bims-medebr 2025-06-08 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–06–08
fifteen papers selected by
Regina F. Fernández, Johns Hopkins University

A Bird's-Eye View of Glycolytic Upregulation in Activated Brain: The Major Fate of Lactate Is Release From Activated Tissue, Not Shuttling to Nearby Neurons.
Tissue-Specific Regulation of Fatty Acid Metabolism in a Mouse Model of Isolated Complex I Deficiency.
Combining old with new: A novel approach to studying human brain metabolism.
Neural Metabolic Networks: Key Elements of Healthy Brain Function.
APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses.
Impairment of Tricarboxylic Acid Cycle (TCA) Cycle in Alzheimer's Disease: Mechanisms, Implications, and Potential Therapies.
Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh Syndrome mice.
GM1 oligosaccharide-mediated rescue in GBA-linked Parkinson's disease via modulation of lysosomal and mitochondrial dysfunctions.
Role of Lysophosphatidic Acid in Neurological Diseases: From Pathophysiology to Therapeutic Implications.
Endolysosomal processing of neuron-derived signaling lipids regulates autophagy and lipid droplet degradation in astrocytes.
Stearoyl-CoA-Desaturase Inhibition normalizes brain lipid saturation, alpha-synuclein homeostasis, and motor function in mutant Gba1-Parkinson mice.
Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects.
Design and Synthesis of Novel PET Radiotracers for Imaging Sphingosine-1-Phosphate Receptor 5 (S1PR5) in the Brain.
The effect of triheptanoin treatment on clinical and laboratory outcomes in patients with long-chain fatty acid oxidation disorder.
Overexpression of thioredoxin 1 contributes to neuroprotection through ATM activation and pentose phosphate pathway modulation after traumatic brain injury.

J Neurochem. 2025 Jun;169(6): e70111

A Bird's-Eye View of Glycolytic Upregulation in Activated Brain: The Major Fate of Lactate Is Release From Activated Tissue, Not Shuttling to Nearby Neurons.

Gerald A Dienel, Douglas L Rothman, Silvia Mangia.

  Glucose is the major, obligatory fuel for the brain, and nearly all glucose is oxidized in the awake, resting state. However, during activation, much of the glucose is not oxidized even though adequate oxygen is available, ATP demand is increased, and glycolysis generates less ATP than oxidation. The fate of the lactate produced by glycolysis is a highly debated topic, in part because its origin and fate in the living brain are difficult to measure. One idea has been that astrocytes generate lactate and shuttle it to neurons as a major fuel, but critical elements of the shuttle model are not validated, and there is no compelling evidence to support shuttling coupled with oxidation in vivo. Metabolic brain imaging reveals rapid loss of labeled metabolites of glucose from activated tissue that is mediated by lactate transporters and gap junctional trafficking among astrocytes. Lactate is highly labeled by [13C- and 14C]glucose, it is diffusible, and it is quickly released to blood and the perivascular-lymphatic drainage system. During intense sensory stimulation, astrocytic glycogen is consumed at half the rate of glucose by all brain cells; it is a major fuel. The oxygen-carbohydrate metabolic mismatch increases when glycogen is included in the calculation, revealing that glycogen is not oxidized. Although the energetics of brain activation is complex, metabolic modeling with comparison to a wide range of experimental data relating metabolism to neurotransmission strongly supports two concepts: (i) glycogenolysis in astrocytes spares blood-borne glucose for activated neurons, and (ii) the increase in cerebral blood flow in excess of oxygen consumption removes protons produced by glycolytic metabolism to maintain tissue pH, pO2, and pCO2 homeostasis. Several studies have identified processes and situations that involve neuronal aerobic glycolysis, and a better understanding of the roles of glycolysis in neuron-astrocyte interactions and functional metabolism in the normal and diseased brain is required.

Keywords:  astrocyte; brain activation; glucose; glycogen; lactate; neuron

DOI:  https://doi.org/10.1111/jnc.70111
Proteomics. 2025 Jun 01. e13969

Tissue-Specific Regulation of Fatty Acid Metabolism in a Mouse Model of Isolated Complex I Deficiency.

Sibonelo Glen Khumalo, Jeremie Zander Lindeque, Marianne Venter.

