bims-medebr 2025-04-20 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–04–20
23 papers selected by
Regina F. Fernández, Johns Hopkins University

β-hydroxybutyrate enhances brain metabolism in normoglycemia and hyperglycemia, providing cerebroprotection in a mouse stroke model.
Editorial: Metabolic dysregulation in neurodegenerative diseases.
Energy metabolism disorders in migraine: triggers, pathways, and therapeutic repurposing.
Mitochondrial mayhem: Disrupting conserved N-terminal motifs in TANGO2 impacts its localization and function.
Ketone body supported respiration in murine isolated brain mitochondria is augmented by alpha-ketoglutarate and is optimized by neuronal SCOT expression.
Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging?
NDUFS8-Related Leigh Syndrome Mimicking a Leukodystrophy.
Starvation Induces Upregulation of Monocarboxylate Transport in Glial Cells at the Drosophila Blood-Brain Barrier.
Exogenous lactate infusion (ELI) in traumatic brain injury: higher dose is better?
Post-cerebral ischemia energy crisis: the role of glucose metabolism in the energetic crisis.
Effects of mitochondrial O-GlcNAcylation in pericytes after mechanical injury.
Upregulating mTOR/S6 K Pathway by CASTOR1 Promotes Astrocyte Proliferation and Myelination in Gpam-/--induced mouse model of cerebral palsy.
Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection.
Essential lipids enrich membrane-associated condensates to rescue synaptic morpho-functional deficits in a mouse model of autism.
Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
Sphingolipidoses: expanding the spectrum of α-synucleinopathies.
Recent Progress in N-Acylethanolamine Research: Biological Functions and Metabolism Regulated by Two Distinct N-Acyltransferases: cPLA2ε and PLAAT Enzymes.
Effect of Sphingomyelin and Vitamin D3 Intake on the Rabbit Brain.
Phosphatidate phosphatase Lipin1 alters mitochondria-associated endoplasmic reticulum membranes (MAMs) homeostasis: effects which contribute to the development of diabetic encephalopathy.
L-Carnitine and Mildronate Demonstrate Divergent Protective Effects on Mitochondrial DNA Quality Control and Inflammation Following Traumatic Brain Injury.
Mitochondrial Cardiolipin-Targeted Tetrapeptide, SS-31, Exerts Neuroprotective Effects Within In Vitro and In Vivo Models of Spinal Cord Injury.
Lipids: emerging actors in mitochondrial protein import.
Lipid Droplet in Lipodystrophy and Neurodegeneration.

J Cereb Blood Flow Metab. 2025 Apr 12. 271678X251334222

β-hydroxybutyrate enhances brain metabolism in normoglycemia and hyperglycemia, providing cerebroprotection in a mouse stroke model.

Deborah M Holstein, Afaf Saliba, Damian Lozano, Jiwan Kim, Kumar Sharma, James D Lechleiter.

  Hyperglycemia in poorly controlled diabetes is widely recognized as detrimental to organ dysfunction. However, the acute effects of hyperglycemia on brain metabolism and function are not fully understood. The potential protective benefit of ketone bodies on mitochondrial function in the brain has also not been well characterized. Here, we evaluated the acute effects of hyperglycemia and β-hydroxybutyrate (BHB) on brain metabolism by employing a novel approach leveraging adenosine triphosphate (ATP)-dependence of bioluminescence originating from luciferin-luciferase activity. Oxygen consumption rate was measured in ex vivo live brain punches to further evaluate mitochondrial function. Our data demonstrate that brain metabolism in mice is affected by acute exposure to high glucose. This short-term effect of glucose exposure was reduced by co-administration with the ketone body BHB. Additionally, we investigated the functional relevance of BHB using an in vivo photothrombotic stroke model to assess its cerebroprotective effects in presence or absence of acute hyperglycemia. BHB significantly reduced infarct size in the brain stroke model, providing functional evidence for its protective role in the brain. These findings suggest that BHB may effectively mitigate the adverse effects of metabolic stress and ischemic events on brain metabolism and function.

Keywords:  Acute hyperglycemia; brain metabolism; in vivo brain imaging; oxygen consumption rate; β-hydroxybutyrate

DOI:  https://doi.org/10.1177/0271678X251334222
Front Cell Neurosci. 2025 ;19 1591313

Editorial: Metabolic dysregulation in neurodegenerative diseases.

Maria Jimenez-Gonzalez.



Keywords:  brain; glucose; metabolism; mitochondria; neurodegeneration

DOI:  https://doi.org/10.3389/fncel.2025.1591313
Front Neurol. 2025 ;16 1561000

Energy metabolism disorders in migraine: triggers, pathways, and therapeutic repurposing.

Wen-Xiu Sun, Ting-Yan Chen, Mao-Mei Song, Ying-Jie Gao, Sui-Yi Xu.

