bims-medebr 2025-08-03 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–08–03
sixteen papers selected by
Regina F. Fernández, Johns Hopkins University

Longitudinal Brain Structural, Neurochemical, and Behavioral Changes Following Traumatic Brain Injury in Immature Rat Brain with ALCAR Treatment.
Oxysterol-Binding Protein ORP6 Regulates Lipid Metabolism and Brain Aβ Production.
Glia-derived noncanonical fatty acid binding protein modulates brain lipid storage and clearance.
Multimodal Nano-DESI Mass Spectrometry Imaging Reveals Phospholipids Accumulation in and around Amyloid Plaques in Alzheimer's Disease.
The physiological and pathological effects of sphingolipid metabolism and signaling in the central nervous system.
MGlu5 Dependent Mitochondrial Translocation of PKCδ: A Mechanism Raising Astrocytic Oxidative Metabolism in Response to Extracellular Glutamate.
Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.
Branched-Chain Amino Acids in Parkinson's Disease: Molecular Mechanisms and Therapeutic Potential.
Analysis of mitochondrial Complex I activity and ATP hydrolysis capacity of ATP synthase in developing rat brains using frozen tissues.
Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases.
Advances in mass spectrometry of lipids for the investigation of Niemann-pick type C disease.
Cardiolipin acyl chain composition tailors the conformation of mammalian ATP synthase dimers.
From lactate to lactylation: potential targets for the treatment of neurodegenerative diseases.
Different effects of Lorenzo's oil components against very long-chain fatty acid-induced endoplasmic reticulum stress in peroxisome-deficient CHO cells.
Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.
Folic Acid Ameliorates Neuronal Ferroptosis in Aging by Up-Regulating SLC7A11-GSH-GPX4 Antioxidant Pathway and Increasing Cystine Levels.

Neurochem Res. 2025 Jul 30. 50(4): 256

Longitudinal Brain Structural, Neurochemical, and Behavioral Changes Following Traumatic Brain Injury in Immature Rat Brain with ALCAR Treatment.

Susanna Scafidi, Su Xu, Jennifer N Jernberg, Tiffany Chu, Gary Fiskum, Mary C McKenna.

  Pediatric survivors of traumatic brain injury (TBI) suffer from long-term neurologic disabilities, including deficits in memory and learning. Proton magnetic resonance spectroscopy (1H-MRS) can assess alterations in brain neurochemical profile non-invasively in vivo over time. Our study aimed to evaluate (1) the longitudinal metabolic alterations in the hippocampus after TBI using in vivo 1H-MRS and MRI in developing rat brain, and (2) test whether treatment with acetyl-L-carnitine (ALCAR) affects hippocampal metabolic profile. Using a controlled cortical impact model of TBI, we used post-natal day (PND) 21 rat pups and acquired longitudinal 1H-MRS of the ipsilateral perilesional and contralateral hippocampi 2-4 h, 24 h, 72 h, 7 days, and 21 days post injury. Behavioral analysis was performed on post-injury days (Dpi) 3-7, 14, and 21-28. ALCAR treated rats received intraperitoneal administration (100 mg/kg) at 1 h, 4 h, 12 h, and 23 h post injury. Our results show that TBI in immature brain results in long-term structural and neurochemical alterations. TBI resulted in long-term decreased hippocampal volume and a reduction in levels of glutamate (Glu), glutamine (Gln),γ-aminobutyric acid (GABA), myo-inositol (Ins) and taurine (Tau) in the ipsilateral (injured) hippocampus up to 72 h post injury. In TBI + vehicle and TBI + ALCAR groups, N-acetyl-aspartate (NAA) remained decreased 21 days post injury. Treatment with ALCAR did not significantly change hippocampal neurochemical profile at 24 h post injury. Behavioral studies in TBI-injured rats demonstrated that sensory motor function decreased initially and recovered with time. The TBI + ALCAR group performed significantly better compared to TBI + vehicle group in both sensory motor and hippocampal dependent recognition memory. Further studies with the longer duration of ALCAR administration are necessary to adequately assess the efficacy of ALCAR following pediatric TBI.

