24), PD (n = 24), and HD (n = 24). All groups include three males and three females, with brain tissues from four cortical regions sacrificed from each individual.
    Results: A total of 243 lipid molecular species spanning five major classes were annotated, revealing distinct disease-specific lipidomic profiles that differentiated HV from the AD, HD, and PD groups via multivariate analysis. Sphingomyelins and oxidized phosphatidylserine [PS (16:1/24:0;O1)] were significantly increased, while lysophosphatidylcholines (LPC 18:2, LPC 17:2) were decreased in the AD group relative to HV. HD exhibited elevated PS (O-17:0/22:6) and ω-6 fatty acid esterified cholesteryl esters (CE 18:2, CE 20:4), alongside decreased essential neuronal lipids such as phosphatidylinositols (PI). The PD lipidome alterations closely resembled those of HD, indicating partially overlapping disruptions in brain lipid metabolism. Receiver operating characteristic analysis identified PS (16:1/24:0;O1), PS (O-17:0/22:6), and PI (18:1/18:1) as potential discriminatory biomarkers with strong diagnostic performance. Regional heatmap analysis revealed significant lipid perturbations were observed in the parietal and occipital lobes across all NDs.
    Conclusion: This study provides a comprehensive overview of disease- and region-specific alterations in the brain lipidome of AD, HD, and PD. The identified lipid species-PS (16:1/24:0;O1), PS (O-17:0/22:6), and PI (18:1/18:1)-may serve as promising candidate biomarkers for NDs diagnosis and warrant further mechanistic and longitudinal validation with large data set.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; lipid biomarkers; lipidomics; liquid chromatography; mass spectrometry
    DOI:  https://doi.org/10.3389/fnagi.2026.1757306
  6. Cells. 2026 Feb 23. pii: 382. [Epub ahead of print]15(4):
    Brain Ketone Bodies in Health, Evolution and Disease.
    Pierre Bougnères.
      Ketone bodies (KBs) are the only energy substrates oxidized by the brain, whose concentration in the circulation can greatly increase when a physiological situation requires it. For example, when an adult human fasts for two days, circulating KBs rise twenty-fold from ~0.1 to ~2 mM. As a fuel, KBs provide the brain with acetyl-CoA that produces ATP or glutamate, notably in certain brain regions. Remarkably, KBs activate the expression of their own cerebral transporters and KB-utilizing enzymes so that circulating levels determine cerebral utilization of KBs. Throughout evolution, the energetic role of KBs has been crucial for the metabolic homeostasis of humans endowed with a large brain and facing unpredictable periods of food shortage. Paradoxically, the brain of modern, regularly fed humans whose ordinary blood KBs are ~0.1 mM, has access to much fewer circulating sources of energy than that of their distant ancestors. KBs can modify certain proteins post-translationally, for example, histones through lysine-butyrylation. KBs could act as short- or long-term epigenetic messengers. These properties of KBs might allow a fetus to directly sense maternal starvation and adapt their cerebral metabolism to this situation, possibly preparing for nutritional constraints in extra-uterine life. KB transcriptional and epigenetic properties could also enable the postnatal organism to retain a molecular memory of its own starvation episodes. No other energy substrate, such as glucose or lactate, has such capacities. Medicine turned its attention to KBs a century ago. Indeed, KBs are the only energy substrates whose circulating levels can be increased, and nutritional interventions can alter them under free-living conditions. This property opens broad prospects for ketogenic diets (KDs) to prevent or rescue neurodegenerative diseases characterized by glucose hypometabolism, notably Alzheimer's disease (AD). However, KDs have not yet found real medical applications, for reasons that are discussed.
    Keywords:  Alzheimer; brain; evolution; ketogenic diet; ketone bodies
    DOI:  https://doi.org/10.3390/cells15040382
  7. Cell Rep Med. 2026 Feb 25. pii: S2666-3791(26)00060-1. [Epub ahead of print] 102643
    SIRT1 mediates brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism.