  Many migraine triggers, such as stress, sleep deprivation, fatigue, strenuous exercise, and fasting, are potentially linked to disturbances in brain energy metabolism, mitochondrial function, and oxidative stress. Alongside efforts to avoid modifiable factors, prophylactic migraine treatments that target brain energy metabolism have garnered increasing attention. However, the current evidence supporting the use of energy-modulating drugs in migraine treatment guidelines remains weak. This narrative review explores the relationship between energy metabolism and cortical spreading depression susceptibility, metabolic alterations in migraine (including glucose and insulin metabolism, insulin resistance, lipid metabolism, and energy metabolism imaging markers), oxidative stress and antioxidant defenses, mitochondrial dysfunction, and the role of energy metabolism-targeted medications in migraine management. Nutrients may help improve mitochondrial function, thereby alleviating brain energy metabolism deficits and oxidative stress in migraine.

Keywords:  antioxidant defenses; insulin resistance; lipid metabolism; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3389/fneur.2025.1561000
J Cell Biol. 2025 May 05. pii: e202503010. [Epub ahead of print]224(5):

Mitochondrial mayhem: Disrupting conserved N-terminal motifs in TANGO2 impacts its localization and function.

Sarah E Sandkuhler, Samuel J Mackenzie.

TANGO2 deficiency in humans leads to progressive neurological impairment, punctuated by life-threatening metabolic crises. In this issue, Lujan and colleagues demonstrate that TANGO2 localizes within the mitochondrial lumen and binds acyl-CoA species, potentially implicating it as a lipid trafficking protein.

DOI: https://doi.org/10.1083/jcb.202503010
Am J Physiol Endocrinol Metab. 2025 Apr 17.

Ketone body supported respiration in murine isolated brain mitochondria is augmented by alpha-ketoglutarate and is optimized by neuronal SCOT expression.

Xin C Davis, Colin S McCoin, E Matthew Morris, Julie Allen, Harrison D Stierwalt, Edziu Franczak, Eric D Queathem, Kyle L Fulghum, Patrycja Puchalska, Peter A Crawford, John P Thyfault.

  Ketone bodies are increasingly examined as an alternative fuel source for the known decreases in glucose utilization that occur with neurodegeneration. Here, we established a protocol to maximize ketone body respiration in isolated brain mitochondria, while quantifying acetyl-CoA and energy charge via liquid chromatography-tandem mass spectrometry in control mice compared to mice with neuron-specific deletion of succinyl- CoA-3-oxoacid-CoA transferase (SCOT), required for CoA transfer from succinyl-CoA to AcAc to support its oxidation. Maximal ADP-dependent AcAc respiration occurred at 1 mM; however, the percent increase above basal was minimal (~15%). Alpha- ketoglutarate (αKG) substantially increased AcAc-dependent respiration in isolated brain mitochondria, putatively through the generation of succinyl-CoA. Using mice with neuron- specific deletion of SCOT, we also examined brain mitochondrial respiration of AcAc and resulting acetyl CoA and energy charge (cellular energy availability via adenosine nucleotide ratios of ATP, ADP, and AMP). As expected, isolated brain mitochondria from SCOT-KO mice had lower AcAc State 3 respiration than control mice. Surprisingly, we did not find differences in mitochondrial energy charge between SCOT control and neuron SCOT-KO mice despite decreased acetyl-CoA level in SCOT-KO mice when AcAc was used as the substrate. In conclusion, we show that KG enhances ketone-supported respiration rate in isolated brain mitochondria, and ketone metabolism in neurons affects acetyl-CoA level in brain mitochondria but not energy charge. Future work will determine if diet, exercise, sex, or age impacts ketone-supported respiration rates in conjunction with differences in markers of brain health.

Keywords:  Brain; Ketone; Mitochondria respiration; SCOT

DOI:  https://doi.org/10.1152/ajpendo.00058.2025
Aging Dis. 2025 Apr 08.

Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging?

Xinxin Zuo.

Down syndrome (DS), caused by trisomy of chromosome 21 (HSA21), is a complex condition associated with neurodevelopmental impairments and accelerated brain aging, often culminating in early-onset Alzheimer's disease (AD). Central to this accelerated aging is mitochondrial imbalance, characterized by disrupted energy metabolism, increased oxidative stress, impaired dynamics, and defective quality control mechanisms like mitophagy. These abnormalities exacerbate neuronal vulnerability, driving cognitive decline and neurodegeneration. This review examines the genetic and biochemical underpinnings of mitochondrial dysfunction in DS, with a focus on the role of HSA21-encoded genes. We also highlight how mitochondrial dysfunction, amplified by oxidative stress and HSA21 gene dosage effects, converges with cellular senescence and neuroinflammation to accelerate Alzheimer-like pathology and brain aging in DS. Finally, we discuss emerging therapeutic strategies targeting mitochondrial pathways, which hold promise for mitigating neurodegenerative phenotypes and improving outcomes in DS.

