bims-medebr 2025-05-11 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–05–11
ten papers selected by
Regina F. Fernández, Johns Hopkins University

Lactate receptor HCAR1 affects axonal development and contributes to lactate's protection of axons and myelin in experimental neonatal hypoglycemia.
Peroxisomal ether-glycerophospholipid synthesis is dysregulated after TBI.
Astrocytic GLUT1 deletion in adult mice enhances glucose metabolism and resilience to stroke.
Astrocyte lactoferrin deficiency affects the construction and function of spinal neurons by regulating cholesterol metabolism.
Loss of the acyltransferase TMEM68 leads to growth delay and dysregulation of triacylglycerol and glycerophospholipid homeostasis in the mouse brain.
Mitochonic acid 5, an ATP production accelerator, protects against neurological damage in ischemic stroke.
Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.
Alzheimer's disease protective allele of Clusterin modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication.
The ketogenic diet and metabolic treatments for neuropsychiatric disorders.
Novel ACAD8 variants identified in Isobutyryl-CoA dehydrogenase deficiency: challenges in phenotypic variability and management.

eNeuro. 2025 May 09. pii: ENEURO.0563-24.2025. [Epub ahead of print]

Lactate receptor HCAR1 affects axonal development and contributes to lactate's protection of axons and myelin in experimental neonatal hypoglycemia.

Lauritz Kennedy, Cecilie Morland, Martine Narum, Linda H Bergersen, Johanne E Rinholm.

Lactate plays an important role in brain energy metabolism. It contributes to normal brain development and to neuroprotection in diabetic hypoglycemia, but its role in neonatal hypoglycemia is unclear. Moreover, lactate can work as a signaling substance via the lactate receptor HCAR1 (Hydroxycarboxylic acid receptor 1). Recent studies indicate that HCAR1 is protective in mouse models of neonatal hypoxic ischemia and has a role in metabolic regulation in glial cells during hypoglycemia. Here we have studied potential impacts of HCAR1 on axonal and myelin development in the cerebral cortex and corpus callosum of young (p21) wild type (WT) mice and HCAR1 KO mice and in cortical organotypic brain slice cultures. The HCAR1 KO mice showed lower axonal area relative to WT in both cortex and corpus callosum. However, the myelin area was unaffected by HCAR1 KO. Using particle- and colocalization analysis we show that HCAR1 KO predominantly reduces axonal size in unmyelinated axons. Using an organotypic brain slice model of neonatal hypoglycemia, we find that lactate protects both axonal and myelin development in hypoglycemia, partially via HCAR1. Lastly, live imaging with a pH-sensitive dye on acute cortical brain slices indicates that cellular lactate uptake is influenced by HCAR1. In conclusion, our findings support a role of HCAR1 in axonal development and in lactate's protective effects in hypoglycemia.Significance statement Lactate is a critical metabolite for brain energy metabolism, with established roles in neuroprotection and development. Our study provides new insights into the role of the lactate receptor HCAR1 in axonal and myelin development in the neonatal brain. We demonstrate that HCAR1 influences axonal size, particularly in unmyelinated axons, and mediates lactate's protective effects during neonatal hypoglycemia. Using in vivo and ex vivo approaches, including organotypic brain slice cultures and live imaging, we show that HCAR1 influences cellular lactate uptake and protects axonal and myelin integrity under hypoglycemic conditions. These findings highlight the dual role of lactate as an energy substrate and signaling molecule via HCAR1, with implications for understanding brain development and resilience to metabolic stress.

DOI: https://doi.org/10.1523/ENEURO.0563-24.2025
J Lipid Res. 2025 May 07. pii: S0022-2275(25)00081-1. [Epub ahead of print] 100821

Peroxisomal ether-glycerophospholipid synthesis is dysregulated after TBI.

Amir Mehrabani-Tabari, Nivedita Hegdekar, Sabrina Bustos, Yulemni Morel, Yuanyuan Ji, Sazia Arefin Kachi, Olivia Pettyjohn-Robin, Sagarina Thapa, Maya Bhattiprolu, Marta M Lipinski, Jace W Jones, Chinmoy Sarkar.