Keywords:  Acetyl-L-carnitine; Developing brain; In vivo proton magnetic resonance spectroscopy; Traumatic brain injury

DOI:  https://doi.org/10.1007/s11064-025-04494-9
J Lipid Res. 2025 Jul 25. pii: S0022-2275(25)00130-0. [Epub ahead of print] 100868

Oxysterol-Binding Protein ORP6 Regulates Lipid Metabolism and Brain Aβ Production.

Arlette A Kasongo, Viyashini Vijithakumar, Khaled S Abd-Elrahman, Radhika Prabhune, Lara Gharibeh, Rachel Nadeau, Isabelle Robillard, Shoshana Spring, Sabrina Robichaud, Shaza Asif, Derrick Gibbings, Kathryn J Moore, John G Sled, Mathieu Ruiz, Mathieu Lavallée-Adam, Stephen S G Ferguson, Baptiste Lacoste, Diane C Lagace, Mireille Ouimet.

  The mammalian brain is the most cholesterol-rich organ of the body, relying on in situ de novo cholesterol synthesis. Maintaining cholesterol homeostasis is crucial for normal brain function. Oxysterol-binding protein (OSBP)-related proteins (ORPs) are highly conserved cytosolic proteins that coordinate lipid homeostasis by regulating cell signaling, inter-organelle membrane contact sites, and non-vesicular transport of cholesterol. Here, we show that ORP6 is highly enriched in the mammalian brain, particularly within neurons and astrocytes, with widespread expression across distinct brain regions, including the hippocampus, which is essential for learning and memory. Whole-body ablation of ORP6 (Osbpl6-/-) in mice resulted in dysregulation of systemic and brain lipid homeostasis, with elevated levels of brain desmosterol and amyloid-beta oligomers (AβOs). Mechanistically, ORP6 knockdown in astrocytes altered the expression of cholesterol metabolism genes, promoting the accumulation of esterified cholesterol in lipid droplets, reducing cholesterol efflux and plasma membrane cholesterol content, and increasing amyloid-beta precursor protein (APP) processing. Our findings underscore the role of ORP6 in systemic and brain lipid homeostasis, highlighting its importance in maintaining overall brain health.

Keywords:  amyloid beta; astrocyte; cholesterol efflux; high-density lipoprotein; lipid droplet; lipid metabolism; oxysterol-binding protein-like 6

DOI:  https://doi.org/10.1016/j.jlr.2025.100868
Sci Adv. 2025 Aug;11(31): eadv2902

Glia-derived noncanonical fatty acid binding protein modulates brain lipid storage and clearance.

Jun Yin, Hsueh-Ling Chen, Anna Grigsby-Brown, Yi He, Myriam L Cotten, Jacob Short, Aidan Dermady, Jingce Lei, Mary Gibbs, Ethan S Cheng, Dean Zhang, Caixia Long, Jennifer Tabet, Lele Xu, Tiffany Zhong, Rinat Abzalimov, Mariam Haider, Rong Sun, Ye He, Qiangjun Zhou, Nico Tjandra, Quan Yuan.

Glia-derived secretory factors are essential for brain development, physiology, and homeostasis, with their dysfunction linked to a variety of neurological disorders. Through genetic and biochemical approaches, we identified odorant binding protein 44a (Obp44a), a noncanonical α-helical fatty acid binding protein (FABP) highly expressed in Drosophila central nervous system glia. Obp44a binds long-chain fatty acids and shuttles between glia and neurons, acting as a secretory lipid chaperone and scavenger to support lipid storage, efflux, and redox homeostasis. Notably, Obp44a is recruited to apoptotic cells and injured axons, especially when glial engulfment is impaired, demonstrating its role in lipid waste management and clearance of cellular debris during development and in pathological states. Our findings highlight FABPs' importance in regulating brain lipid dynamics and neuronal response to stress and injury. By visualizing FABP function in vivo, this study provides insights into how defective lipid regulation may contribute to neuronal stress and disease progression.

DOI: https://doi.org/10.1126/sciadv.adv2902
ACS Chem Neurosci. 2025 Jul 31.

Multimodal Nano-DESI Mass Spectrometry Imaging Reveals Phospholipids Accumulation in and around Amyloid Plaques in Alzheimer's Disease.

Manxi Yang, Xindi Tang, Mushfeqa Iqfath, Emerson Hernly, Daisy Unsihuay, Palak Manchanda, Kaushik Sharma, Zihan Qu, Hang Hu, Connor Beveridge, Gaurav Chopra, Julia Laskin.

