bims-medebr 2025-04-27 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–04–27
twenty papers selected by
Regina F. Fernández, Johns Hopkins University

Early plasma ceramide and sphingomyelin levels reflect APOE genotype but not familial Alzheimer's disease gene mutations in female 5xFAD mice, with brain-region specific sphingolipid alterations.
From energy metabolism to mood regulation: The rise of lactate as a therapeutic target.
Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
Metabolic origin and significance of 3-methylglutaryl CoA.
GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons.
Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration.
FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.
FTY720 Modulating Microglia-Mediated Cholesterol Recycling via TREM2 Promotes Remyelination Following Ischemic Damage.
YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.
Exosome-Mediated Mitochondrial Regulation: A Promising Therapeutic Tool for Alzheimer's Disease and Parkinson's Disease.
SOAT1 dysregulation in astrocytes drives Blood-Brain barrier dysfunction and neuroinflammation in Alzheimer's disease.
Hidden β-γ Dehydrogenation Products in Long-Chain Fatty Acid Oxidation Unveiled by NMR: Implications on Lipid Metabolism.
Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.
A parallel reaction monitoring-mass spectrometric method for studying lipid biosynthesis in vitro using 13C16-palmitate as an isotope tracer.
CPT1C DEFICIENCY IN SF1 NEURONS IMPAIRS EARLY METABOLIC ADAPTATION TO DIETARY FATS, LEADING TO OBESITY.
Acyl-CoA-binding proteins: bridging long-chain acyl-CoA metabolism to gene regulation.
Proteomic analysis of hippocampus reveals metabolic reprogramming in a piglet model of mild hypoxic ischemic encephalopathy.
Restricted Surface Diffusion of Cytochromes on Bioenergetic Membranes with Anionic Lipids.
Inactivation of Laforin Phosphatase and Increased Glucose Uptake Underlie Glycogen Synthase-Mediated Neuronal Survival Under Oxidative Stress.
CNS Mitochondria-Derived Vesicle in Blood: Potential Biomarkers for Brain Mitochondria Dysfunction.

Neurobiol Dis. 2025 Apr 17. pii: S0969-9961(25)00139-1. [Epub ahead of print]210 106923

Early plasma ceramide and sphingomyelin levels reflect APOE genotype but not familial Alzheimer's disease gene mutations in female 5xFAD mice, with brain-region specific sphingolipid alterations.

Daan van Kruining, Mario Losen, Jonas Dehairs, Johannes V Swinnen, Etienne Waelkens, Maarten Honing, Pilar Martinez-Martinez.

  Pathophysiological changes associated with Alzheimer's disease (AD) begin decades before dementia onset, with age and APOE ε4 genotype as major risk factors [1-4]. Primary risk factors for developing AD include aging and number of copies of the apolipoprotein E (APOE) ε4 allele. Altered sphingolipid metabolism is increasingly implicated in early AD. However, the relationship between early plasma and brain sphingolipid changes-particularly in the context of APOE genotype-remains poorly defined. In this study, we analyzed plasma and brain sphingolipid profiles in transgenic AD mice carrying human APOE3 or APOE4 variants, with or without familial AD mutations (E3FAD and E4FAD). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we assessed 110 sphingolipid species across four major classes (ceramides (Cers), hexosylceramides (HexCers), lactosylceramides (LacCers), and sphingomyelins (SMs)) at 2, 4, and 6 months in plasma and at 6 months in brain tissue in the cortex, hippocampus, striatum, and cerebellum. Our results demonstrate that early plasma sphingolipid alterations are largely driven by APOE genotype rather than AD pathology. Specifically, APOE4 carriers showed significant increases in SM species and reductions in Cer species compared to APOE3 carriers, independent of age or AD genotype. Brain lipid profiles showed minimal changes across genotypes after region correction. However, combined p-value analyses revealed APOE- and EFAD-dependent differences in the composition of primarily cortical sphingolipids. ROC analyses demonstrated high discriminative power of plasma sphingolipids for APOE, but not for AD genotype. These findings suggest that early plasma lipid profiles in female 5xFAD mice are more strongly influenced by APOE genotype than by overt AD pathology, potentially reflecting systemic pathways linked to APOE4-associated AD risk, while early disease-associated changes in the brain appear to be subtle and region-specific. These results underscore the importance of accounting for APOE genotype in early-stage AD lipidomic studies and in the interpretation of peripheral lipid biomarkers.