  Ether-glycerophospholipids (ether-GPs), the ether bond- (- O -) containing glycerophospholipids are major components of brain lipidome. Ether-GPs play a crucial role in regulating neuronal function, and their deficiency has been implicated in many neurodegenerative diseases. However, how they are affected after traumatic brain injury (TBI) is not known. Our data demonstrate a significant decrease in ether-GPs abundance in the mouse cortex following controlled cortical impact (CCI) induced TBI. This is at least in part due to the impairment of peroxisomal ether-GP synthesis in the mouse brain after TBI. We detected dysregulation of peroxisomal ether-GPs synthesizing enzymes - glyceronephosphate-O-acyltransferase (GNPAT) and alkylglycerone phosphate synthase (AGPS) in the injured mouse brains. Our data demonstrate a significant decline in GNPAT level in the peroxisomal fraction and a marked accumulation of AGPS in the cytosol of mouse cortices after TBI. To restore ether-GPs level in the injured brain, we treated TBI mice with an ether-GP precursor - 1-O-octadecylglycerol (OAG) to bypass peroxisomal ether-GPs synthesizing steps. OAG partially restored the levels of several ether-GPs, attenuated inflammatory cytokine expression and improved their functional recovery after TBI. Taken together, our data demonstrate that decline in ether-GPs abundance after TBI is at least in part due to the impairment in peroxisomal ether-GPs synthesis and that restoration of ether-GPs by OAG treatment can improve TBI outcomes.

Keywords:  Ether-glycerophospholipids; Lipid; Neurodegeneration; Traumatic brain injury (TBI)

DOI:  https://doi.org/10.1016/j.jlr.2025.100821
Nat Commun. 2025 May 06. 16(1): 4190

Astrocytic GLUT1 deletion in adult mice enhances glucose metabolism and resilience to stroke.

Laetitia Thieren, Henri S Zanker, Jeanne Droux, Urvashi Dalvi, Matthias T Wyss, Rebecca Waag, Pierre-Luc Germain, Lukas M von Ziegler, Zoe J Looser, Ladina Hösli, Luca Ravotto, E Dale Abel, Johannes Bohacek, Susanne Wegener, L Felipe Barros, Mohamad El Amki, Bruno Weber, Aiman S Saab.

Brain activity relies on a steady supply of blood glucose. Astrocytes express glucose transporter 1 (GLUT1), considered their primary route for glucose uptake to sustain metabolic and antioxidant support for neurons. While GLUT1 deficiency causes severe developmental impairments, its role in adult astrocytes remains unclear. Here, we show that astrocytes and neurons tolerate the inducible, astrocyte-specific deletion of GLUT1 in adulthood. Sensorimotor and memory functions remain intact in male GLUT1 cKO mice, indicating that GLUT1 loss does not impair behavior. Despite GLUT1 loss, two-photon glucose sensor imaging reveals that astrocytes maintain normal resting glucose levels but exhibit a more than two-fold increase in glucose consumption, indicating enhanced metabolic activity. Notably, male GLUT1 cKO mice display reduced infarct volumes following stroke, suggesting a neuroprotective effect of increased astrocytic glucose metabolism. Our findings reveal metabolic adaptability in astrocytes, ensuring glucose uptake and neuronal support despite the absence of their primary transporter.

DOI: https://doi.org/10.1038/s41467-025-59400-2
Exp Cell Res. 2025 May 05. pii: S0014-4827(25)00191-0. [Epub ahead of print]449(1): 114595

Astrocyte lactoferrin deficiency affects the construction and function of spinal neurons by regulating cholesterol metabolism.

Xin Tong, Xin Liu, Yu-Xuan Jiang, Jia-Rui Su, Jun-Qi Luan, Chuang Guo.