  Alzheimer's disease (AD), characterized by β-amyloid plaques, is increasingly recognized by lipid dysregulation as a key factor in its pathology. Mass spectrometry imaging (MSI), a powerful tool for mapping the spatial distribution of biomolecules in tissue sections, is ideally suited for investigating region-specific molecular alterations in diseased animal tissues. Recent MSI advancements have revealed plaque-associated molecular features in the AD brain, highlighting the role of metabolic dysfunction in disease progression. In this study, we developed a novel multimodal MSI approach using nanospray desorption electrospray ionization (nano-DESI) for dual polarity mode lipid and peptide imaging in the brain tissues of 5-7-month-old transgenic familial AD mice (5xFAD), followed by fluorescence imaging of β-amyloid plaques on the same tissue section. Our results revealed the accumulation of several peptides and phospholipids, including phosphatidylethanolamines (PE), phosphatidylinositols (PI), phosphatidylglycerols (PG), and phosphatidylcholines (PC) in and/or surrounding β-amyloid plaques in the hippocampus, isocortex, and thalamus regions of the AD brain. Furthermore, we observed that several fatty acids (FAs) were enhanced in the plaque-enriched subiculum region of the hippocampus. Our results demonstrate the power of the multimodal nano-DESI MSI approach for comprehensive mapping of molecular pathology with high spatial resolution, providing unique insights into disease metabolism and potential biomarkers.

Keywords:  Alzheimer’s disease; amyloid plaques; mass spectrometry imaging; multimodal imaging; nano-DESI; spatial lipidomics

DOI:  https://doi.org/10.1021/acschemneuro.5c00144
Brain Pathol. 2025 Jul 31. e70033

The physiological and pathological effects of sphingolipid metabolism and signaling in the central nervous system.

Tian Li, Haoying He, Ejuan Zhang, Fengjiao Hu, Zhuo Wang, Jian Xu, Mengliu Zeng, Biwen Peng.

  Sphingolipids are essential, complex lipids that are abundant in the cell membranes of eukaryotic cells, particularly concentrated in the myelin and neuronal membranes of the central nervous system (CNS). These lipids are crucial components of the cell membrane, affecting their structure and fluidity, and thus regulating various biological processes, including signal transduction, cell differentiation, apoptosis, and autophagy. The metabolic pathways of sphingolipids are highly complex and conserved, and this metabolic process can produce multiple metabolites. Metabolites such as ceramide (Cer) and sphingosine-1-phosphate (S1P) are vital in CNS signaling, affecting neurodevelopment, myelination, and synaptic plasticity. Thus, disruption of sphingolipid metabolism is closely related to neurological disorders. This article provides the latest studies concerning the known features of sphingolipid and sphingolipid metabolism, highlighting its physiological and pathological roles in the CNS.

Keywords:  central nervous system; neurodegenerative diseases; sphingolipids; sphingosine 1‐phosphate, ceremide; treatment

DOI:  https://doi.org/10.1111/bpa.70033
J Neurochem. 2025 Aug;169(8): e70163

MGlu5 Dependent Mitochondrial Translocation of PKCδ: A Mechanism Raising Astrocytic Oxidative Metabolism in Response to Extracellular Glutamate.

Kiavasch M N Farid, Rodrigo Lerchundi, Christine R Rose, Amin Derouiche.