  Isolated complex I deficiency (ICD) is commonly associated with mitochondrial diseases and closely mimics subacute necrotising encephalomyelopathy. This disorder is characterised by metabolic perturbations that affect energy metabolism pathways, including fatty acid metabolism. Here, we examined the tissue-specific changes in fatty acid metabolism in the Ndufs4 KO mice by employing mass-spectrometry-based proteomics as a hypothesis-generating approach. We investigated proteomic changes in six tissues, including brain regions (brainstem, cerebellum, olfactory bulb), heart, kidney and liver, focusing on proteins involved in fatty acid metabolism. Although it is expected that most tissues, except for the brain, will utilise fatty acids as alternative energy sources when oxidative phosphorylation (OXPHOS) is deficient, our data revealed a more complex response. In the liver, fatty acid consumption (oxidation) was favoured as expected, but in the heart, fatty acid synthesis was favoured. In the kidney, proteins involved in almost all fatty acid metabolic processes (oxidation and synthesis) were downregulated. Our data demonstrate that metabolic adaptations in fatty acid metabolism to ICD were tissue-specific and often in opposing directions. Understanding the differential adaptations across tissues could inform future treatment targets for mitochondrial disorders.

Keywords:  NDUFS4 knock out; complex I deficiency; fatty acid metabolism; proteomics

DOI:  https://doi.org/10.1002/pmic.13969
Neuron. 2025 Jun 04. pii: S0896-6273(25)00314-9. [Epub ahead of print]113(11): 1651-1652

Combining old with new: A novel approach to studying human brain metabolism.

Tyler Blazey, Manu S Goyal.

In this issue of Neuron, Wang et al. provide a detailed assessment of the metabolites and lipids utilized by the whole human brain. They report that the brain consumes glucose, lactate, glutamate, and triglycerides while producing glutamine, pyruvate, and free fatty acids.

DOI: https://doi.org/10.1016/j.neuron.2025.04.031
J Neurochem. 2025 Jun;169(6): e70084

Neural Metabolic Networks: Key Elements of Healthy Brain Function.

Nimrod Madrer, Nirma D Perera, Nonthué A Uccelli, Alice Abbondanza, Jens V Andersen, Emma Veronica Carsana, Matthew D Demmings, Regina F Fernandez, Matheus Garcia de Fragas, Ismail Gbadamosi, Divita Kulshrestha, Ricardo A S Lima-Filho, Oana C Marian, Kia H Markussen, Andrew J McGovern, Elliott S Neal, Sukanya Sarkar, Eva Šimončičová, Jazmín Soto-Verdugo, Sozerko Yandiev, Ignacio Fernández-Moncada.

  Neural networks are responsible for processing sensory stimuli and driving the synaptic activity required for brain function and behavior. This computational capacity is expensive and requires a steady supply of energy and building blocks to operate. Importantly, the neural networks are composed of different cell populations, whose metabolic profiles differ between each other, thus endowing them with different metabolic capacities, such as, for example, the ability to synthesize specific metabolic precursors or variable proficiency to manage their metabolic waste. These marked differences likely prompted the emergence of diverse intercellular metabolic interactions, in which the shuttling and cycling of specific metabolites between brain cells allows the separation of workload and efficient control of energy demand and supply within the central nervous system. Nevertheless, our knowledge about brain bioenergetics and the specific metabolic adaptations of neural cells still warrants further studies. In this review, originated from the Fourth International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Schmerlenbach, Germany (2022), we describe and discuss the specific metabolic profiles of brain cells, the intercellular metabolic exchanges between these cells, and how these bioenergetic activities shape synaptic function and behavior. Furthermore, we discuss the potential role of faulty brain metabolic activity in the etiology and progression of Alzheimer's disease, Parkinson disease, and Amyotrophic lateral sclerosis. We foresee that a deeper understanding of neural networks metabolism will provide crucial insights into how higher-order brain functions emerge and reveal the roots of neuropathological conditions whose hallmarks include impaired brain metabolic function.

Keywords:  astrocytes; glycolysis; lipids; mitochondria; neurodegeneration; neurons

DOI:  https://doi.org/10.1111/jnc.70084
Neurobiol Dis. 2025 May 30. pii: S0969-9961(25)00199-8. [Epub ahead of print]212 106983

APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses.