DOI: https://doi.org/10.14336/AD.2025.0189
J Child Neurol. 2025 Apr 16. 8830738251328199

NDUFS8-Related Leigh Syndrome Mimicking a Leukodystrophy.

Bailyn Hogue, Mekka R Garcia, Connolly G Steigerwald, Maria J Borja, Nicolas J Abreu.

  Leigh syndrome is a progressive infantile neurodegenerative disorder of mitochondrial metabolism that often leads to decompensation in the setting of metabolic stress. It is genetically heterogenous with varied inheritance patterns. One subtype includes NDUFS8-related autosomal recessive Leigh syndrome. This nuclear gene encodes a complex I subunit of the mitochondrial complex chain. Although Leigh syndrome is typically associated with basal ganglia and brainstem involvement, cases of confluent white matter disease have been described with NDUFS8-related disorders. We present the case of a 6-month-old girl with initial imaging suggestive of a leukodystrophy, later found to have a novel homozygous variant in NDUFS8. In conjunction with the clinical course, a diagnosis of Leigh syndrome was made. This case highlights that mitochondrial disorders should be considered on the differential for confluent cerebral white matter disease in early childhood.

Keywords:  Leigh syndrome; NDUFS8; leukodystrophy; leukoencephalopathy; white matter

DOI:  https://doi.org/10.1177/08830738251328199
Glia. 2025 Apr 16.

Starvation Induces Upregulation of Monocarboxylate Transport in Glial Cells at the Drosophila Blood-Brain Barrier.

Andrés González-Gutiérrez, Jorge Gaete, Andrés Esparza, Andrés Ibacache, Esteban G Contreras, Jimena Sierralta.

  Living organisms can sense and adapt to constant changes in food availability. Maintaining a homeostatic supply of energy molecules is crucial for animal survival and normal organ functioning, particularly the brain, due to its high-energy demands. However, the mechanisms underlying brain adaptive responses to food availability have not been completely established. The nervous system is separated from the rest of the body by a physical barrier called the blood-brain barrier (BBB). In addition to its structural role, the BBB regulates the transport of metabolites and nutrients into the nervous system. This regulation is achieved through adaptive mechanisms that control the transport of nutrients, including glucose and monocarboxylates such as lactate, pyruvate, and ketone bodies. In Drosophila melanogaster, carbohydrate transporters increase their expression in glial cells of the BBB in response to starvation. However, changes in the expression or activity of Drosophila monocarboxylate transporters (dMCTs) at the BBB have not yet been reported. Here, we show that neuronal ATP levels remain unaffected despite reduced energy-related metabolites in the hemolymph of Drosophila larvae during starvation. Simultaneously, the transport of lactate and beta-hydroxybutyrate increases in the glial cells of the BBB. Using genetically encoded sensors, we identified Yarqay as a proton-coupled monocarboxylate transporter whose expression is upregulated in the subperineurial glia of the BBB during starvation. Our findings reveal a novel component of the adaptive response of the brain to starvation: the increase in the transport of monocarboxylates across the BBB, mediated by Yarqay, a novel dMCT enriched in the BBB.

Keywords:   Drosophila melanogaster ; blood–brain barrier; brain energy metabolism; genetically encoded sensors; monocarboxylate transporters; subperineurial glial cells

DOI:  https://doi.org/10.1002/glia.70021
Crit Care. 2025 Apr 14. 29(1): 153

Exogenous lactate infusion (ELI) in traumatic brain injury: higher dose is better?

Paul Vespa, Stephanie Wolahan, Manuel Buitrago-Blanco, Courtney Real, Jesus Ruiz-Tejeda, David L McArthur, Jeffrey N Chiang, Denes Agoston, Thomas C Glenn.

   BACKGROUND/OBJECTIVE: Traumatic brain injury (TBI) is a life-threatening critical neurological injury resulting in widespread metabolic dysfunction in need of novel metabolic therapy. Exogenous lactate appears to improve brain metabolism, but the dose of lactate required remains uncertain. However, the ideal dose of lactate remains unclear. We present a comparison of low vs high dose exogenous sodium lactate infusion in a small cohort and the previous existing literature. We propose a systematic protocol to better study the question of dose-effect n in a future larger study.
METHODS: We analyzed the metabolic and physiologic effects of various doses of exogenous sodium lactate infusion (ELI) in the existing published literature and our own, single center cohort of patients with coma from severe TBI. Low dose ELI targeting arterial lactate concentration of 2-3 mMol was compared with high dose ELI targeting 4-6 mM. Effects of ELI on brain metabolism and intracranial pressure (ICP) were reviewed. A precision high-dose protocol was piloted and results compared against the existing literature.
RESULTS: Across various studies, metabolic response to ELI was variable and not consistently beneficial. High-dose ELI targeting arterial concentration of 4-6 mM resulted in consistent metabolic improvement and in ICP reduction (p < 0.01). The precision high dose protocol reliably resulted in higher arterial concentration.
CONCLUSIONS: High dose ELI appears to have more consistent beneficial effects on brain metabolism and intracranial pressure.
TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02776488. Date registered: 2016-05-17. Retrospectively Registered.