  Synaptic activity imposes high demands of local energy production on astrocytes. However, the (an)aerobic pathways and fuel for generation of energy equivalents in astrocytes are still debated. Also, mechanisms to ensure rapid metabolic adaptation to bouts of neuronal activity have not been sufficiently explored. Here, we show a mechanism in astrocytes linking extracellular glutamate to upregulation of oxidative phosphorylation. We stimulated primary astrocytes with glutamate, and applied fluorescent immunocytochemistry with anti-protein kinase Cδ (PKCδ), anti-pyruvate dehydrogenase (PDH) and anti-phospho-PDH antibodies, and object oriented image analysis. Glutamate induces mitochondrial translocation of PKCδ and subsequent activation of the mitochondrial enzyme PDH-the point-of-no-return in the utilization of carbohydrates. Using the specific mGlu5 antagonist 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), the metabotropic glutamate receptor 5 (mGlu5) was identified as the key receptor inducing mitochondrial PKCδ translocation and PDH activation. We demonstrate by luminometric ATP assay and subtype-specific inhibitors of PKC and mGlu5 that the distinct initial drop in intracellular ATP following glutamate application is counteracted by the mGlu5/PKCδ-dependent mitochondrial activation. mGlu5 inhibition decreases ATP production also in astrocytes in the acute brain slice. Collectively, these findings reveal that astrocytes possess a potential for oxidative phosphorylation that can be stimulated by extracellular glutamate and the mGlu5/PKCδ/PDH axis, suggesting targets for pathologies involving excess glutamate. This also focuses the issue of activity-induced glia-neuronal metabolic interaction on perisynaptic energetics and the glia-synaptic microenvironment. Up-regulation of astrocytic metabolism via the mGlu5/PKCδ/PDH axis may affect only those perisynaptic astrocyte processes (PAPs) close to the active synapse(s), leaving other astrocyte domains and the whole cell unchanged.

Keywords:  glia‐synaptic interaction; neurometabolic coupling; pyruvate dehydrogenase; pyruvate dehydrogenase phosphatase; tripartite synapse

DOI:  https://doi.org/10.1111/jnc.70163
Alzheimers Dement. 2025 Aug;21(8): e70519

Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.

Huanyao Gao, Kate Jensen, Jarred Nesbitt, Mark Ostroot, Gregory A Cary, Jesse Wiley, Sergey Trushin, Jens O Watzlawik, Wolfdieter Springer, Alexander Galkin, Priyanka Baloni, Cory Funk, Eugenia Trushina.

   INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4-/- mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2.
METHODS: Cortico-hippocampal tissue from Ndufs4-/- and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets.
RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4-/- mice showing greater compensatory adaptations and treatment responses.
DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics.
HIGHLIGHTS: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer's disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.

Keywords:  Alzheimer's disease; Ndufs4 knockout mice; biological domains; mitochondrial complex I; mitochondria‐targeted therapeutics; mitophagy; sex‐specific differences; sex‐specific response; transcriptomic analysis; ubiquitin; weak complex I inhibitors

DOI:  https://doi.org/10.1002/alz.70519
Int J Mol Sci. 2025 Jul 21. pii: 6992. [Epub ahead of print]26(14):

Branched-Chain Amino Acids in Parkinson's Disease: Molecular Mechanisms and Therapeutic Potential.

Hui-Yu Huang, Shu-Ping Tsao, Tu-Hsueh Yeh.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in motor symptoms such as bradykinesia, tremor, rigidity, and postural instability, as well as a wide variety of non-motor manifestations. Branched-chain amino acids (BCAAs)-leucine, isoleucine, and valine-are essential nutrients involved in neurotransmitter synthesis, energy metabolism, and cellular signaling. Emerging evidence suggests that BCAA metabolism is intricately linked to the pathophysiology of PD. Dysregulation of BCAA levels has been associated with energy metabolism, mitochondrial dysfunction, oxidative stress, neuroinflammation, and altered neurotransmission. Furthermore, the branched-chain ketoacid dehydrogenase kinase (BCKDK), a key regulator of BCAA catabolism, has been implicated in PD through its role in modulating neuronal energetics and redox homeostasis. In this review, we synthesize current molecular, genetic, microbiome, and clinical evidence on BCAA dysregulation in PD to provide an integrative perspective on the BCAA-PD axis and highlight directions for future translational research. We explored the dualistic role of BCAAs as both potential neuroprotective agents and metabolic stressors, and critically examined the therapeutic prospects and limitations of BCAA supplementation and BCKDK targeting.

Keywords:  Parkinson’s disease; amino acid metabolism; branched-chain amino acids (BCAAs); branched-chain ketoacid dehydrogenase kinase (BCKDK); gut–brain axis; mitochondrial dysfunction; neuroinflammation; precision therapeutics

DOI:  https://doi.org/10.3390/ijms26146992
MicroPubl Biol. 2025 ;2025

Analysis of mitochondrial Complex I activity and ATP hydrolysis capacity of ATP synthase in developing rat brains using frozen tissues.