Cassi M Friday, Isaiah O Stephens, Cathryn T Smith, Sangderk Lee, Diksha Satish, Nicholas A Devanney, Sarah Cohen, Josh M Morganti, Scott M Gordon, Lance A Johnson.

  Excess lipid droplet (LD) accumulation is implicated in various diseases, including Alzheimer's disease (AD), yet the mechanisms underlying this accumulation remain unclear. Apolipoprotein E (ApoE) is a droplet-associated protein, and its E4 variant confers the greatest genetic risk for late-onset AD while also being linked to increased neuroinflammation and LD accumulation. In this study, we compared the lipid and protein composition of hepatic LDs in targeted replacement mice expressing human E3 (neutral) or E4 (risk variant), under both baseline conditions and following lipopolysaccharide (LPS) administration. Lipidomic analysis revealed that E4 LDs exhibit a shift in glycerophospholipid distribution, with an increase in phosphatidylcholine species, such that their baseline profile resembles that of LPS-treated LDs. Quantitative proteomics indicated that E4 LDs are enriched in proteins related to vesicle transport but show decreased levels of proteins involved in fatty acid β-oxidation. Notably, many LD-associated proteins overlapped with those identified in AD postmortem and microglial 'omics studies, suggesting a role for LDs in AD pathogenesis. To further explore these findings, primary microglia from E3 and E4 mice were exposed to exogenous lipids, LPS, and necroptotic N2A cells. Under most conditions, E4 microglia accumulated more LDs and secreted higher levels of proinflammatory cytokines (TNF, IL-1β, IL-10) compared to E3 microglia, although their LPS response was blunted. These data suggest that altered LD dynamics in E4 microglia may contribute to the increased AD risk associated with APOE4.

Keywords:  APOE4; Alzheimer's disease; Apolipoprotein E4; Fatty acid metabolism; Lipid droplets; Lipidomic; Microglia; Neuroinflammation; Proteomics

DOI:  https://doi.org/10.1016/j.nbd.2025.106983
Aging Dis. 2025 Jun 02.

Impairment of Tricarboxylic Acid Cycle (TCA) Cycle in Alzheimer's Disease: Mechanisms, Implications, and Potential Therapies.

Gudimetla Susmitha Mohan, Rahul Kumar.

Alzheimer's disease (AD) is a neurodegenerative condition defined by the gradual impairment of cognitive functions, synaptic disarray, and extensive neuronal loss. Emerging evidence suggests that metabolic impairment, specifically within tricarboxylic acid (TCA) cycle, is instrumental in the AD pathophysiology. TCA cycle represents an indispensable pathway in metabolism that is responsible for energy production, and the maintenance of cellular homeostasis, particularly in neurons. Several in vitro, clinical, and in vivo studies reported that several TCA cycle enzymes disrupt during AD. Disruption in TCA cycle enzymes exhibits more pronounced impact on the brain owing to its high metabolic activity and continuous demand for energy, where any reduction in ATP production can severely impair neuronal function, synaptic plasticity, and overall cognitive processes. The current review explores the mechanisms underlying AD related impairment in TCA cycle, focussing on the molecular alterations of TCA enzymes. We also discussed potential activators and inhibitors of TCA cycle enzymes as a potential therapeutic intervention to restore AD related metabolic balance.

DOI: https://doi.org/10.14336/AD.2025.0472
bioRxiv. 2025 May 16. pii: 2025.05.16.654318. [Epub ahead of print]

Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh Syndrome mice.

Sahitya Ranjan Biswas, Porter L Tomsick, Colin Kelly, Brooke A Lester, Julia P Milner, Sara N Henry, Yaris Soto, Samantha Brindley, Nicole DeFoor, Paul D Morton, Alicia M Pickrell.

Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Single cell RNA sequencing along with histological and anatomical assessments were performed in NDUFS4 KO mice and compared with controls to determine the impact of Complex I deficiency on neural stem cells, their neuronal and oligodendroglial progeny, lineage progression, and overt differences in specific brain regions. Our findings show disruptions in all categories, specifically within the subventricular zone and corpus callosum. Given that LS is purely considered a neurodegenerative disease, we propose that mitochondrial dysfunction is a neurodevelopmental signature predating classic diagnosis in LS.