Keywords:  Coma; Intracranial pressure; Lactate; Metabolic crisis; Oxidative metabolism; Traumatic brain injury

DOI:  https://doi.org/10.1186/s13054-025-05374-y
Brain Inj. 2025 Apr 16. 1-11

Post-cerebral ischemia energy crisis: the role of glucose metabolism in the energetic crisis.

Jia-Ting Li, Dian Ou, Yi-Ming Shi, Le Bao, Yan-Ling Li, Ting-Ting Xiong, Yang Bai, Huang Ding.

   BACKGROUND: Cells universally employ an efficiency-driven metabolic switch mechanism during nutritional changes, growth, and differentiation, transitioning from oxidative phosphorylation (OXPHOS) to glycolysis to ensure survival under hypoxic conditions or high energy demands. In cerebral ischemia, inadequate blood supply causes oxygen and energy deprivation, prompting brain cells to initiate glycolytic reprogramming to meet urgent energy needs. While this adaptation is a temporary solution, it may lead to lactic acidosis, aggravated inflammation, and increased free radical production. Prolonged reperfusion with sustained glycolysis can exacerbate brain cell damage, potentially causing irreversible harm.
OBJECTIVES: This review systematically examines the dynamic changes in glucose metabolic transport mechanisms and the roles of immediate, early, intermediate, and late responder cells, along with their regulatory factors, in glycolytic reprogramming.
METHODS: Using a temporal analysis framework based on the body's natural response sequence to pathological events, we elucidate how cells at different stages collaborate to address glucose metabolism reprogramming under pathological conditions.
CONCLUSIONS: Reversing glucose metabolism reprogramming and inhibiting glycolysis may improve the pathological processes of ischemic stroke, offering potential therapeutic benefits.

Keywords:  Chinese medicine; Ischemic cerebral stroke; glial cells; glial-vascular unit; glucose metabolism; glycometabolic reprogramming

DOI:  https://doi.org/10.1080/02699052.2025.2492751
Brain Res. 2025 Apr 16. pii: S0006-8993(25)00206-9. [Epub ahead of print] 149647

Effects of mitochondrial O-GlcNAcylation in pericytes after mechanical injury.

Ji Hyun Park, Dong Bin Back, Shuzhen Guo, Masayoshi Tanaka, Hajime Takase, Michael J Whalen, Ken Arai, Kazuhide Hayakawa, Eng H Lo.

  Damage to vascular cells comprise an important part of traumatic brain injury (TBI) but the underlying pathophysiology remains to be fully elucidated. Here, we investigate the loss of O-Linked β-N-acetylglucosamine(O-GlcNAc) modification (O-GlcNAcylation) and mitochondrial disruption in vascular pericytes as a candidate mechanism. In mouse models in vivo, TBI rapidly induces vascular oxidative stress and down-regulates mitochondrial O-GlcNAcylation. In pericytes but not brain endothelial cultures in vitro, mechanical stretch injury down-regulates mitochondrial O-GlcNAcylation. This is accompanied by disruptions in mitochondrial dynamics, comprising a decrease in mitochondrial fusion and an increase in mitochondrial fission proteins. Pharmacologic rescue of endogenous mitochondrial O-GlcNAcylation with an O-GlcNAcase inhibitor Thiamet-G or addition of exogenous O-GlcNAc-enhanced extracellular mitochondria ameliorates the mitochondrial disruption in pericytes damaged by mechanical injury. Finally, in a pericyte-endothelial co-culture model, mechanical injury increased trans-cellular permeability; adding Thiamet-G or O-GlcNAc-enhanced extracellular mitochondria rescued trans-cellular permeability following mechanical injury. These proof-of-concept findings suggest that mitochondrial O-GlcNAcylation in pericytes may represent a novel therapeutic target for ameliorating oxidative stress and vascular damage after mechanical injury following TBI.

Keywords:  Mitochondrial dynamics; O-GlcNAcylation; Oxidative stress; Traumatic brain injury; Vascular pericyte

DOI:  https://doi.org/10.1016/j.brainres.2025.149647
Mol Neurobiol. 2025 Apr 15.

Upregulating mTOR/S6 K Pathway by CASTOR1 Promotes Astrocyte Proliferation and Myelination in Gpam-/--induced mouse model of cerebral palsy.

Zhaofang Chen, Liru Liu, Xiaolin Guo, Yage Zhang, Mengru Zhong, Yi Xu, Tingting Peng, Tingting Peng, Yuan Zhang, Qingfen Hou, Danxia Fan, Ting Gao, Lu He, Hongmei Tang, Hao Hu, Kaishou Xu.