Pamela J Yao, Rachel Munk, Myriam Gorospe, Dimitrios Kapogiannis.

In a previous study, we analyzed the activity of the mitochondrial respiratory Complex II, Complex IV and ATP synthase in frozen tissues of postnatal rat brains (Yao et al., 2023). In this study, we expand our capability of assessing mitochondrial functions using frozen tissue samples. We optimize protocols for measuring the activity of Complex I, and ATP hydrolysis capacity - known as the reverse action - of ATP synthase. We show that the specific functions of these mitochondrial proteins increase linearly as the brain develops.

DOI: https://doi.org/10.17912/micropub.biology.001641
Neurotherapeutics. 2025 Jul 28. pii: S1878-7479(25)00186-2. [Epub ahead of print] e00708

Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases.

Tomohiro Nakamura, Anamika Sharma, Stuart A Lipton.

  Neuronal synaptic activity relies heavily on mitochondrial energy production, as synaptic transmission requires substantial ATP. Accordingly, mitochondrial dysfunction represents a key underlying factor in synaptic loss that strongly correlates with cognitive decline in Alzheimer's disease and other neurocognitive disorders. Increasing evidence suggests that elevated nitro-oxidative stress impairs mitochondrial bioenergetic function, leading to synaptic degeneration. In this review, we highlight the pathophysiological roles of nitric oxide (NO)-dependent posttranslational modifications (PTMs), particularly S-nitrosylation of cysteine residues, and their impact on mitochondrial metabolism. We focus on the pathological S-nitrosylation of tricarboxylic acid cycle enzymes, particularly α-ketoglutarate dehydrogenase, as well as electron transport chain proteins. This aberrant PTM disrupts mitochondrial energy production. Additionally, we discuss the consequences of aberrant protein S-nitrosylation on mitochondrial dynamics and mitophagy, further contributing to mitochondrial dysfunction and synapse loss. Finally, we examine current strategies to ameliorate S-nitrosylation-mediated mitochondrial dysfunction in preclinical models of neurodegenerative diseases and explore future directions for developing neurotherapeutics aimed at restoring mitochondrial metabolism in the context of nitro-oxidative stress.

Keywords:  Cognitive decline; Protein S-nitrosylation; Synapse loss; TCA cycle; α-Ketoglutarate dehydrogenase

DOI:  https://doi.org/10.1016/j.neurot.2025.e00708
Lipids Health Dis. 2025 Jul 30. 24(1): 254

Advances in mass spectrometry of lipids for the investigation of Niemann-pick type C disease.

Roshan Javanshad, Wenping Li, Koralege C Pathmasiri, Stephanie M Cologna.

Niemann-Pick type C (NPC) disease is a devastating, fatal, neurodegenerative disease and a form of lysosomal storage disorder. It is caused by mutations in either NPC1 or NPC2 genes, leading to the accumulation of cholesterol and other lipids in the late endosome/lysosome system, a hallmark of the disease. Due to aberrant lipid trafficking in NPC, various techniques have been employed to study cholesterol and lipid dysregulation. Among them, mass spectrometry (MS)-based lipidomics has emerged as a state-of-the-art approach, providing valuable insights into disease pathophysiology, progression, and therapeutic target development. This review highlights the MS instruments used for lipidomics studies and discusses lipid biomarkers identified using MS in the context of NPC disease. Furthermore, integrating lipidomics with other -omics approaches, and leveraging the power of artificial intelligence, should be prioritized in future studies to holistically understand NPC disease.

DOI: https://doi.org/10.1186/s12944-025-02675-7
Commun Chem. 2025 Jul 30. 8(1): 220

Cardiolipin acyl chain composition tailors the conformation of mammalian ATP synthase dimers.

M Makowski, V G Almendro-Vedia, I López-Montero.

The interplay between ATP synthase dimers and the four-tailed lipid cardiolipin (CL) shapes mitochondrial cristae structure and function. In the mitochondrial disorder Barth syndrome (BTHS), cristae membranes accumulate a less unsaturated, three-tailed form of cardiolipin (MLCL). These cristae become structurally and functionally compromised through mechanisms poorly understood. We have studied through molecular dynamics simulations how BTHS lipid composition affects the conformation of the ATP synthase dimer. The wedge-shaped transmembrane region of the ATP synthase dimer attracts cardiolipins through shape complementarity. MLCL showed decreased affinity for the dimer interface than CLs of the healthy model. A more heterogeneous lipid environment with a higher elastic strain promoted a dimer conformation that would stabilize wider intracrista spaces, and hence, less efficient OXPHOS reactions in BTHS. Our results provide clues on the role played by the CL acyl chain composition in the architecture and function of mitochondria in health and BTHS.