    Karim Matmat, Ziad Hassan, Grégory Pourié, Yaser Atlasi, Snehaa Vivienne Seal, Manon Jeandel, Carole Arnold, Sachin Luharia, Rémy Umoret, Ramia Safar, Almut Heinken, Jean-Marc Alberto, Okan Baspinar, Justine Paoli, Sebastien Hergalant, Pierre Rouyer, Jean-Michel Camadro, Laurent Lignières, David Coelho, Jean-Louis Guéant, Rosa-Maria Guéant-Rodriguez.
      Inborn errors of vitamin B12 metabolism (IECM) resulting from impaired methionine synthase (MTR) activity cause severe cognitive and neurological deficits that remain unresponsive to conventional B12 supplementation. Using a brain-specific Mtr knockout mouse model, we identify the NAD+-dependent deacetylase SIRT1 as a central regulator of the pathological phenotype and evaluate the therapeutic efficacy of its pharmacological activator SRT2104. MS deficiency induces profound metabolic, mitochondrial, and epigenomic alterations in the hippocampus, including promoter hypermethylation of the pyruvate dehydrogenase complex, impaired tricarboxylic acid (TCA) cycle activity, and reduced SIRT1 expression. At the functional level, we observe disrupted Wnt signaling associated with decreased neurogenesis, increased astrocytosis, and cognitive impairment. SRT2104 treatment restores mitochondrial and energy metabolism, normalizes Wnt signaling and neurogenesis markers, and rescues learning and memory performance. These findings identify SIRT1 as a therapeutic target in B12-related neurodevelopmental disorders and support the clinical repurposing of SRT2104 to alleviate persistent neurological symptoms.
    Keywords:  SIRT1; Wnt signaling; drug repurposing; energy metabolism; inborn errors of cobalamin metabolism; methionine synthase; neurodevelopment; neurogenesis; one-carbon metabolism; vitamin B12 deficiency
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102643
  8. Neurol Int. 2026 Jan 28. pii: 24. [Epub ahead of print]18(2):
    Ketogenic Strategies in Neonatal Hypoxic-Ischemic Encephalopathy-The Road to Opening Up: A Scoping Review.
    Raffaele Falsaperla, Vincenzo Sortino, Cristina Malaventura, Silvia Fanaro, Elisa Ballardini, Aloise Martina, Annamaria Sapuppo, Agnese Suppiej.
       BACKGROUND: Neonatal hypoxic-ischemic encephalopathy remains a leading cause of neonatal mortality and long-term neurodevelopmental disability worldwide. Despite the widespread adoption of therapeutic hypothermia, a substantial proportion of affected infants experience death or significant neurological impairment. Given their metabolic vulnerability, ketogenic diet strategies and ketone bodies have emerged as potential adjunctive neuroprotective interventions. This scoping review aims to critically evaluate the mechanistic rationale, preclinical evidence, and clinical feasibility of ketogenic approaches.
    METHODS: A scoping review of the literature was conducted, including experimental and clinical studies investigating ketogenic diets, endogenous ketosis, and exogenous ketone supplementation in neonatal hypoxia-ischemia. Evidence was synthesized across mechanistic, preclinical, nutritional, and clinical domains, with particular attention to developmental context, timing of intervention, safety considerations, and translational relevance in the contest of therapeutic hypothermia.
    RESULTS: Preclinical studies consistently demonstrate that ketone bodies enhance cerebral energy metabolism, support mitochondrial function, reduce excitotoxic signaling, and attenuate oxidative stress and neuroinflammation in the immature brain. Neonatal models show preferential utilization of β-hydroxybutyrate over glucose during hypoxic-ischemic stress, suggesting intrinsic metabolic advantages. Emerging evidence also supports potential long-term effects on epigenetic regulation and white matter development, although direct causal validation in neonatal HIE remains limited. Nutritional studies indicate that carefully monitored enteral and parenteral feeding is feasible in critically ill neonates, identifying a potential window for metabolic interventions.
    CONCLUSIONS: Ketogenic strategies represent a plausible, multimodal approach to targeting the metabolic and inflammatory sequelae of neonatal HIE. While current evidence is insufficient to support clinical implementation, this scoping review provides a hypothesis-generating framework to guide future translational research and the design of carefully controlled clinical trials in neonatal neurocritical care.