  GPAM, a key enzyme for lipid synthesis, is predominantly expressed in astrocytes (ASTs), where it facilitates lipid supply for myelin formation. Our previous studies identified GPAM as a novel causative gene for cerebral palsy (CP) and led to the development of a CP mouse model with GPAM deficiency (Gpam-/-). The model closely recapitulated the clinical phenotype of children with CP, due to the restricted proliferation of ASTs in the brain, reduced the amount of lipid, thinner brain white matter, and myelin dysplasia. The mammalian target of rapamycin (mTOR) pathway plays an important role in cell proliferation and lipid synthesis. Cytosolic arginine sensor (CASTOR1) interacts with GATOR2 to regulate mTOR complex 1 (mTORC1). Targeted degradation of CASTOR1 can activate the mTOR pathway. However, it remains unclear the involvement of mTOR pathway in neurological diseases such as CP. In this study, we demonstrated that the mTOR pathway was inhibited in Gpam-/- mice. Notably, CASTOR1 could regulate the activity of mTOR/S6K pathway, functioning as a negative upstream regulator. Furthermore, inhibition of CASTOR1 upregulated mTOR/S6K signaling, promoting astrocyte proliferation and myelination, which in turn enhanced motor function in the Gpam-/--induced CP mouse model. Collectively, these findings reveal the role of astrocytic mTOR in the pathogenesis of CP mice, broaden the therapeutic strategies, and provide a promising candidate target for CP treatment.

Keywords:  Astrocyte; Cerebral palsy; Genetic animal mode; MTOR/S6 K; Motor ability; Myelination

DOI:  https://doi.org/10.1007/s12035-025-04901-w
bioRxiv. 2025 Apr 05. pii: 2025.04.04.647282. [Epub ahead of print]

Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection.

Thomas J Waller, Catherine A Collins, Monica Dus.

Neurons rely on tightly regulated metabolic networks to sustain their high-energy demands, particularly through the coupling of glycolysis and oxidative phosphorylation. Here, we investigate the role of pyruvate kinase (PyK), a key glycolytic enzyme, in maintaining axonal and synaptic integrity in the Drosophila melanogaster neuromuscular system. Using genetic deficiencies in PyK, we show that disrupting glycolysis induces progressive synaptic and axonal degeneration and severe locomotor deficits. These effects require the conserved dual leucine zipper kinase (DLK), Jun N-terminal kinase (JNK), and activator protein 1 (AP-1) Fos transcription factor axonal damage signaling pathway and the SARM1 NADase enzyme, a key driver of axonal degeneration. As both DLK and SARM1 regulate degeneration of injured axons (Wallerian degeneration), we probed the effect of PyK loss on this process. Consistent with the idea that metabolic shifts may influence neuronal resilience in context-dependent ways, we find that pyk knockdown delays Wallerian degeneration following nerve injury, suggesting that reducing glycolytic flux can promote axon survival under stress conditions. This protective effect is partially blocked by DLK knockdown and fully abolished by SARM1 overexpression. Together, our findings help bridge metabolism and neurodegenerative signaling by demonstrating that glycolytic perturbations causally activate stress response pathways that dictate the balance between protection and degeneration depending on the system's state. These results provide a mechanistic framework for understanding metabolic contributions to neurodegeneration and highlight the potential of metabolism as a target for therapeutic strategies.
Abstract Figure:

DOI: https://doi.org/10.1101/2025.04.04.647282
Cell Rep. 2025 Apr 14. pii: S2211-1247(25)00344-4. [Epub ahead of print]44(5): 115573

Essential lipids enrich membrane-associated condensates to rescue synaptic morpho-functional deficits in a mouse model of autism.

Jason Arsenault, Tian Kong, Rayan Saghian, Octavia Yifang Weng, Salil Saurav Pathak, Chengye Yang, Owen Y Chao, Gaddy Rakhaminov, Julie D Forman-Kay, Jonathon A Ditlev, Yi-Mei Yang, Lu-Yang Wang.

  Synaptic proteins form intracellular condensates with their scaffolds, but it is unknown whether and how essential lipids transform dynamic cytosolic condensates into stable, functional macromolecular assemblies at the membrane. We show that docosahexaenoic acid (DHA), independent of canonical fatty acid receptor 4 signaling, facilitates the re-localization of cytosolic "full-droplet" condensates composed of the key synaptic elements PSD95 and Kv1.2 to the plasma membrane as "half-droplets." To exploit the therapeutic potential of DHA in vivo, we briefly place juvenile wild-type and Fmr1 KO mice, modeling human fragile X syndrome (FXS), under DHA-enriched or -depleted diets. DHA reverses the inhibitory overtone by promoting the re-localization of presynaptic PSD95-Kv1.2 condensates to interneuron terminal membranes and corrects morpho-functional synaptic defects and stereotypic behaviors. These findings reveal an unexpected role of essential lipids in translocating dynamic condensates into stable synaptic condensates, providing long-lasting benefits for rectifying excitation-inhibition imbalance in FXS and potentially other neurodevelopmental disorders.