DOI: https://doi.org/10.1038/s42004-025-01611-1
Rev Neurosci. 2025 Jul 31.

From lactate to lactylation: potential targets for the treatment of neurodegenerative diseases.

Bingbing Wang, Shenghao Qian, Caizhen Shi, Li Dan, Tianyu Zhai, Can Zhang, Juan Shen, Yanling Yang, Lin Zhao.

  Traditionally, lactate is regarded as a byproduct of anaerobic metabolism. With the deepening of related research, the roles of lactate in cellular energy metabolism, signal transduction, and microenvironment regulation have attracted increasing attention. Against this research background, the discovery of a novel post-translational modification - lactylation modification - has further expanded its biological functions. In the context of the increasingly aging global population, neurodegenerative diseases (ND) have become a significant challenge threatening global public health. Studies have reported that lactate metabolic disorders are common metabolic characteristics in the occurrence and development of ND. In summary, this article focuses on reviewing lactate and lactylation in the brain and their roles in ND. It comprehensively outlines the process from lactate to lactylation, highlights the close connection between brain lactate metabolism and ND, and explores potential molecular mechanisms underlying disease development - providing new perspectives for understanding ND pathogenesis. Additionally, this review systematically summarizes potential therapeutic strategies for ND based on regulating lactate metabolism, aiming to offer innovative approaches for disease prevention, diagnosis, and treatment.

Keywords:  lactate; lactylation; neurodegenerative diseases (ND); signaling molecule; targeted therapy

DOI:  https://doi.org/10.1515/revneuro-2025-0068
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jul 27. pii: S1388-1981(25)00078-2. [Epub ahead of print] 159670

Different effects of Lorenzo's oil components against very long-chain fatty acid-induced endoplasmic reticulum stress in peroxisome-deficient CHO cells.

Hanif Ali, Mone Yamanishi, Rumana Yesmin Hasi, Majidul Islam, Yoshimasa Hamada, Masato Miyake, Seiichi Oyadomari, Emi Kiyokage, Kazunori Toida, Ryushi Kawakami, Mutsumi Aihara, Tamotsu Tanaka.

  Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by mutations in the ABCD1 gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). The accumulation of saturated VLCFAs, such as C24:0 and C26:0, is believed to impair myelination. A mixture of C18:1 (oleic acid) and C22:1 (erucic acid), known as Lorenzo's oil, has been used to reduce these saturated VLCFAs. However, despite lowering saturated VLCFA levels, Lorenzo's oil proved ineffective in preventing neurological symptoms. Previously, we found that VLCFA-induced apoptosis is prevented by C18:1 supplementation in peroxisome-deficient Chinese Hamster Overy (CHO) cells. In this study, we investigated the mechanism underlying the rescue effect of C18:1 and examined the effect of C22:1, another component of Lorenzo's oil. Supplementation with C18:1 completely rescued the cells from VLCFA-induced apoptosis. In contrast, C22:1 enhanced VLCFA cytotoxicity and diminished the protective effect of C18:1. We found that VLCFA-induced apoptosis is mediated via the endoplasmic reticulum (ER) stress response possibly by disruption of ER structure, whereas C18:1 attenuated this ER stress. Quantitative lipidomics revealed that VLCFAs were predominantly incorporated into phosphatidylcholine (PC), accompanied by a significant reduction in PC species containing C18:1. Among these, PC 36:2 (18:1/18:1) showed a pattern of change that correlated with cellular viability. These results indicate that C18:1, but not C22:1, protects peroxisome-deficient CHO cells by ameliorating the ER stress response, likely through improving ER structure distorted by VLCFA accumulation.

Keywords:  Apoptosis; Endoplasmic reticulum stress; Oleic acid; Peroxisome disease; Very long-chain fatty acids

DOI:  https://doi.org/10.1016/j.bbalip.2025.159670
Neurochem Res. 2025 Jul 28. 50(4): 251

Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.