    Keywords:  hypoxic–ischemic encephalopathy; ketogenic diet; ketone bodies; neonatal neuroprotection
    DOI:  https://doi.org/10.3390/neurolint18020024
  9. Cell Metab. 2026 Feb 20. pii: S1550-4131(26)00020-3. [Epub ahead of print]
    Modeling lipid homeostasis using stable isotope tracing and flux analysis.
    Karl Wessendorf-Rodriguez, Maureen L Ruchhoeft, Christopher W Murray, Yale Huang, Ethan L Ashley, Hector M Galvez, Grace H McGregor, Shrikaar Kambhampati, Reuben J Shaw, Christian M Metallo.
      Lipids enable compartmentation and coordinate membrane-localized signaling events in cells, and dysregulation of lipid metabolism is linked to many disease states. However, limited tools are available for quantifying metabolic fluxes across the lipidome. To measure fluxes encompassing lipid homeostasis in cells and tissue slices, we apply stable isotope tracing, liquid chromatography-high-resolution mass spectrometry, and network-based isotopologue modeling to non-small cell lung cancer (NSCLC) models. Lipid metabolic flux analysis (Lipid-MFA) enables quantitation of fatty acid synthesis, elongation, headgroup assembly, and salvage reactions within virtually any biological system. Using Lipid-MFA, we observed decreased fatty acid synthase and very long-chain fatty acid (VLCFA) elongation fluxes, along with increased sphingolipid recycling, in p53-deficient versus liver kinase B1 (LKB1)-deficient NSCLC tumors using precision-cut lung slice culture. We also apply Lipid-MFA to demonstrate the unique trafficking of ceramides with distinct n-acyl chain lengths, highlighting the utility of this approach in elucidating molecular mechanisms in lipid homeostasis.
    Keywords:  ELOVL1; LKB1; TP53; ceramide; lipid homeostasis; metabolic flux analysis; non-small cell lung cancer; precision-cut lung slice culture; sphingolipids; very long-chain fatty acids
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.020
  10. Nat Cell Biol. 2026 Feb 26.
    Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
    Sandra Heinen, Vitasta Tiku, Alexander Grevel, Marie Hugenroth, Lars Ellenrieder, Isabelle Steymans, Mariya Licheva, Sara Bonini, Silke Oeljeklaus, Nicole Okon, Jessica Lambertz, Sylvia Poppe, Jiyao Song, Lars Fester, Chris Meisinger, Bettina Warscheid, Matthias Eckhardt, Nils Wiedemann, Dominic Winter, Claudine Kraft, Fabian den Brave, Maria Bohnert, Nikolaus Pfanner, Thomas Becker.
      Mitochondria play central roles in the energetics and metabolism of eukaryotic cells. Their outer membrane is essential for protein transport, membrane dynamics, signalling and metabolic exchange with other cellular compartments. The mitochondrial import (MIM) complex functions as main translocase for importing the precursors of more than 90% of integral outer-membrane proteins. Here we report that the MIM complex performs a second major function in lipid-droplet homeostasis. Lipid droplets are crucial in cellular lipid metabolism and as storage organelles for neutral lipids. The lipid metabolism enzyme Ayr1 captures the MIM complex, promoting the formation of mitochondria-lipid droplet contact sites. MIM and Ayr1 enhance the lipid droplet number in cells. Ayr1 binds to MIM via its single hydrophobic segment in a substrate-mimicry mechanism but remains bound and is not released into the outer membrane. The functional diversity is mediated by different MIM complexes: MIM-Ayr1 for recruiting lipid droplets and MIM-preprotein for protein insertion into the outer membrane. Our work uncovers translocase capture as a mechanism for functional conversion of a membrane protein complex from protein insertion to lipid metabolism.
    DOI:  https://doi.org/10.1038/s41556-026-01890-3
  11. J Lipid Res. 2026 Feb 23. pii: S0022-2275(26)00033-7. [Epub ahead of print] 101007
    LPLAT10/LPEAT2 produces atypical phospholipids with an unsaturated fatty acid at the sn-1 position.