Keywords:  CP: Neuroscience; biomolecular condensate; cerebellum; docosahexaenoic acid; fragile X syndrome; neuroinflammation; phase separation; voltage gated potassium channel

DOI:  https://doi.org/10.1016/j.celrep.2025.115573
Sci Adv. 2025 Apr 18. 11(16): eadw1489

Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.

Maximilian Sichrovsky, Denis Lacabanne, Jonathan J Ruprecht, Jessica J Rana, Klaudia Stanik, Mariangela Dionysopoulou, Alice P Sowton, Martin S King, Scott A Jones, Lee Cooper, Steven W Hardwick, Giulia Paris, Dimitri Y Chirgadze, Shujing Ding, Ian M Fearnley, Shane M Palmer, Els Pardon, Jan Steyaert, Vanessa Leone, Lucy R Forrest, Sotiria Tavoulari, Edmund R S Kunji.

The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction-associated steatotic liver disease. We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo-electron microscopy, revealing its alternating access rocker-switch mechanism. The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions.

DOI: https://doi.org/10.1126/sciadv.adw1489
J Neural Transm (Vienna). 2025 Apr 17.

Sphingolipidoses: expanding the spectrum of α-synucleinopathies.

Daniel Erskine, Agnieszka K Bronowska, Tiago F Outeiro, Johannes Attems.

  Although α-synuclein pathology is typically associated with Lewy body diseases and multiple systems atrophy, increasing evidence indicates that it also occurs in a group of lysosomal storage disorders termed sphingolipidoses caused by the incomplete degradation, and subsequent accumulation, of a class of lipids termed sphingolipids. Notably, a number of genes that cause sphingolipidoses are also risk genes for Lewy body diseases, suggesting aetiological links between these distinct disorders. In the present review, we discuss the sphingolipidoses in which α-synuclein pathology has been reported: Gaucher disease, Krabbe disease, metachromatic leukodystrophy, Tay-Sachs disease and Anderson-Fabry disease, and describe the characteristic clinical and pathological features of these disorders, in addition to the evidence suggesting α-synuclein pathology occurs in these disorders. Finally, we evaluate the pathological mechanisms that underlie these rare disorders, with particular attention to how the enzymatic deficiency, substrate accumulation, or both, could contribute to the genesis of α-synuclein pathology and the implications of this for Lewy body diseases.

Keywords:  Alpha-synuclein; Lewy; Lysosomal storage disorder; Neurodegeneration; Parkinson’s; Sphingolipid

DOI:  https://doi.org/10.1007/s00702-025-02925-z
Int J Mol Sci. 2025 Apr 03. pii: 3359. [Epub ahead of print]26(7):

Recent Progress in N-Acylethanolamine Research: Biological Functions and Metabolism Regulated by Two Distinct N-Acyltransferases: cPLA2ε and PLAAT Enzymes.

Toru Uyama, Sumire Sasaki, Miki Okada-Iwabu, Makoto Murakami.

  N-Acylethanolamines (NAEs) are a class of lipid mediators that consist of long-chain fatty acids condensed with ethanolamine and exert various biological activities depending on their fatty acyl groups. NAEs are biosynthesized from membrane phospholipids by two-step reactions or alternative multi-step reactions. In the first reaction, N-acyltransferases transfer an acyl chain from the sn-1 position of phospholipids to the amino group (N position) of phosphatidylethanolamine (PE), generating N-acyl-PE (NAPE), a precursor of NAE. So far, two types of N-acyltransferases have been identified with different levels of Ca2+-dependency: cytosolic phospholipase A2 ε (cPLA2ε) as a Ca2+-dependent N-acyltransferase and phospholipase A and acyltransferase (PLAAT) enzymes as Ca2+-independent N-acyltransferases. Recent in vivo studies using knockout mice with cPLA2ε and PLAAT enzymes, combined with lipidomic approaches, have clarified their roles in the skin and brain and in other physiological events. In this review, we summarize the current understanding of the functions and properties of these enzymes.

Keywords:  N-acylethanolamine; N-acyltransferase; PLA1; PLA2; PLAAT; cPLA2ε; endocannabinoid; glycerophospholipid; inflammation; organelle

DOI:  https://doi.org/10.3390/ijms26073359
Int J Mol Sci. 2025 Apr 01. pii: 3269. [Epub ahead of print]26(7):

Effect of Sphingomyelin and Vitamin D3 Intake on the Rabbit Brain.