Keywords:  APOE genotype; Alzheimer's disease; Liquid chromatography-tandem mass spectrometry (LC-MS/MS); Sphingolipid metabolism

DOI:  https://doi.org/10.1016/j.nbd.2025.106923
J Adv Res. 2025 Apr 20. pii: S2090-1232(25)00262-0. [Epub ahead of print]

From energy metabolism to mood regulation: The rise of lactate as a therapeutic target.

Sen Zhang, Jie Xia, Wenke He, Yong Zou, Wenbin Liu, Lingxia Li, Zhuochun Huang, Qing Li, Zhengtang Qi, Weina Liu.

   BACKGROUND: Disruption of cerebral energy metabolism is increasingly recognized as a key factor in the pathophysiology of mood disorders. Lactate, beyond its role as a metabolic byproduct, is now understood to be a critical player in brain energy homeostasis and a modulator of neuronal function. Recent advances in understanding lactate shuttling between astrocytes and neurons have opened new avenues for exploring its multifaceted roles in mood regulation. Exercise, known to modulate brain lactate levels, further underscores the potential of lactate as a therapeutic target in mood disorders.
AIM OF REVIEW: This review delves into the alterations in cerebral lactate associated with mood disorders, emphasizing their implications for brain energy dynamics and signaling pathways. Additionally, we discuss the therapeutic potential of lactate in mood disorders, particularly through its capacity to remodel cerebral function. We conclude by assessing the promise of exercise-induced lactate production as a novel strategy for mood disorder treatment.
KEY SCIENTIFIC CONCEPTS OF THE REVIEW: Alterations in brain lactate may contribute to the pathogenesis of mood disorders. In several studies, lactate is not only a substrate for brain energy metabolism, but also a molecule that triggers signaling cascades. Specifically, lactate is involved in the regulation of neurogenesis, neuroplasticity, endothelial cell function, and microglia lysosomal acidification, therefore improving mood disorders. Meanwhile, exercise as a low-risk intervention strategy can improve mood disorders through lactate regulation. Thus, the evidence from this review supports that lactate could be a potential therapeutic target for mood disorder, contributing to a deeper understanding of mood disorder pathogenesis and intervention.

Keywords:  Cerebral function remodeling; Exercise; Lactate; Mood disorders; Neuroenergetics

DOI:  https://doi.org/10.1016/j.jare.2025.04.018
Nat Cell Biol. 2025 Apr 21.

Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.

Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P Praharaj, Stewart Morley, Bookyong Ko, Mona H Soflaee, Harrison J Tom, Harrison Brown, Hieu S Vu, Shih-Chia Tso, Chad A Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K Allen, Gerta Hoxhaj.

Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.

DOI: https://doi.org/10.1038/s41556-025-01655-4
Clin Chim Acta. 2025 Apr 17. pii: S0009-8981(25)00199-8. [Epub ahead of print] 120320

Metabolic origin and significance of 3-methylglutaryl CoA.

Elizabeth A Jennings, Zane H Abi-Rached, Robert O Ryan.

  3-Methylglutaryl (3MG) CoA is not part of any biochemical pathway, yet its byproducts, 3MG carnitine and 3MG acid, are disease biomarkers. Both compounds are excreted in HMG CoA lyase deficiency, while 3MG aciduria occurs in inborn errors of metabolism (IEM) associated with compromised mitochondrial energy metabolism. In one such disorder (i.e., TMEM70 deficiency), 3MG carnitine is also present. Moreover, in a number of chronic and acute maladies, elevated levels of 3MG carnitine are present. The precursor of 3MG CoA istrans-3-methylglutaconyl (3MGC) CoA. Whentrans-3MGC CoA levels rise, a portion of this metabolite pool is reduced to 3MG CoA, potentially via a side reaction involving glutaryl CoA dehydrogenase (GCDH), which normally catalyzes the oxidative decarboxylation of glutaryl CoA to crotonyl CoA and CO2. This reaction occurs via a two-step process wherein glutaryl CoA is initially oxidized to glutaconyl CoA, coupled to reduction of the enzyme's FAD prosthetic group. Enzyme-bound glutaconyl CoA is then decarboxylated to the reaction product, crotonyl CoA. Before GCDH can accept another glutaryl CoA the flavin prosthetic group must be oxidized to FAD by donating electrons to electron transferring flavoprotein (ETF). However, genetic- or disease-induced defects in electron transport chain function can impede this reaction. We propose thattrans-3MGC CoA is a substrate for reduced GCDH and, when glutaryl CoA andtrans-3MGC CoA are present, GCDH is able to bypass ETF and cycle between oxidized and reduced states, producing crotonyl CoA and CO2from glutaryl CoA, and 3MG CoA fromtrans-3MGC CoA.