    Hiroki Kawana, Rikuta Kataoka, Yukitaka Sato, Hirofumi Ohnishi, Taiga Iwama, Yuta Shimanaka, Daisuke Saigusa, Kuniyuki Kano, Nozomu Kono, Junken Aoki.
      Major membrane phospholipids contain saturated fatty acids, such as palmitic acid (C16:0) and stearic acid (C18:0), at the sn-1 position. Although atypical phospholipids containing unsaturated fatty acids at the sn-1 position exist as minor components, the biosynthetic pathway responsible for their production has remained elusive. Here, we report that LPLAT10 (also known as LPEAT2 or LPCAT4) is a lysophospholipid acyltransferase responsible for generating phospholipids with an unsaturated fatty acid at the sn-1 position. In vitro, LPLAT10 incorporated both saturated and unsaturated fatty acids into lysophospholipids bearing LPC, LPE, and LysoPS, selectively at the sn-1 position. LPLAT10 appeared to have a relatively higher affinity for unsaturated fatty acid-CoAs. Consistently, only phospholipids with unsaturated fatty acids such as oleic (C18:1), linoleic (C18:2), arachidonic (C20:4), and docosahexaenoic (C22:6) acids at the sn-1 position decreased in the brain from Lplat10-deficient mice. Despite their low abundance, these atypical phospholipids may have specific roles, given that LPLAT10 is highly expressed in neurons and its encoding genes are highly conserved among vertebrates above fish.
    Keywords:  LPCAT4; LPEAT2; LPLAT10; Land’s cycle; lysophospholipids; sn-1 position; unsaturated fatty acid
    DOI:  https://doi.org/10.1016/j.jlr.2026.101007
  12. Brain Sci. 2026 Feb 12. pii: 220. [Epub ahead of print]16(2):
    Malonyl-CoA Decarboxylase: A Spotlight on Brain Aspects.
    Monique Fonseca-Teixeira, Elaine Silva Brito, Clara Beltrao-Valente, Bruna Klippel Ferreira, Patricia Fernanda Schuck, Gustavo Costa Ferreira.
      Malonyl-CoA decarboxylase (MCD) is an enzyme that controls malonyl-CoA levels and regulates fatty acid synthesis and oxidation. Although its physiological relevance in peripheral tissues is well known, the role of MCD in the central nervous system remains poorly understood. MCD is expressed in mitochondria, cytosol, and peroxisomes and may be regulated by PPAR-α, AMPK, and SIRT4 in tissues such as muscle, liver and kidney. In the brain, MCD expression varies during development and can respond to nutritional states. Inherited MCD deficiency (malonic aciduria) leads to the toxic accumulation of malonic acid and predominantly affects the central nervous system. The underlying mechanisms leading to brain damage in MCD patients remain unclear. Conversely, pharmacological modulation of MCD activity has been studied in obesity, diabetes, and ischemic injury, highlighting its therapeutic potential. There are still major gaps regarding MCD cellular distribution, regulatory pathways, and metabolic interaction with CPT1c (carnitine palmitoyltransferase 1c) in neural metabolism. A deeper understanding of the role of MCD in brain physiology and pathology may indicate novel therapeutic strategies targeting metabolic disorders that involve altered malonyl-CoA dynamics. Here, we discuss the current knowns and unknowns regarding MCD physiology, regulation, and pathophysiology, emphasizing brain aspects.
    Keywords:  brain; fatty acid metabolism; malonic acid; malonic aciduria; malonyl-CoA; metabolic disorders
    DOI:  https://doi.org/10.3390/brainsci16020220
  13. Biomolecules. 2026 Feb 10. pii: 280. [Epub ahead of print]16(2):
    Unraveling GDAP1: Bridging Mitochondrial Biology and Peripheral Neuropathy.
    Lara Cantarero, Janet Hoenicka, Francesc Palau.