Federico Fiorani, Alda Quattrone, Samuela Cataldi, Roberto Maria Pellegrino, Carla Emiliani, Cataldo Arcuri, Alessandra Mirarchi, Giulio Curone, Laura Menchetti, Tommaso Beccari, Claudia Floridi, Martina Mandarano, Gabriele Brecchia, Elisabetta Albi.

  Sphingomyelin is a crucial molecule in the sphingolipid metabolic pathway, and its action is closely related to that of vitamin D3. Both molecules are recognized for their involvement in brain pathophysiology. In this study, the effect of a sphingomyelin + vitamin D3-enriched diet was investigated in rabbits. The results showed a strong immunopositive GFAP staining in the brain's white matter. Furthermore, a remodeling of the balance between glycero-phospholipids and ether-phospholipids was observed in the brain, along with an increase in ceramides and hexose ceramides, molecules relevant for the structure, function, and stability of myelin. Taken together, these findings provide clues as to how the combination sphingomyelin + vitamin D3 may play a vital role in normal brain physiology and could potentially be leveraged in the context of neurodegenerative diseases.

Keywords:  brain; diet; rabbit; sphingomyelin; vitamin D3

DOI:  https://doi.org/10.3390/ijms26073269
J Neuroinflammation. 2025 Apr 18. 22(1): 111

Phosphatidate phosphatase Lipin1 alters mitochondria-associated endoplasmic reticulum membranes (MAMs) homeostasis: effects which contribute to the development of diabetic encephalopathy.

Shan Huang, Mengyu Hua, Wei Liu, Ziyun Zhuang, Xiaolin Han, Xiaochen Zhang, Zhonghao Liang, Xiaojing Liu, Nengjun Lou, Shuyan Yu, Shihong Chen, Xianghua Zhuang.

  Diabetic encephalopathy (DE) is a common, chronic central nervous system complication of diabetes mellitus, and represents a condition without a clear pathogenesis or effective therapy. Findings from recent studies have indicated that a dyshomeostasis of mitochondria-associated endoplasmic reticulum membranes (MAMs) may be involved in the development of neurodegenerative diseases such as DE. MAMs represent a dynamic contact site between mitochondrial and endoplasmic reticulum (ER) membranes, where phospholipid components are exchanged with each other. Previous work within our laboratory has revealed that Lipin1, a critical enzyme related to phospholipid synthesis, is involved in the pathogenesis of DE. Here, we show that Lipin1 is downregulated within the hippocampus of a DE mouse model, an effect which was accompanied with a decrease in MAMs. Knockdown of Lipin1 in the hippocampus of normal mice resulted in a reduction of MAMs, ER stress, abnormal mitochondrial function, as well as impaired synaptic plasticity and cognitive function. These same phenomena were observed in the DE model, while an upregulation of Lipin1 within the hippocampus of DE mice improved these symptoms. Low levels of Lipin1 in DE mice were also associated with neuroinflammation, while an overexpression of Lipin1 significantly ameliorated the neuroinflammation observed in DE mice. In conclusion, Lipin1 ameliorates pathological changes associated with DE in a mouse model via prevention of dyshomeostasis in MAMs. Such findings suggest that Lipin1 may be serve as a new potential target for the treatment of DE.

Keywords:  Cognitive dysfunction; Diabetic encephalopathy; Lipin1; MAMs; Mitochondria

DOI:  https://doi.org/10.1186/s12974-025-03441-3
Int J Mol Sci. 2025 Mar 22. pii: 2902. [Epub ahead of print]26(7):

L-Carnitine and Mildronate Demonstrate Divergent Protective Effects on Mitochondrial DNA Quality Control and Inflammation Following Traumatic Brain Injury.

Artem P Gureev, Veronika V Nesterova, Polina I Babenkova, Mikhail E Ivanov, Egor Y Plotnikov, Denis N Silachev.

  Traumatic brain injuries (TBIs) are a serious problem affecting individuals of all ages. Mitochondrial dysfunctions represent a significant form of secondary injury and may serve as a promising target for therapeutic intervention. Our research demonstrated that craniotomy, which precedes the experimental induction of trauma in mice, can cause considerable damage to mitochondrial DNA (mtDNA), disrupt the regulatory expression of angiogenesis, and increase inflammation. However, the reduction in the mtDNA copy number and glial activation occur only after a direct impact to the brain. We explored two potential therapeutic agents: the dietary supplement L-carnitine-a potential reserve source of ATP for the brain-and the cardiac drug mildronate, which inhibits L-carnitine but activates alternative compensatory pathways for the brain to adapt to metabolic disturbances. We found that L-carnitine injections could protect against mtDNA depletion by promoting mitochondrial biogenesis. However, they also appeared to aggravate inflammatory responses, likely due to changes in the composition of the gut microbiome. On the other hand, mildronate enhanced the expression of genes related to angiogenesis while also reducing local and systemic inflammation. Therefore, both compounds, despite their opposing metabolic effects, have the potential to be used in the treatment of secondary injuries caused by TBI.