Keywords:  3-methylglutaric acid; 3-methylglutaryl carnitine; Biomarker; Glutaryl CoA dehydrogenase; Mitochondria

DOI:  https://doi.org/10.1016/j.cca.2025.120320
Commun Biol. 2025 Apr 22. 8(1): 647

GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons.

Zixuan Yuan, Mahmud Arif Pavel, Scott B Hansen.

The γ-aminobutyric acid (GABA) type A receptor (GABAAR), a GABA activated pentameric chloride channel, mediates fast inhibitory neurotransmission in the brain. The lipid environment is critical for GABAAR function. How lipids regulate the channel in the cell membrane is not fully understood. Here we employed super resolution imaging of lipids to demonstrate that the agonist GABA induces a rapid and reversible membrane translocation of GABAAR to phosphatidylinositol 4,5-bisphosphate (PIP2) clusters in mouse primary cortical neurons. This translocation relies on nanoscopic separation of PIP2 clusters and lipid rafts (cholesterol-dependent ganglioside clusters). In a resting state, the GABAAR associates with lipid rafts and this colocalization is enhanced by uptake of astrocytic secretions. These astrocytic secretions delay desensitization and enhance maximum current. In an Alzheimer's Disease (AD) mouse model with high brain cholesterol, GABAAR shifts into lipid rafts. Our findings suggest cholesterol is a signaling molecule and astrocytes regulates GABAARs in neurons by secreting cholesterol. The findings have implications for treating mood disorders and AD associated with altered brain lipids.

DOI: https://doi.org/10.1038/s42003-025-08026-7
Cell Mol Neurobiol. 2025 Apr 21. 45(1): 38

Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration.

Donghui Na, Zechen Zhang, Meng Meng, Meiyu Li, Junyan Gao, Jiming Kong, Guohui Zhang, Ying Guo.

  Aging is characterized by a gradual decline in physiological functions, with brain aging being a major risk factor for numerous neurodegenerative diseases. Given the brain's high energy demands, maintaining an adequate ATP supply is crucial for its proper function. However, with advancing age, mitochondria dysfunction and a deteriorating energy metabolism lead to reduced overall energy production and impaired mitochondrial quality control (MQC). As a result, promoting healthy aging has become a key focus in contemporary research. This review examines the relationship between energy metabolism and brain aging, highlighting the connection between MQC and energy metabolism, and proposes strategies to delay brain aging by targeting energy metabolism.

Keywords:  Brain aging; Energy metabolism; Mitochondrial quality control; Neurons

DOI:  https://doi.org/10.1007/s10571-025-01555-z
Glia. 2025 Apr 18.

FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.

Mariana Bresque, Daniel Esteve, Garret Balmer, Haylee L Hamilton, Joshua S Stephany, Mariana Pehar, Marcelo R Vargas.

  Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.

Keywords:  LPS; NF‐κB; astrocytes; inflammation; microglia

DOI:  https://doi.org/10.1002/glia.70023
Stroke. 2025 Apr 22.

FTY720 Modulating Microglia-Mediated Cholesterol Recycling via TREM2 Promotes Remyelination Following Ischemic Damage.

Jian-Bing Yu, Chen Hong, Xue-Wei Ren, Wei Guo, Ye-Fan Chen, Juan Ji, Xi-Yue Zhang, Xiu-Lan Sun.