      The mitochondrial outer membrane (OMM) plays a crucial role in maintaining cellular homeostasis by regulating mitochondrial dynamics, organelle interactions, and stress responses. In peripheral neurons-cells with high metabolic demands and long axons-the OMM acts as a vital platform for coordinating bioenergetics, calcium signaling, and redox balance. Ganglioside-induced differentiation-associated protein 1 (GDAP1), an OMM-anchored protein, has emerged as a key regulator of mitochondrial fission and transport, redox homeostasis, and mitochondrial membrane contact sites (MCSs). Genetic variants in GDAP1 cause Charcot-Marie-Tooth disease (CMT), emphasizing its essential role in peripheral nerve function. This review highlights the multifaceted functions of GDAP1 in neuronal physiology and as a model protein that integrates organelle communication and mitochondrial biology. We further discuss how GDAP1 dysfunction leads to structural and functional impairments in peripheral neurons, proposing the OMM and its microenvironment as critical targets for therapeutic intervention in inherited neuropathies.
    Keywords:  Charcot-Marie-Tooth disease; GDAP1; axon; axonopathy; glial cells; lysosomes; membrane contact sites; mitochondria; neuroinflammation; neuron; neuropathies; outer mitochondrial membrane; peroxisomes
    DOI:  https://doi.org/10.3390/biom16020280
  14. Mol Cell. 2026 Feb 26. pii: S1097-2765(26)00099-7. [Epub ahead of print]
    Aspartate availability drives differential engagement of the malate-aspartate shuttle.
    Julia S Brunner, Anna E Bridgeman, Benjamin T Jackson, Sangita Chakraborty, Maider Fagoaga-Eugui, Katrina I Paras, Abigail Xie, Paige K Arnold, Julia Losner, Lydia W S Finley.
      The malate-aspartate shuttle is a major electron shuttle that transfers reducing equivalents from the cytosol to the mitochondria, where they can be safely deposited onto the electron transport chain. Nevertheless, many proliferating cells discard reducing equivalents in the form of lactate, raising the question of what factors limit electron shuttle use. Here, we show that aspartate availability determines engagement of the malate-aspartate shuttle. In proliferating cells, increasing aspartate availability enhances use of the malate-aspartate shuttle and increases metabolism of glucose-derived pyruvate in mitochondria, a process that requires regeneration of oxidized electron carriers in the cytosol. During differentiation, elevated flux through the malate-aspartate shuttle cells enables cells to fuel mitochondrial networks from glucose-derived carbon. Engineering aspartate demand reverses this metabolic signature of differentiated cells. Together, these results demonstrate that cell-state-specific demand for aspartate is sufficient to determine use of the malate-aspartate shuttle and drives changing mitochondrial substrate preferences during differentiation.
    Keywords:  GOT1; GOT2; TCA cycle; Warburg effect; aspartate; differentiation; electron shuttles; malate-aspartate shuttle; metabolism; proliferation
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.004
  15. Exp Neurol. 2026 Feb 25. pii: S0014-4886(26)00066-X. [Epub ahead of print] 115703
    Mitochondrial dysfunction and disrupted neuronal lipid homeostasis in Parkinson's disease: Potential mechanisms and therapeutic implications.
    Zehao Quan, Chun-Yuan Ku, Tian Xie, Ho Tin Fok, Daniel Schweitzer, Isaac Akefe.
       BACKGROUND: Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterised by dopaminergic neuron loss and pathological accumulation of alpha-synuclein. Emerging evidence highlights a crucial interplay between mitochondrial dysfunction and disrupted lipid homeostasis as central mechanisms driving PD pathogenesis.
    OBJECTIVE: This scoping review synthesises current evidence on the relationship between mitochondrial dysfunction and neuronal lipid dysregulation in PD and identifies potential therapeutic targets within these intersecting pathways.
    METHODS: Following the PRISMA-ScR guidelines, a comprehensive literature search was conducted across PubMed, Embase, and Web of Science for studies published between 2015 and 2025. Two independent reviewers screened and selected eligible studies based on predefined inclusion criteria.
    RESULTS: Analysis revealed four central interconnected pathological mechanisms: ferroptosis, alpha-synuclein-lipid interactions, mitochondrial dysfunction, and impaired autophagy/mitophagy. These mechanisms collectively contribute to oxidative stress, membrane destabilisation, and bioenergetic collapse, driving dopaminergic neuronal vulnerability.