  Astrocytes play pivotal roles in central nervous system (CNS) homeostasis, with emerging evidence implicating astrocyte-derived lactoferrin (Lf) in neurodevelopmental and neurodegenerative processes. This study investigates Lf's functional significance in spinal cord integrity using astrocyte-specific Lf knockout (cKO) mice. Behavioral analyses of 1-month-old male cKO mice revealed impaired motor coordination (increased balance beam scores and prolonged pole-climbing latency) and delayed nociceptive responses (increased thermal withdrawal latency). Morphological assessments demonstrated neuron-specific pathology: motor neurons exhibited atrophy and reduced Nissl substance staining, spinal ganglion cells showed quantitative depletion with vacuolar degeneration, and protein expression analyses confirmed declines in neuronal markers (NeuN), synaptic components (SNAP25, PSD95), axonal and myelin related proteins (NF-L, MBP), and neurotransmitter transporters (AChE). Notably, glial cell populations remained unaffected. Mechanistic investigations identified reduced spinal cholesterol content accompanied by downregulation of cholesterol biosynthesis and transport regulators (Srebp2, HMGCR, ApoE, ABCA1) and activation of AMP-activated protein kinase (AMPK). These findings establish astrocytic Lf as a critical modulator of cholesterol metabolism essential for maintaining neuronal structural and functional integrity in the spinal cord. The discovered Lf-cholesterol regulatory axis provides novel insights into the pathogenesis of spinal cord disorders and highlights potential therapeutic targets for neurodegenerative conditions.

Keywords:  Astrocyte; Cholesterol; Lactoferrin; Neurons; Spinal cord

DOI:  https://doi.org/10.1016/j.yexcr.2025.114595
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 May 06. pii: S1388-1981(25)00030-7. [Epub ahead of print] 159622

Loss of the acyltransferase TMEM68 leads to growth delay and dysregulation of triacylglycerol and glycerophospholipid homeostasis in the mouse brain.

Chunyan Zhang, Tingting Li, Christoph Heier, Huimin Pang, Feifei Huang, Xingxin Fu, Pingan Chang.

  Lipid droplets (LDs) are ubiquitous cellular storage organelles for triacylglycerol (TAG) that have recently been implicated in brain development and aging, and the progression of neurodegenerative diseases. However, the enzymes responsible for brain TAG synthesis are incompletely understood. Transmembrane protein 68 (TMEM68) catalyzes TAG synthesis independent of canonical diacylglycerol acyltransferase (DGAT) enzymes and is highly expressed in the brain. In the current study, we addressed the role of TMEM68 in murine brain TAG metabolism using a global Tmem68 knockout mouse model. We found that loss of TMEM68 led to decreased TAG levels in the cerebral cortex and a concomitant increase in polyunsaturated glycerophospholipid species. These changes in lipid pattern were associated with perturbed expression of genes involved in fatty acid and glycerophospholipid metabolism. While brain size and morphology were largely unaffected, TMEM68 deficiency caused reductions in white adipose tissue mass, decreased insulin-like growth factor 1 levels, and retarded weight gain. In conclusion, our study identifies TMEM68 as regulator of TAG and glycerophospholipid homeostasis in the central nervous system and discloses a requirement of the enzyme for postnatal development and energy metabolism.

Keywords:  Brain; Glycerophospholipid; Lipid droplets; Postnatal development; TMEM68; Triacylglycerol

DOI:  https://doi.org/10.1016/j.bbalip.2025.159622
Brain Res. 2025 May 06. pii: S0006-8993(25)00223-9. [Epub ahead of print] 149664

Mitochonic acid 5, an ATP production accelerator, protects against neurological damage in ischemic stroke.

Shinomi Sasaibe, Yukie Yoshioka, Yoshiki Kuse, Shinsuke Nakamura, Masamitsu Shimazawa.

  Cerebral infarction is a severe condition that causes motor dysfunction and disorientation due to irreversible neuronal cell death. After an ischemic stroke, the lack of oxygen and nutrients induces cerebral neuronal damage along with mitochondrial dysfunction. Therefore, activating mitochondrial function is a promising strategy for treating ischemic stroke. This study aimed to examine whether Mitochonic acid 5 (MA-5), a compound that targets mitochondria to stimulate ATP synthesis, has protective effects against cerebral ischemia/reperfusion (I/R) injury. We first confirmed that MA-5 significantly increases ATP production after 1 h of exposure to neuron-like cells. MA-5 also increased ATP production coupled respiration in SH-SY5Y cells after the induction of OGD/R. After inducing cerebral I/R in mice via transient midbrain occlusion (t-MCAO), the administration of MA-5 reduced neurological deficits and infarct volume. In addition, MA-5 suppressed the increase in the Bax/Bcl-2 ratio, an index of mitochondria-mediated apoptosis after t-MCAO. Taken together, these results suggest that MA-5 may be a useful therapeutic agent against ischemic stroke by activating mitochondrial function.