   BACKGROUND: Following ischemic white matter damage, microglia are responsible for phagocytosing and degrading cholesterol-rich myelin debris, storing them as lipid droplets. However, our understanding of how microglia process this engulfed material remains limited. Our previous findings identified FTY720 as a high-affinity ligand for microglial TREM2 (triggering receptor expressed on myeloid cells 2). Therefore, we aimed to reveal the role of FTY720 targeting TREM2 in regulating microglial cholesterol metabolism during remyelination.
METHODS: Chronic ischemic white matter damage was induced by bilateral carotid artery stenosis in male wild-type and TREM2-/- mice. FTY720 was administered daily via intraperitoneal injection for 28 days following bilateral carotid artery stenosis surgery. Cognitive function, white matter integrity, accumulation of cholesterol and lipid droplets in microglia, and oligodendrocyte differentiation were evaluated using behavioral tests, transmission electron microscopy, immunofluorescence, and biochemical analyses. In vitro coculture systems were used to evaluate cholesterol transfer and remyelination efficacy.
RESULTS: FTY720 significantly alleviated cognitive deficits and promoted remyelination in bilateral carotid artery stenosis mice, as evidenced by enhanced performance in the Morris water maze and reduced demyelination observed via transmission electron microscopy and immunofluorescence. This therapeutic effect was absent in TREM2-/- bilateral carotid artery stenosis mice. Mechanistically, FTY720 promoted the redistribution of ABCA1 (ATP-binding cassette transporter A1) from lysosomes to the cell membrane in microglia via TREM2, which facilitated cholesterol efflux and reduced the accumulation of intracellular cholesterol and lipid droplets. Additionally, in vitro coculture experiments revealed that FTY720 enhanced cholesterol transfer from microglia to oligodendrocytes through TREM2, thereby promoting oligodendrocyte myelination.
CONCLUSIONS: Our study suggested that FTY720 regulated the recycling of myelin-derived cholesterol from microglia through TREM2, supplying cholesterol to oligodendrocytes and supporting remyelination, thus offering a novel therapeutic target for ischemic white matter damage.

Keywords:  cholesterol; fingolimod hydrochloride; microglia; remyelination; stroke

DOI:  https://doi.org/10.1161/STROKEAHA.124.049745
J Inherit Metab Dis. 2025 May;48(3): e70029

YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.

Anthi Demetriadou, Olga Grafakou, Theodoros Georgiou, Daniela Burska, Anna Malekkou, Jana Krizova, Efstathia Paramera, Gavriella Mavrikiou, Maria Dionysiou, Athina Theodosiou, Carolina Sismani, Violetta Anastasiadou, Ioannis Ioannou, Evangelos Papakonstantinou, Hana Hansikova, Anthi Drousiotou, Petros P Petrou.

  3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient-derived fibroblasts. Furthermore, our results indicate that YME1L1L667V is associated with attenuated activity of rate-limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build-up of 3-methylglutaconic and 3-methylglutaric acid due to the diversion of acetyl-CoA, not efficiently processed in the Krebs cycle, towards the formation of 3-methylglutaconyl-CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3-MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.

Keywords:  3‐methylglutaconic aciduria; YME1L1; inherited metabolic disorders; mitochondrial disorders; mitochondrial dysfunction; mitochondrial fragmentation

DOI:  https://doi.org/10.1002/jimd.70029
Int J Nanomedicine. 2025 ;20 4903-4917

Exosome-Mediated Mitochondrial Regulation: A Promising Therapeutic Tool for Alzheimer's Disease and Parkinson's Disease.

Young Hyun Jung, Hyo Youn Jo, Dae Hyun Kim, Yeon Ju Oh, Minsoo Kim, Seunghyun Na, Ho-Yeon Song, Hyun Jik Lee.

  Alzheimer's disease (AD) and Parkinson's disease (PD) are representative neurodegenerative diseases with abnormal energy metabolism and altered distribution and deformation of mitochondria within neurons, particularly in brain regions such as the hippocampus and substantia nigra. Neurons have high energy demands; thus, maintaining a healthy mitochondrial population is important for their biological function. Recently, exosomes have been reported to have mitochondrial regulatory potential and antineurodegenerative properties. This review presents the mitochondrial abnormalities in brain cells associated with AD and PD and the potential of exosomes to treat these diseases. Specifically, it recapitulates research on the molecular mechanisms whereby exosomes regulate mitochondrial biogenesis, fusion/fission dynamics, mitochondrial transport, and mitophagy. Furthermore, this review discusses exosome-triggered signaling pathways that regulate nuclear factor (erythroid-derived 2)-like 2-dependent mitochondrial antioxidation and hypoxia inducible factor 1α-dependent metabolic reprogramming. In summary, this review aims to provide a profound understanding of the regulatory effect of exosomes on mitochondrial function in neurons and to propose exosome-mediated mitochondrial regulation as a promising strategy for AD and PD.