    CONCLUSIONS: The findings underscore a complex, bidirectional relationship between mitochondrial dysfunction and lipid dysregulation in PD. Therapeutic strategies targeting iron accumulation, lipid peroxidation, and alpha-synuclein aggregation are promising. However, further mechanistic studies are required to clarify these interactions and advance the development of effective disease-modifying interventions.
    Keywords:  Alpha-Synuclein; Cholesterol; Lipid homeostasis; Mitochondrial dysfunction; Neurodegeneration; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115703
  16. Front Pharmacol. 2026 ;17 1759491
    Metabolomic analysis of plasma and brain tissues in fentanyl-induced conditioned place preference mice.
    Kaili Du, Xiaoyu Ning, Yongze Han, Xiaoyu Jiang, Zhuoyi Wang, Tao Wang, Hongliang Su, Ting Liu, Bin Cong, Caixia Cheng, Keming Yun.
      Fentanyl abuse has been associated with neurological and psychological harm. However, the metabolic changes within the peripheral circulation and central nervous system involved in fentanyl addiction have not been well explored. In the present study, metabolic changes in plasma, caudate putamen (CPu), hippocampus (Hip), and prefrontal cortex (PFC) were investigated in mouse models of drug addiction based on fentanyl-induced conditioned place preference (CPP). Metabolic profiles were measured using untargeted UHPLC-Q-Exactive HFX mass spectrometry. A total of 131, 196, 104, and 52 altered metabolites were identified in plasma, CPu, Hip, and PFC, respectively. The identified metabolites mainly included lipid mediators, carbohydrate metabolites, fatty acids, amino acids (AAs) and their derivatives, and nucleotide metabolites. The disturbed metabolic pathways were primarily involved in lipid metabolism, carbohydrate metabolism, AA metabolism, nucleotide metabolism, and the metabolism of cofactors and vitamins. These findings indicate disturbances in cell membrane metabolism, energy metabolism, AA metabolism, and neurotransmitter systems caused by fentanyl addiction. Our study provides a valuable resource for future investigations aimed at defining the role of metabolites in fentanyl addiction, which may help develop new pharmacotherapies.
    Keywords:  caudate putamen; conditioned place preference; fentanyl; hippocampus; metabolomics; plasma; prefrontal cortex
    DOI:  https://doi.org/10.3389/fphar.2026.1759491
  17. bioRxiv. 2026 Feb 11. pii: 2026.02.10.704675. [Epub ahead of print]
    Organelle communication networks rewire to support lipid metabolism during neuronal differentiation.
    Maria Clara Zanellati, Zachary Coman, Disha Bhowmik, Chih-Hsuan Hsu, Richa Basundra, Shannon N Rhoads, Ngudiankama R Mfulama, Brandie M Ehrmann, Mohanish Deshmukh, Sarah Cohen.
      Cell fate transitions require coordinated remodeling of intracellular organelles, but how the organelle interactome rewires during neurogenesis remains unclear. Here we combine multispectral imaging with quantitative organelle signature analysis to simultaneously map eight organelles at single-cell resolution as human induced pluripotent stem cells (iPSCs) differentiate into forebrain-like neurons. We find compartment and time-specific rescaling of organelles and a progressive increase in higher-order membrane contacts, with mitochondria emerging as an early interaction hub. Later, endoplasmic reticulum (ER)-organelle contacts dominate with ER-peroxisome contacts promoting plasmalogen biosynthesis, membrane homeostasis and synapse formation. Disrupting this contact impairs plasmalogen production, synaptic organization, and neuronal activity, identifying the ER-peroxisome axis as a key regulator of neuronal maturation.
    DOI:  https://doi.org/10.64898/2026.02.10.704675
  18. Genes (Basel). 2026 Feb 04. pii: 192. [Epub ahead of print]17(2):
    The Citric Acid Cycle Modulates Neurologic Health and Is a Therapeutic Target of Dietary and Genetic Modification in Metabolic Disease.