DOI: https://doi.org/10.1101/2025.05.16.654318
Glycoconj J. 2025 Jun 04.

GM1 oligosaccharide-mediated rescue in GBA-linked Parkinson's disease via modulation of lysosomal and mitochondrial dysfunctions.

Giulia Lunghi, Carola Pedroli, Ilaria Tagliabue, Dorina Dobi, Maria Grazia Ciampa, Laura Mauri, Laura Rouvière, Alexandre Henriques, Noelle Callizot, Sandro Sonnino, Elena Chiricozzi, Maria Fazzari.

  Mutations in the glucocerebrosidase GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase, represent the most frequent genetic risk factor for Parkinson's disease, leading to lysosomal dysfunction, α-synuclein aggregation, and mitochondrial impairment. In this study, we investigated the therapeutic potential of GM1 ganglioside and its oligosaccharide portion (OligoGM1) in a cellular model of GBA-associated Parkinson's disease, using SH-SY5Y neuroblastoma cells carrying the L444P GBA mutation. We observed that both GM1 and OligoGM1 reduced α-synuclein accumulation and improved cell viability. Notably, only OligoGM1 attenuated lysosomal overload and restored mitophagy. Additionally, OligoGM1 significantly prevented 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity, including lysosomal dysfunction, reactive oxidative species-overproduction, and mitochondrial energy failure, whereas GM1 failed to provide protection. These findings highlight the selective and multifaceted neuroprotective actions of OligoGM1 under both genetic conditions and environmental stress. Due to its small, hydrophilic nature and capacity to cross the blood-brain barrier, OligoGM1 emerges as a promising therapeutic candidate for GBA-related and potentially idiopathic forms of Parkinson's Disease.

Keywords:   (4 to 6): GM1 oligosaccharide; GBA ; Lysosomal impairment; Mitochondria dysfunctions; Parkinson’s disease; Therapeutic agent

DOI:  https://doi.org/10.1007/s10719-025-10185-y
Front Biosci (Landmark Ed). 2025 Apr 30. 30(5): 28245

Role of Lysophosphatidic Acid in Neurological Diseases: From Pathophysiology to Therapeutic Implications.

Simona Dedoni, Valeria Avdoshina, Maria C Olianas, Pierluigi Onali.

  Lysophosphatidic acid (LPA), a bioactive lipid molecule, has been identified as a critical regulator of several cellular processes in the central nervous system, with significant impacts on neuronal function, synaptic plasticity, and neuroinflammatory responses. While Alzheimer's disease, Multiple Sclerosis, and Parkinson's disease have garnered considerable attention due to their incidence and socioeconomic significance, many additional neurological illnesses remain unclear in terms of underlying pathophysiology and prospective treatment targets. This review synthesizes evidence linking LPA's function in neurological diseases such as traumatic brain injury, spinal cord injury, cerebellar ataxia, cerebral ischemia, seizures, Huntington's disease, amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, autism, migraine, and human immunodeficiency virus (HIV)-associated complications Despite recent advances, the specific mechanisms underlying LPA's actions in various neurological disorders remain unknown, and further research is needed to understand the distinct roles of LPA across multiple disease conditions, as well as to investigate the therapeutic potential of targeting LPA receptors in these pathologies. The purpose of this review is to highlight the multiple functions of LPA in the aforementioned neurological diseases, which frequently share the same poor prognosis due to a scarcity of truly effective therapies, while also evaluating the role of LPA, its receptors, and signaling as promising actors for the development of alternative therapeutic strategies to those proposed today.

Keywords:  HIV; Huntington’s disease; amyotrophic lateral sclerosis; autism; cerebral ischemia; lysophosphatidic acid; neurological diseases; seizures; spinal cord injury; traumatic brain injury

DOI:  https://doi.org/10.31083/FBL28245
Nat Commun. 2025 May 31. 16(1): 5073

Endolysosomal processing of neuron-derived signaling lipids regulates autophagy and lipid droplet degradation in astrocytes.

Jagannatham Naidu Bhupana, Angelid Pabon, Ho Hang Leung, Mohamed Asik Rajmohamed, Sang Hoon Kim, Yan Tong, Mi-Hyeon Jang, Ching-On Wong.