Qian Yu, Li Li, Shuyi Yu, Jialin Han, Qian Cheng, Zhikang Cui, Hang Chen, Ming Li, Zhiming Lu.

  Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive neurodegeneration and a variety of cognitive deficits. Of note, mitochondrial malfunctions occur early in the disease's development. Mitophagy impairment leads to the build-up of damaged mitochondria inside the cells, causing malfunction and eventual death of the cells. This review summarizes the mechanisms linking mitochondrial damage and autophagy dysregulation to AD and highlights potential therapeutic opportunities. We summarize how mitochondrial dysfunction contributes to AD, including defects in mitochondrial biogenesis, impaired dynamics, the impact of AD-related protein aggregates on mitochondrial integrity, and defective axonal transport. We also explore the roles of mitophagy in AD, including its function in the removal of harmed proteins and organelles. Finally, we highlight the therapeutic strategies for the treatment of AD, targeting molecular components involved in mitochondrial damage and autophagy dysregulation in AD, i.e., antioxidants, mitochondrial modulators, and mitophagy enhancers.

Keywords:  Alzheimer’s disease; Aβ; Mitochondrial dysfunction; Mitophagy; p-tau

DOI:  https://doi.org/10.1007/s11064-025-04490-z
Int J Mol Sci. 2025 Jul 11. pii: 6669. [Epub ahead of print]26(14):

Folic Acid Ameliorates Neuronal Ferroptosis in Aging by Up-Regulating SLC7A11-GSH-GPX4 Antioxidant Pathway and Increasing Cystine Levels.

Yue Wang, Jingwen Zhang, Zehao Wang, Qinghan Ren, Zhenshu Li, Guowei Huang, Wen Li.

  Age-related neurodegeneration is characterized by oxidative stress and iron-dependent cell death, yet the neuroprotective mechanisms of folic acid in modulating ferroptosis remain unclear. This study systematically investigated the role of folic acid in inhibiting ferroptosis and attenuating neuronal damage in aging, with a focus on the solute carrier family 7 member 11 (SLC7A11)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) antioxidant pathway, using aged rats supplemented with folic acid (<0.1, 2.0, and 4.0 mg/kg·diet) for 22 months, with young adult rats as controls. Brain iron accumulation and ferroptosis-related proteins (SLC7A11, GPX4, Ferritin heavy chain 1 (FTH1)) were evaluated. In vitro, HT-22 hippocampal neuronal cells were pre-treated with folic acid (0, 10, 20 μmol/L) for 72 h before combining with Erastin (10 μmol/L)-induced ferroptosis for an additional 24 h. Intracellular Fe2+, lipid peroxidation (LPO), malondialdehyde (MDA), reactive oxygen species (ROS), along with cystine, GSH, and ferroptosis-related protein levels were quantified. Stable sh-SLC7A11 knockdown and control (sh-NC) cell lines were used to validate the dependency of folic acid's protective effects on SLC7A11 expression. Folic acid supplementation in aged rats dose-dependently reduced aging-related brain iron accumulation and enhanced the expression of SLC7A11, GPX4, and FTH1. In Erastin-induced HT-22 cells, folic acid significantly mitigated ferroptosis hallmarks. Mechanistically, folic acid increased extracellular cystine uptake and intracellular GSH synthesis, thereby activating the SLC7A11-GSH-GPX4 antioxidant pathway. Notably, molecular docking technique suggested that compared to GPX4, folic acid stabilized SLC7A11's active conformation. sh-SLC7A11 knockdown completely abolished folic acid-mediated protection against ferroptosis, as evidenced by restored loss of cystine, GSH and GPX4 production. This study innovatively emphasized the critical role of folic acid supplementation in inhibiting ferroptosis by up-regulating the SLC7A11-GSH-GPX4 antioxidant pathway, primarily through enhancing cystine availability and SLC7A11 expression. These findings established folic acid as a potential dietary intervention for aging-related neurodegenerative diseases characterized by neuronal ferroptosis, providing preclinical evidence for folic acid based neuroprotection.

Keywords:  SLC7A11; aging; cystine; ferroptosis; folic acid; neuroprotection

DOI:  https://doi.org/10.3390/ijms26146669