Keywords:  L-carnitine; gene expression; gut microbiome; inflammation; mildronate; mitochondrial DNA; traumatic brain injury

DOI:  https://doi.org/10.3390/ijms26072902
Int J Mol Sci. 2025 Apr 02. pii: 3327. [Epub ahead of print]26(7):

Mitochondrial Cardiolipin-Targeted Tetrapeptide, SS-31, Exerts Neuroprotective Effects Within In Vitro and In Vivo Models of Spinal Cord Injury.

Baylen Ravenscraft, Do-Hun Lee, Heqiao Dai, Abbie Lea Watson, Gabriela Inés Aparicio, Xianlin Han, Ling-Xiao Deng, Nai-Kui Liu.

  Spinal cord injury (SCI) affects millions globally, leading to severe motor and sensory deficits with no effective clinical treatment. Cardiolipin (CL), a mitochondria-specific phospholipid, plays a critical role in bioenergetics and apoptosis. Emerging evidence suggests that CL alterations contribute to secondary SCI pathology, but their precise role and underlying mechanisms remain fully understudied. In this study, we investigated the protective effects of SS-31 on CL alteration, neuronal death, tissue damage, and behavioral recovery after SCI using both in vitro and in vivo models, lipidomics analysis, histological evaluation, and behavioral assessments. In vitro investigations used primary spinal cord neuron cultures, challenged with either rotenone or glutamatergic excitotoxicity, with protective capabilities measured via cell death assays and neurite morphological analysis. In vivo investigations used female adult C57Bl/6 mice, challenged with a contusive SCI. The results showed that SS-31 reduced rotenone- and glutamate-induced mitochondrial dysfunction and neuronal death in a dose-dependent manner in vitro. Additionally, SS-31 attenuated rotenone- and glutamate-induced neurite degeneration in vitro. Lipidomics analysis revealed a reduction in CL at 24 h post-SCI in adult mice, which was attenuated by SS-31 in a dose-dependent manner. Consistent with this effect, SS-31 improved behavioral recovery after SCI in adult mice, although it had no significant effect on tissue damage. These findings suggest that CL alteration may play a key role in the pathogenesis of SCI, at least in the C57BL/6 mouse, and as such could be an attractive therapeutic target for ameliorating secondary SCI.

Keywords:  SS-31; cardiolipin; lipid; mitochondrial function; neuroprotection; spinal cord injury

DOI:  https://doi.org/10.3390/ijms26073327
Trends Biochem Sci. 2025 Apr 15. pii: S0968-0004(25)00060-X. [Epub ahead of print]

Lipids: emerging actors in mitochondrial protein import.

Mayra A Borrero-Landazabal, Vanessa Linke, Agnieszka Chacinska.

  Lipids are emerging as functional players in mitochondrial protein import beyond constituting membranes. Cryo-electron microscopy structures of protein translocases such as translocase of the outer membrane (TOM) and insertases such as translocase of the inner membrane (TIM22) link lipids to protein import by suggesting structural and functional roles for lipids in protein translocation and insertion, and for protein insertases in lipid scrambling.

Keywords:  membrane complexes; mitochondrial biology; mitochondrial protein import; protein–lipid interactions

DOI:  https://doi.org/10.1016/j.tibs.2025.03.011
Biol Cell. 2025 Apr;117(4): e70009

Lipid Droplet in Lipodystrophy and Neurodegeneration.

Priyatama Behera, Monalisa Mishra.

  Lipid droplets are ubiquitous yet distinct intracellular organelles that are gaining attention for their uses outside of energy storage. Their formation, role in the physiological function, and the onset of the pathology have been gaining attention recently. Their structure, synthesis, and turnover play dynamic roles in both lipodystrophy and neurodegeneration. Factors like development, aging, inflammation, and cellular stress regulate the synthesis of lipid droplets. The biogenesis of lipid droplets has a critical role in reducing cellular stress. Lipid droplets, in response to stress, sequester hazardous lipids into their neutral lipid core, preserving energy and redox balance while guarding against lipotoxicity. Thus, the maintenance of lipid droplet homeostasis in adipose tissue, CNS, and other body tissues is essential for maintaining organismal health. Insulin resistance, hypertriglyceridemia, and lipid droplet accumulation are the severe metabolic abnormalities that accompany lipodystrophy-related fat deficit. Accumulation of lipid droplets is detected in almost all neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and Hereditary spastic paraplegia. Hence, the regulation of lipid droplets can be used as an alternative approach to the treatment of several diseases. The current review summarizes the structure, composition, biogenesis, and turnover of lipid droplets, with an emphasis on the factors responsible for the accumulation and importance of lipid droplets in lipodystrophy and neurodegenerative disease.

Keywords:  cellular stress; lipid droplet; lipodystrophy; neurodegenerative diseases

DOI:  https://doi.org/10.1111/boc.70009