Dynamic regulation of metabolic activities in astrocytes is critical to meeting the demands of other brain cells. During neuronal stress, lipids are transferred from neurons to astrocytes, where they are stored in lipid droplets (LDs). However, it is not clear whether and how neuron-derived lipids trigger metabolic adaptation in astrocytes. Here, we uncover an endolysosomal function that mediates neuron-astrocyte transcellular lipid signaling. We identify Tweety homolog 1 (TTYH1) as an astrocyte-enriched endolysosomal protein that facilitates autophagic flux and LD degradation. Astrocyte-specific deletion of mouse Ttyh1 and loss of its Drosophila ortholog lead to brain accumulation of neutral lipids. Computational and experimental evidence suggests that TTYH1 mediates endolysosomal clearance of ceramide 1-phosphate (C1P), a sphingolipid that dampens autophagic flux and LD breakdown in mouse and human astrocytes. Furthermore, neuronal C1P secretion induced by inflammatory cytokine interleukin-1β causes TTYH1-dependent autophagic flux and LD adaptations in astrocytes. These findings reveal a neuron-initiated signaling paradigm that culminates in the regulation of catabolic activities in astrocytes.

DOI: https://doi.org/10.1038/s41467-025-60402-3
JCI Insight. 2025 Jun 03. pii: e188413. [Epub ahead of print]

Stearoyl-CoA-Desaturase Inhibition normalizes brain lipid saturation, alpha-synuclein homeostasis, and motor function in mutant Gba1-Parkinson mice.

Silke Nuber, Harrison Hsiang, Esra'a Keewan, Tim E Moors, Sydney J Reitz, Anupama Tiwari, Gary P H Ho, Elena Su, Wolf Hahn, Marie-Alexandre Adom, Riddhima Pathak, Matthew Blizzard, Sangjune Kim, Han Seok Ko, Xiaoqun Zhang, Per Svenningsson, Dennis J Selkoe, Saranna Fanning.

  Loss-of-function mutations in the GBA1 gene are a prevalent risk factor for Parkinson's disease (PD). Defining features are Lewy bodies that can be rich in α-synuclein (αS), vesicle- and other lipid membranes coupled with striatal dopamine loss and progressive motor dysfunction. Of these, lipid abnormalities are the least understood. An altered lipid metabolism in PD patient-derived neurons, carrying mutations in either GBA1, encoding for glucocerebrosidase, or αS can shift the physiological αS tetramer-monomer (T:M) equilibrium, resulting in PD phenotypes. We previously reported inhibition of stearoyl-CoA desaturase (SCD), the rate-limiting enzyme for fatty acid desaturation, stabilized αS tetramers and improved motor deficits in αS mice. Here we show that mutant GBA-PD cultured neurons have increased SCD products (monounsaturated fatty acids, MUFAS) and reduced αS T:M ratios that were improved by inhibiting SCD. Oral treatment of symptomatic L444P- and E326K Gba1 mutant mice with 5b also improved the αS T:M homeostasis and dopaminergic striatal integrity. Moreover, SCD inhibition normalized GCase maturation and dampened lysosomal and lipid-rich clustering, key features of neuropathology in GBA-PD. In conclusion, this study supports brain MUFA metabolism links GBA1 genotype and wildtype αS homeostasis to downstream neuronal and behavioral impairments, identifying SCD as a therapeutic target for GBA-PD.

Keywords:  Cell biology; Neuroscience; Parkinson disease

DOI:  https://doi.org/10.1172/jci.insight.188413
J Lipid Res. 2025 May 29. pii: S0022-2275(25)00092-6. [Epub ahead of print] 100832

Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects.

Jeongah Oh, Sneha Muralidharan, Qing Zhao, Johannes Scholz, Iris D Zelnik, Shani Blumenreich, Tammar Joseph, Tamir Dingjan, Pradeep Narayanaswamy, Hyungwon Choi, Heiko Hayen, Federico Torta, Anthony H Futerman.