    Keri J Fogle, Sarah K Lindley, Sidney L Satterfield, Beakal A Amsalu, Joseph R Figura, Samantha L Eicher, Luke A Scherz, Michael J Palladino.
      Background/Objectives: Primary metabolic diseases including mitochondrial encephalomyopathies (ME), glycolytic enzymopathies, and disorders of lipid and amino acid metabolism can manifest with severe neurological and neuromuscular symptoms. Conversely, it is increasingly appreciated that primary neurodegenerative diseases can have metabolic etiology and pathophysiology. Pharmacological treatments have limited benefit for these classes of diseases, but dietary therapy is increasingly recognized as a tool for bolstering metabolic processes that can ameliorate neurological symptoms. The ketogenic diet is the best-established example, having long been used as a therapy for epilepsy. Replenishing metabolic intermediates (anaplerosis) especially substrates of the citric acid cycle (CAC) is currently being explored, with ongoing clinical trials of simple metabolic intermediates such as oxaloacetate or NAD+ to treat neurodegenerative diseases. We have shown ketogenic and anaplerotic therapies to be effective in a Drosophila model of ME; however, the full therapeutic potential and role of the CAC in neuronal health is still not well understood. Methods: Here, we have used genetic, behavioral, and dietary approaches to elucidate critical links between the CAC and neurological function. Results: We have found that stimulating the CAC can improve and sustain neurological health in the face of severe metabolic disease, and that its functions include a previously unrecognized role in maintaining normal circadian rhythms, whose disruption is often an early indicator or complicating factor in neurological and neurodegenerative disease. We investigated the hypothesis that the production of GTP by the CAC may be an important mechanistic contributor to the role of the CAC in neurological health and disease, and may underlie its therapeutic potential. Conclusions: Overall, our findings expand our understanding of the role of the CAC in neurological health and disease, support its development as a therapeutic target, and provide a foundation for further studies investigating the intersection between neurological disease and metabolic function.
    Keywords:  Leigh Syndrome; anaplerosis; circadian rhythms; citric acid cycle; genetics; ketogenic diet; mitochondrial encephalomyopathy; nucleoside diphosphate kinase
    DOI:  https://doi.org/10.3390/genes17020192
  19. Mov Disord. 2026 Feb 23.
    Brain Sphingolipid and Phospholipid Levels Are Altered in XK Disease.
    Gabriel Miltenberger-Miltenyi, Vasco A Conceição, Klaudia F Laborc, Attila Jones, John F Crary, Claudia De Sanctis, Emma L Thorn, Lily Yu-Chia Chiu, Stephanie McQuillan, Kurt Farrell, Renu Nandakumar, Safa Al-Sarraj, Dennis Dickson, Amie Hiller, Susan Morgello, Angelika Mühlebner, Esther Sammler, Claire Troakes, Wim Van Hecke, Henk-Jan Westeneng, Randall Woltjer, Zbigniew K Wszolek, Ruth H Walker.
       BACKGROUND: XK disease is a multisystem neurodegenerative disorder caused by mutations in the XK gene that codes for the lipid scramblase XK.
    OBJECTIVE: The aim was to describe the lipidomic spectrum in postmortem brain tissue from XK patients.
    METHODS: We measured the levels of 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of 5 XK patients and 6 controls.
    RESULTS: In XK patients, we observed increased levels of triacylglycerol, monoacylglycerol, phosphatidylserine, and ceramide in the CN. Acylated phosphatidylglycerol levels were reduced in both the CN and putamen. Acyl carnitine, dihydrosphingomyelin, and monosialodihexosylganglioside were reduced, whereas N-acyl phosphatidylethanolamine was increased in the DLPFC. N-Acyl serine was reduced in all three regions.
    CONCLUSIONS: Our findings provide initial evidence of abnormal sphingolipid and phospholipid concentrations in the brains of XK patients and may provide insights into mechanisms of neurodegeneration in this disease. © 2026 International Parkinson and Movement Disorder Society.
    Keywords:  XK disease; brain; phospholipid; sphingolipid
    DOI:  https://doi.org/10.1002/mds.70220
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