Keywords:  Alzheimer’s disease; Parkinson’s disease; exosome; mitochondria; neurodegenerative disease

DOI:  https://doi.org/10.2147/IJN.S513816
Brain Behav Immun. 2025 Apr 22. pii: S0889-1591(25)00170-9. [Epub ahead of print]

SOAT1 dysregulation in astrocytes drives Blood-Brain barrier dysfunction and neuroinflammation in Alzheimer's disease.

Lian Huang, Fu Zeng, Hui Wei, Tong Su, Yuwen Su, Yarong Ling, Qi Niu, Qi Xu.

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to memory loss and cognitive decline, in which blood-brain barrier (BBB) and astrocyte dysfunction are significantly involved. Recent evidence suggests that dysregulation of lipid metabolism in astrocytes contributes to BBB disruption and neuroinflammation in AD. Sterol O-acyltransferase 1 (SOAT1), an enzyme involved in cholesterol esterification, has been implicated in BBB disruption and neuroinflammation, but its specific role in AD remains unclear. This study aimed to investigate the impact of SOAT1 on lipid metabolism, BBB integrity, and neuroinflammation in AD. Using Oil Red O staining of human autopsy brain tissue and reanalysis of publicly available single-nucleus RNA sequencing (snRNA-seq) data, we identified a significant increase in lipid droplet accumulation and lipid metabolism gene expression, particularly in astrocytes, in the brains of AD patients. Furthermore, in vitro BBB models and the 5 × FAD mouse model were used to explore how SOAT1 expression influences BBB function. Our results demonstrated that elevated SOAT1 expression in astrocytes was positively correlated with increased lipid droplet accumulation and compromised BBB integrity. Knockdown of SOAT1 using siRNA or treatment with the SOAT1 inhibitor K604 restored BBB function, reduced neuroinflammation, and improved cognitive function in 5 × FAD mice. These findings suggest that SOAT1 plays a critical role in astrocytic lipid metabolism and BBB dysfunction in AD. Targeting SOAT1 may be a promising therapeutic approach to alleviate neuroinflammation and restore cognitive function in AD patients.

DOI: https://doi.org/10.1016/j.bbi.2025.04.032
ACS Bio Med Chem Au. 2025 Apr 16. 5(2): 262-267

Hidden β-γ Dehydrogenation Products in Long-Chain Fatty Acid Oxidation Unveiled by NMR: Implications on Lipid Metabolism.

Simone Fabbian, Beatrice Masciovecchio, Elisabetta Schievano, Gabriele Giachin.

We present a comprehensive analysis of the initial α,β-dehydrogenation step in long-chain fatty acid β-oxidation (FAO). We focused on palmitoyl-CoA oxidized by two mitochondrial acyl-CoA dehydrogenases, very-long-chain acyl-CoA dehydrogenase (VLCAD) and acyl-CoA dehydrogenase family member 9 (ACAD9), both implicated in mitochondrial diseases. By combining MS and NMR, we identified the (2E)-hexadecenoyl-CoA as the expected α-β-dehydrogenation product and also the E and Z stereoisomers of 3-hexadecenoyl-CoA: a "γ-oxidation" product. This finding reveals an alternative catalytic pathway in mitochondrial FAO, suggesting a potential regulatory role for ACAD9 and VLCAD during fatty acid metabolism.

DOI: https://doi.org/10.1021/acsbiomedchemau.4c00140
J Mol Biol. 2025 Apr 21. pii: S0022-2836(25)00227-X. [Epub ahead of print] 169161

Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.

Bishal Basak, Erika L F Holzbaur.

  Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis(ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.

Keywords:  PINK1; Parkin; autophagosomes; lysosomes; mitochondria; mitophagy; neurodegeneration

DOI:  https://doi.org/10.1016/j.jmb.2025.169161
Anal Chim Acta. 2025 Jun 08. pii: S0003-2670(25)00397-6. [Epub ahead of print]1354 344003

A parallel reaction monitoring-mass spectrometric method for studying lipid biosynthesis in vitro using 13C16-palmitate as an isotope tracer.

Kyeong-Seog Kim, Young Gyun Ko, Woo Seok Yang, Hye Young Kim, Joo-Youn Cho.