  The sphingolipidome contains thousands of structurally distinct sphingolipid (SL) species. This enormous diversity is generated by the combination of different long-chain-bases (LCBs), N-acyl chains and head groups. In mammals, LCBs are N-acylated with different fatty acids (from C14 to C32, with different degrees of saturation) by six ceramide synthases (CerS1-6) to generate dihydroceramides (DHCer), with each CerS exhibiting specificity towards acyl-Coenzyme As of defined chain length. CerS2 synthesizes very-long-chain (VLC) DHCer, and mice in which CerS2 has been deleted display a number of pathologies. We now expand previous analyses of the mouse sphingolipidome by examining 264 individual SL species in 18 different tissues, building an extensive SL tissue atlas of wild type and CerS2 null mice. While many of the changes in SL levels were similar to those reported earlier, a number of unexpected findings in CerS2 null mouse tissues were observed, such as the decrease in ceramide 1-phosphate levels in the brain, the increase in C26-SL levels in the lung and no changes in levels of ceramides containing t18:0-LCBs (phytosphinganine). Furthermore, analysis of levels of other metabolites revealed changes in at least six major metabolic pathways, including some that impinge upon the SL metabolism. Together, these data highlight the complex changes that occur in the lipidome and metabolome upon depletion of CerS2, indicating how sphingolipids are connected to many other pathways and that care must be taken when assigning a relationship between tissue pathology and one or other specific SL species.

Keywords:  Mass spectrometry; ceramide; ceramide1-phosphate; cerebrosides; glycosphingolipids; sphingolipidomics; sphingolipids; sphingomyelin

DOI:  https://doi.org/10.1016/j.jlr.2025.100832
J Med Chem. 2025 Jun 06.

Design and Synthesis of Novel PET Radiotracers for Imaging Sphingosine-1-Phosphate Receptor 5 (S1PR5) in the Brain.

Jiawen Lang, Wenjuan Zhou, Tianyu Huang, Hao Jiang, Hong Chen, Shuxian Xu, Lin Qiu, Madison Heady, Yanbo Yu, Matthew R Brier, Ying-Hwey Nai, Caroline Guglielmetti, Joel S Perlmutter, Zhude Tu.

Sphingosine-1-phosphate receptor-5 (S1PR5) is highly expressed in oligodendrocytes and it plays an important role in neurodegenerative disorders like multiple sclerosis. We designed, synthesized, and determined the binding potencies of 27 novel S1PR5 ligands. Four radiotracers [11C]7, [18F]7a, [11C]12a, and [18F]12b were synthesized for the characterization of their in vitro and in vivo binding properties. [18F]7a had good rat brain uptake with 0.62%ID/g at 5 min, while the other three radiotracers had lower brain uptake. [18F]7a had Kd values of 2.2, 4.6, and 27.6 nM for recombinant human S1PR5 cell membranes, C57BL/6 mouse brain, and human cerebral cortex, respectively. Pretreatment with S1PR5 potent modulators effectively impacted rodent brain uptake of [18F]7a. Cuprizone-fed mice had reduced [18F]7a brain uptake, reflecting the loss of oligodendrocytes and decreased S1PR5 expression. [18F]7a also showed good brain uptake and retention in macaque, and no radiometabolites entered the rat brain, further supporting its potential as a promising radiotracer for imaging S1PR5 in the brain.

DOI: https://doi.org/10.1021/acs.jmedchem.5c00881
Eur J Pediatr. 2025 May 31. 184(6): 382

The effect of triheptanoin treatment on clinical and laboratory outcomes in patients with long-chain fatty acid oxidation disorder.

Engin Köse, Aslı İnci, Havva Yazıcı, Tanyel Zübarioğlu, Sebile Kılavuz, Kısmet Çıkı, Esra Er, Mehmet Cihan Balcı, Ayça Burcu Kahraman, Neslihan Önenli Mungan, Çiğdem Aktuğlu Zeybek, Sema Kalkan Uçar, Leyla Tümer, Fatma Tuba Eminoğlu.