Keywords:  Brain; Ischemic stroke; Mitochondria; Neuron; Oxygen-glucose deprivation/reoxygenation (OGD/R)

DOI:  https://doi.org/10.1016/j.brainres.2025.149664
Aging Cell. 2025 May 02. e70085

Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.

Hiroaki Tamashiro, Kaori Ishikawa, Koichi Sadotomo, Emi Ogasawara, Kazuto Nakada.

  mtDNA mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear. Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced. To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal. These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.

Keywords:  aging; mitochondria; mitochondrial DNA

DOI:  https://doi.org/10.1111/acel.70085
Mol Neurodegener. 2025 May 03. 20(1): 51

Alzheimer's disease protective allele of Clusterin modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication.

Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew J Moulton, Lindsey D Goodman, Zhiping P Pang, Alan R Sanders, Hugo J Bellen, Gopal Thinakaran, Jubao Duan.

   BACKGROUND: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied.
METHODS: Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation.
RESULTS: We identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal CLU and promoting neuron excitability. And, neuronal CLU facilitated neuron-to-glia lipid transfer and astrocytic lipid droplet formation coupled with reactive oxygen species (ROS) accumulation. These changes caused astrocytes to uptake less glutamate thereby altering neuron excitability.
CONCLUSIONS: For a strong AD-associated locus near Clusterin (CLU), we connected an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication. Our study provides insights into how CLU confers resilience to AD through neuron-glia interactions.

Keywords:  Allele-specific open chromatin; Alzheimer’s disease; Clusterin; Genome-wide association study; IPSC; Lipid droplets; Neuron excitability; Neuron-glia lipid transfer; Protective allele

DOI:  https://doi.org/10.1186/s13024-025-00840-1
BJPsych Open. 2025 May 09. 11(3): e94

The ketogenic diet and metabolic treatments for neuropsychiatric disorders.

Christopher M Palmer.

  The ketogenic diet, initially developed for epilepsy treatment, has gained attention as a potential intervention for neuropsychiatric disorders. A groundbreaking study by Campbell et al highlights its feasibility and potential efficacy in bipolar disorder, shedding light on shared mechanisms across neuropsychiatric disorders and the promise of metabolic treatment approaches.

Keywords:  Ketogenic; bipolar; diet; metabolic; neuropsychiatric

DOI:  https://doi.org/10.1192/bjo.2025.50
Front Genet. 2025 ;16 1532902

Novel ACAD8 variants identified in Isobutyryl-CoA dehydrogenase deficiency: challenges in phenotypic variability and management.

Yilun Tao, Dong Han, Jianfang Li, Xiaoyun Li, Luna Hao, Wenxia Song, Lihong Wang, Xiaoze Li.

  Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive disorder caused by biallelic variants in the ACAD8 gene, which disrupts valine metabolism. In this study, we report seven individuals identified through newborn screening (NBS) with elevated C4-acylcarnitine levels, including five confirmed patients and two heterozygous carriers. Genetic analysis identified 12 distinct ACAD8 variants, seven of which were novel (c.221C>T, c.518T>C, c.727A>G, c.868G>A, c.947A>T, c.966G>A, c.1058T>C). According to ACMG classification criteria, c.221C>T was classified as likely pathogenic, while the remaining variants were categorized as variants of uncertain significance (VUS). During a mean follow-up of 4.81 years, all patients maintained normal growth patterns but two patients developed neurological symptoms that included recurrent febrile seizures and sensory integration dysfunction. These findings expand the ACAD8 variant spectrum, highlight the phenotypic variability of IBDD, and underscore the importance of long-term follow-up and individualized management strategies.

Keywords:  ACAD8 gene; isobutyryl-CoA dehydrogenase deficiency; newborn screening; next-generation sequencing; novel variant

DOI:  https://doi.org/10.3389/fgene.2025.1532902