   BACKGROUND: Palmitate, which is the end product of fatty acid synthase, is the key fatty acid for understanding of lipid biosynthetic process in mammalian cells. Mass spectrometry (MS) methodology using 13C-palmitate can trace the lipid biosynthesis such as glycerolipids, glycerophospholipids, and sphingolipids. However, due to the interferences of natural heavy isotopes, accurate measurement of 13C-labeled lipid species has been limited. Here we describe a high-throughput isotope tracing experiment to assess lipid biosynthesis using parallel reaction monitoring-MS (PRM-MS) with 13C16-palmitate as an isotope tracer.
RESULTS: The developed method can trace 14 13C16-labeled lipid classes without disturbance from the heavy isotope patterns of natural lipids. Lipid class-based separation was achieved through hydrophilic interaction liquid chromatography (HILIC) which allows facile identification of lipid, and PRM-MS was performed for accurate detection of the 13C16-labeled lipids. A fibroblast (NIH/3T3) cell line was used as an in vitro model, and the NIH/3T3 cells were treated with bovine serum albumin (BSA)-bound 13C16-palmitate. The isotopic disturbance from natural lipid was eliminated using 13C16-palmitate, rather than 13C1-palmitate, as an isotope tracer. After 24 h of incubation with 0.1 mmol/L of BSA-bound 13C16-palmitate in the fibroblasts, NIH/3T3 cells synthesized the 127 13C16-labeled lipid species of glycerolipids, glycerophospholipids, and sphingolipids. Finally, in the NIH/3T3 cells incubated for 1, 6, and 24 h after the treatment of the isotope tracer exhibited an increased profile of 13C16-labeled lipidome, depending on duration of incubation.
SIGNIFICANCE: The HILIC/PRM-MS method using 13C16-palmitate as an isotope tracer enables identification of 13C16-labeled lipid species by annotating 13C16-labeled position, including the 13C16-fatty acyl chain and 13C16-sphingolipid headgroup, without interference of natural heavy isotope patterns. This lipidomic flux analysis using PRM approach is expected to provide insights into assessment of isotope-labeled lipids.

Keywords:  HILIC-MS/MS; Isotope tracing; Lipid biosynthesis; Lipidomics; Parallel reaction monitoring

DOI:  https://doi.org/10.1016/j.aca.2025.344003
Mol Metab. 2025 Apr 21. pii: S2212-8778(25)00062-6. [Epub ahead of print] 102155

CPT1C DEFICIENCY IN SF1 NEURONS IMPAIRS EARLY METABOLIC ADAPTATION TO DIETARY FATS, LEADING TO OBESITY.

A Fosch, D S Pizarro, S Zagmutt, A C Reguera, G Batallé, M Rodríguez-García, J García-Chica, O Freire-Agulleiro, C Miralpeix, P Zizzari, D Serra, L Herrero, M López, D Cota, R Rodríguez-Rodríguez, N Casals.

  SF1 neurons of the ventromedial hypothalamus (VMH) play a pivotal role in regulating body weight and adiposity, particularly in response to a high-fat diet (HFD), as well as in the recovery from insulin-induced hypoglycemia. While the brain-specific CPT1C isoform is well known for its role in controlling food intake and energy homeostasis, its function within specific hypothalamic neuronal populations remains largely unexplored. Here, we demonstrate that CPT1C in SF1 neurons is essential for appropriate responses to dietary fats. Mice deficient in CPT1C within SF1 neurons fail to adjust their caloric intake during initial HFD exposure, which is associated with impaired activation of the melanocortin system. Furthermore, these mice exhibit disrupted metabolic gene expression in the liver, muscle, and adipose tissue, leading to increased adiposity independently of food intake. In contrast, their response to glucose or insulin challenges remains intact. After long-term HFD exposure, SF1-Cpt1c-KO mice are more prone to developing obesity and glucose intolerance than control littermates, with males exhibiting a more severe phenotype. Interestingly, CPT1C deficiency in SF1 neurons also results in elevated hypothalamic endocannabinoid (eCB) levels under both chow and HFD conditions. We propose that this sustained eCB elevation reduces VMH activation by fatty acids and impairs the SF1-POMC drive upon fat intake. Our findings establish CPT1C in SF1 neurons as a critical regulator of VMH-driven dietary fat sensing, satiety, and lipid metabolic adaptation.

Keywords:  CPT1C; SF1 neurons; adiposity; endocannabinoids; food intake; high-fat diet

DOI:  https://doi.org/10.1016/j.molmet.2025.102155
New Phytol. 2025 Apr 22.