  Long-chain fatty acid oxidation disorders (LC-FAOD) are a rare metabolic condition that results in impaired fatty acid utilization, leading to metabolic crises, hospitalization, and reduced quality of life. Despite dietary management, many patients experience ongoing complications. Triheptanoin, a seven-carbon triglyceride, has emerged as a therapeutic alternative by providing an energy source and supporting metabolic stability. This study aims to evaluate the clinical outcomes of LC-FAOD patients receiving triheptanoin therapy in Türkiye. A retrospective nationwide study was conducted to analyze 14 patients with LC-FAOD who received oral triheptanoin as part of a compassionate use program in Türkiye. The study collected data on emergency department visits, hospitalizations, metabolic decompensation episodes, creatine kinase (CK) levels, hypoglycemia, and cardiac function. Additionally, patient-reported outcomes were assessed through surveys. The findings of the study demonstrated that triheptanoin treatment led to a significant reduction in the number of emergency service applications and hospitalizations per month (p < 0.01). A notable decrease in the frequency of myalgia attacks was observed, while the decline in rhabdomyolysis episodes did not reach statistical significance. Furthermore, creatine kinase levels during metabolic crises exhibited a substantial decrease following triheptanoin therapy (p < 0.0001).Among patients with cardiomyopathy, cardiac function showed improvement in four out of seven patients. Survey data indicated an improvement in appetite, physical performance, and overall quality of life.
CONCLUSION: Triheptanoin treatment has been demonstrated to be associated with significant clinical improvements in patients diagnosed with LC-FAOD, including a reduction in the frequency of emergency department visits, hospitalizations, and metabolic crises. These findings provide support for the utilization of triheptanoin as a therapeutic approach that holds promise in the management of LC-FAOD.
WHAT IS KNOWN: • Long-chain fatty acid oxidation disorders (LC-FAOD) are associated with significant morbidity due to metabolic crises, despite conventional dietary treatment including medium-chain triglycerides (MCT).
WHAT IS NEW: • This nationwide study demonstrates that triheptanoin therapy significantly reduces emergency visits, hospitalizations, and creatine kinase levels during crises, and improves patient-reported outcomes, including physical activity and quality of life, in LC-FAOD patients in Türkiye.

Keywords:  Creatine kinase; Long-chain fatty acid oxidation disorders; Medium-chain triglycerides; Triheptanoin

DOI:  https://doi.org/10.1007/s00431-025-06216-3
Exp Neurol. 2025 May 29. pii: S0014-4886(25)00190-6. [Epub ahead of print]392 115326

Overexpression of thioredoxin 1 contributes to neuroprotection through ATM activation and pentose phosphate pathway modulation after traumatic brain injury.

Lei Meng, Bingyi Song, Xuan Shi, Aojie Duan, Dengfeng Lu, Yubo Ren, Yu Zhang, Renjie Shou, Haiying Li, Zhong Wang, Jiangang Liu, Zongqi Wang, Xiaoou Sun.

   BACKGROUND: Traumatic brain injury (TBI) induces oxidative stress, leading to secondary injury and neuronal apoptosis. The thioredoxin (Trx) system, a key regulator of redox homeostasis, and the pentose phosphate pathway (PPP), the primary source of NADPH, play critical roles in mitigating oxidative damage. This study investigates the neuroprotective effects of Trx1 in modulating oxidative stress through the Trx1-ATM-PPP axis.
METHODS: Adenovirus-mediated Trx1 overexpression was performed in a controlled cortical impact (CCI) mouse model four weeks prior to injury. Neuronal apoptosis, G6PD activity, NADPH levels, and ATM phosphorylation (P-ATM) were evaluated post-CCI. Behavioral deficits were assessed one week post-injury. In vitro, primary neurons were subjected to scratch injury and analyzed for Trx1 effects on P-ATM, G6PD, and NADPH.
RESULTS: Trx1 overexpression significantly reduced neuronal apoptosis in vivo and in vitro. P-ATM levels were elevated following CCI, and Trx1 overexpression further enhanced P-ATM without altering total ATM expression. G6PD activity and NADPH levels were significantly increased in the Trx1-overexpression group, indicating upregulation of PPP flux. Behavioral assessments revealed improvements in exploratory behavior, anxiety, and memory in CCI mice with Trx1 overexpression.
CONCLUSION: Trx1 mitigates secondary injury in TBI by enhancing PPP flux through ATM phosphorylation, promoting NADPH production and reducing oxidative stress. These findings identify the Trx1-ATM-PPP axis as a potential therapeutic target for TBI treatment.

Keywords:  ATM phosphorylation; NADPH; Neuroprotection; Oxidative stress; Pentose phosphate pathway; Thioredoxin; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.expneurol.2025.115326