Acyl-CoA-binding proteins: bridging long-chain acyl-CoA metabolism to gene regulation.

Allegra Wundersitz, Kurt M V Hoffmann, Joost T van Dongen.

  Acyl-Coenzyme A-binding proteins (ACBPs) sequester and transport long-chain acyl-Coenzyme A (LCA-CoA) molecules, key intermediates in lipid metabolism, membrane biogenesis, and energy production. In addition, recent research emphasizes their regulatory role in linking the metabolic state to gene expression. In animals, ACBPs coordinate acetyl-CoA metabolism and enzyme activity, thereby affecting gene expression through broad signaling networks. In plants, ACBPs contribute to development and stress responses, with hypoxia research showing their involvement in detecting LCA-CoA fluctuations to trigger genetic acclimation. This review explores ACBPs in LCA-CoA signaling and gene regulation, emphasizing their function as universal 'translators' of metabolic states for cellular acclimation. Further ACBP research will offer novel regulatory insights into numerous signaling pathways fundamental to health, development, and environmental responses across kingdoms.

Keywords:  acyl‐CoA‐binding proteins; long‐chain acyl‐CoA signaling; metabolic regulation; plant hypoxia signaling; stress responses; unsaturated lipids

DOI:  https://doi.org/10.1111/nph.70142
PLoS One. 2025 ;20(4): e0320869

Proteomic analysis of hippocampus reveals metabolic reprogramming in a piglet model of mild hypoxic ischemic encephalopathy.

Dawn B Lammert, Regina F Fernandez, Xiuyun Liu, Jingyao Chen, Raymond C Koehler, Susanna Scafidi, Joseph Scafidi.

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a leading cause of long-term neurologic morbidity. Fifty percent of HIE cases are mild and do not have clearly defined therapeutic interventions. Emergent evidence now demonstrates that up to 25% of children with mild HIE suffer motor and developmental delay by 18 months and 35% have cognitive impairments by age 5 years. Interestingly, the hippocampus, which is responsible for learning and memory, does not show overt injury but does demonstrate volume changes on imaging that correlate with cognitive and behavioral outcomes. Although there is extensive data regarding pathophysiological changes following moderate and severe HIE, there is a paucity of understanding regarding the extent, duration, and compensatory adaptations in the mild neonatal HIE brain. We performed hippocampal proteomic analysis using a swine model of mild neonatal hypoxia-asphyxia. Hippocampi were collected at 24 or 72 hours after injury, and proteomics was performed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Pathway analysis demonstrated that several metabolic pathways are temporally regulated after mild HIE. Specifically, amino acid, carbohydrate, and one-carbon metabolism increased at 24 hours while fat metabolism and oxidative phosphorylation decreased at 24 hours. Downregulation of oxidative phosphorylation was more pronounced at 72 hours. Our data demonstrate that metabolic reprogramming occurs after mild HIE, and these changes persist up to 72 hours after injury. These results provide new evidence that mild HIE disrupts brain metabolism, emphasizing the need for a better understanding of the underlying pathophysiology of mild HIE and development of targeted therapeutic interventions for this population.

DOI: https://doi.org/10.1371/journal.pone.0320869
Membranes (Basel). 2025 Apr 13. pii: 124. [Epub ahead of print]15(4):

Restricted Surface Diffusion of Cytochromes on Bioenergetic Membranes with Anionic Lipids.

Aaron Chan, Emad Tajkhorshid.

  Bioenergetic membranes of mitochondria, thylakoids, and chromatophores are primary sites of ATP production in living cells. These membranes contain an electron transport chain (ETC) in which electrons are shuttled between a series of redox proteins during the generation of ATP via oxidative phosphorylation. The phospholipid composition of these membranes, which often include negative lipids, plays a role in determining the electrostatics of their surface owing to the spatial distribution of their charged head groups. Cardiolipin (CDL) is a phospholipid commonly associated with bioenergetic membranes and is also a significant contributor to the negative surface charge. Interactions between cytochromes and phospholipid head groups in the membrane can in principle affect the rate of its travel between ETC components, hence influencing the rate of ATP turnover. Here, we use molecular dynamic (MD) simulations that feature an accelerated membrane model, termed highly mobile membrane mimetic (HMMM), to study protein-lipid interactions during the diffusion of cytochrome c2 between redox partners in a bioenergetic membrane. We observe a "skipping" mode of diffusion for cytochromes along with a bias for binding to anionic lipids, particularly with a strong preference for CDL. During diffusion, cytochrome c2 maintains a relatively fixed tilt with respect to the membrane normal with wider fluctuations in its angle with respect to the plane of the membrane. The obtained results describing the behavior of cytochrome c2 on a representative bioenergetic membrane have direct ramifications in shuttling motions of other similar electron-carrying elements in other bioenergetic membranes, which are composed of a significant amount of anionic lipids. The mode of surface-restricted diffusion reported here would modulate rapid electron transfer between the ETC complexes anchored in bioenergetic membranes by reducing the search space between them.

Keywords:  bioenergetic membranes; cardiolipin; electron transfer; enhanced sampling; molecular dynamics

DOI:  https://doi.org/10.3390/membranes15040124
Mol Neurobiol. 2025 Apr 22.

Inactivation of Laforin Phosphatase and Increased Glucose Uptake Underlie Glycogen Synthase-Mediated Neuronal Survival Under Oxidative Stress.

Akanksha Onkar, Deepashree Sheshadri, Kamali Nagarajan, Subramaniam Ganesh.

  Recent studies demonstrate that exposure of neurons to physiological stressors triggers glycogen synthase (GS) activation and glycogen synthesis as a transient cell survival mechanism. However, the mechanisms that regulate glycogen synthesis during stress and its role in neuronal physiology remain unclear. This study investigated the mechanisms that guide GS activation and glycogen accumulation under oxidative stress conditions as a model stressor. We use neuronal cell lines to demonstrate that hydrogen peroxide-induced oxidative stress activates GS and glycogen synthesis in neuronal cells. We further demonstrate that the stress-induced glycogen accumulation is dependent on the membrane localization of the Glut3 glucose transporters and increased glucose uptake during stress. The stress-induced activation of glycogen synthesis, however, is independent of intracellular glucose level, suggesting a parallel mechanism for activating GS and glucose uptake in neurons under physiological stress. We demonstrate that oxidative stress results in the inactivation of laforin phosphatase, leading to the membrane localization of Glut3 and activation of GS. Using the Drosophila model, we demonstrate that increased GS activity and concomitant glycogen accumulation are pro-survival mechanisms for neurons under oxidative stress. Our study thus offers novel insights into the pathways that regulate glycogen metabolism in neurons under oxidative stress and underscores their importance for neuronal survival.

Keywords:  Glycogen metabolism; Neurodegeneration; Neuroprotection; Physiological stress; Stress-response mechanism

DOI:  https://doi.org/10.1007/s12035-025-04955-w
Ann Clin Transl Neurol. 2025 Apr 25.

CNS Mitochondria-Derived Vesicle in Blood: Potential Biomarkers for Brain Mitochondria Dysfunction.

Qi Liu, Wentao Chen, Yahong Wu, Zhen Guo, Jun Chen, Chen Tian, Pan Wang, Shaopeng Zeng, Bin Xu, Jing Duan, Shilong Han, Xiao Xiong, Jing Zhang.

   OBJECTIVE: Mitochondrial dysfunction is a hallmark of neurodegenerative diseases like Alzheimer's (AD) and Parkinson's (PD). Our goal was to develop practical, noninvasive methods to assess mitochondrial status through the detection of mitochondria-derived vesicles (MDVs).
METHODS: We explored blood-borne MDVs, a recently identified class of extracellular vesicles, as potential biomarkers for CNS mitochondrial status.
RESULTS: The study identified MDVs from neurons, astrocytes, and oligodendrocytes specifically in human plasma. A novel nanoflow cytometry was developed to evaluate the level of neuron-, astrocyte-, and oligodendrocyte-derived MDVs in plasma in AD and PD patients. Importantly, analyses of discovery and validation cohorts revealed significantly lower brain cell-specific MDVs in AD and PD patients compared to healthy controls.
INTERPRETATION: This study suggests that blood MDVs could serve as noninvasive biomarkers for mitochondrial dysfunction in AD, PD, and beyond, potentially aiding in monitoring mitochondrial-focused therapies for neurological disorders.

Keywords:  Alzheimer's diseases; Parkinson's diseases; mitochondrial dysfunction; mitochondria‐derived vesicles

DOI:  https://doi.org/10.1002/acn3.70060