bims-medebr 2025-05-04 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–05–04
sixteen papers selected by
Regina F. Fernández, Johns Hopkins University

Glia phagocytose neuronal sphingolipids to infiltrate developing synapses.
Lipid metabolism alterations in peripheral neuropathies.
The therapeutic potential of a polyunsaturated fatty acid-enriched high-fat diet in Leigh syndrome: Insights from a preclinical model.
Regulation of synaptic function and lipid metabolism.
Astrocytic FABP5 mediates retrograde endocannabinoid transport at central synapses.
The role of protein lactylation in brain health and disease: current advances and future directions.
Metabolic Regulation as a Potential Therapeutic Approach for Alzheimer's Disease.
ApoE4 requires lipidation enhancement to resolve cellular lipid and protein abnormalities following NPC1 inhibition.
Lactate Provides Metabolic Substrate Support and Attenuates Ischemic Brain Injury in Mice, Revealed by 1H-13C Nuclear Magnetic Resonance Metabolic Technique.
Ceramides may Play a Central Role in the Pathogenesis of Alzheimer's Disease: a Review of Evidence and Horizons for Discovery.
Sex-dependent upregulation in oxylipins involved in inflammation resolution in the cerebellum of Niemann-pick disease C1 mice.
In Vivo Quantification of Creatine Kinase Kinetics in Mouse Brain Using 31P-MRS at 7 T.
Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.
Regional differences in progenitor metabolism shape brain growth during development.
Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.
Mitochondria - the CEO of the cell.

bioRxiv. 2025 Apr 22. pii: 2025.04.14.648777. [Epub ahead of print]

Glia phagocytose neuronal sphingolipids to infiltrate developing synapses.

Emma K Theisen, Irma Magaly Rivas-Serna, Ryan J Lee, Taylor R Jay, Govind Kunduri, Tasha T Nguyen, Vera Mazurak, M Thomas Clandinin, Thomas R Clandinin, John P Vaughen.

The complex morphologies of mature neurons and glia emerge through profound rearrangements of cell membranes during development. Despite being integral components of these membranes, it is unclear whether lipids might actively sculpt these morphogenic processes. By analyzing lipid levels in the developing fruit fly brain, we discover dramatic increases in specific sphingolipids coinciding with neural circuit establishment. Disrupting this sphingolipid bolus via genetic perturbations of sphingolipid biosynthesis and catabolism leads to impaired glial autophagy. Remarkably, glia can obtain sphingolipid precursors needed for autophagy by phagocytosing neurons. These precursors are then converted into specific long-chain ceramide phosphoethanolamines (CPEs), invertebrate analogs of sphingomyelin. These lipids are essential for glia to arborize and infiltrate the brain, a critical step in circuit maturation that when disrupted leads to reduced synapse numbers. Taken together, our results demonstrate how spatiotemporal tuning of sphingolipid metabolism during development plays an instructive role in programming brain architecture.
Highlights: Brain sphingolipids (SLs) remodel to very long-chain species during circuit maturation Glial autophagy requires de novo SL biosynthesis coordinated across neurons and glia Glia evade a biosynthetic blockade by phagolysosomal salvage of neuronal SLsCeramide Phosphoethanolamine is critical for glial infiltration and synapse density.

DOI: https://doi.org/10.1101/2025.04.14.648777
Neuron. 2025 Apr 29. pii: S0896-6273(25)00262-4. [Epub ahead of print]

Lipid metabolism alterations in peripheral neuropathies.

Alessio Silva, Robert Prior, Maurizio D'Antonio, Johannes V Swinnen, Ludo Van Den Bosch.

  Alterations in lipid metabolism are increasingly recognized as central pathological hallmarks of inherited and acquired peripheral neuropathies. Correct lipid balance is critical for cellular homeostasis. However, the mechanisms linking lipid disturbances to cellular dysfunction and whether these changes are primary drivers or secondary effects of disease remain unresolved. This is particularly relevant in the peripheral nervous system, where the lipid-rich myelin integrity is critical for axonal function, and even subtle perturbations can cause widespread effects. This review explores the role of lipids as structural components as well as signaling molecules, emphasizing their metabolic role in peripheral neurons and Schwann cells. Additionally, we explore the genetic and environmental connections in both inherited and acquired peripheral neuropathies, respectively, which are known to affect lipid metabolism in peripheral neurons or Schwann cells. Overall, we highlight how understanding lipid-centric mechanisms could advance biomarker discovery and therapeutic interventions for peripheral nerve disorders.

Keywords:  Charcot-Marie-Tooth disease; Schwann cells; lipid metabolism; lipid rafts; lipid signaling; lipid storage; motor neurons; peripheral neuropathies; sensory neurons

DOI:  https://doi.org/10.1016/j.neuron.2025.04.006
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 25. pii: S0925-4439(25)00221-2. [Epub ahead of print] 167873

The therapeutic potential of a polyunsaturated fatty acid-enriched high-fat diet in Leigh syndrome: Insights from a preclinical model.

Luciano Willemse, Karin Terburgh, Roan Louw.

   INTRODUCTION: Leigh syndrome is often caused by Ndufs4 mutations. The Ndufs4 knockout (KO) mouse model recapitulates key disease features, including systemic inflammation, neurodegeneration, and motor deficits. While dietary interventions such as the ketogenic diet show promise in mitigating mitochondrial dysfunction, conflicting results highlight uncertainties regarding its efficacy. Here, we evaluate the therapeutic potential of a polyunsaturated fatty acid (PUFA)-enriched high-fat diet (HFD) in Ndufs4 KO mice.
METHODS: Dietary intervention began at postnatal day 23, with mice receiving either a normal diet (ND) or a HFD enriched with PUFAs. Phenotypic evaluation, including locomotor function, clasping behaviour, and survival, continued until natural death. In a second group of animals, biochemical analyses were conducted after three weeks on the diets, using Western blot to evaluate neurometabolic and inflammatory regulators, flow cytometry to quantify serum inflammation markers, and metabolic profiling to identify alterations in neurometabolism and the neurolipidome.
RESULTS: The HFD significantly extended lifespan and improved clasping behaviour in Ndufs4 KO mice but had no effect on locomotor activity or grip strength decline. While whole-brain mTOR (p70S6K1, 4E-BP1) and SIRT1 (PGC1-α, TNF-α) signalling pathways remained unaffected, the diet significantly reduced serum pro-inflammatory markers TNF and IL-6. Furthermore, the PUFA-enriched HFD partially restored disruptions in TCA cycle, ketone body, branched-chain amino acid, and lipid metabolism, indicating potential metabolic reprogramming.
CONCLUSION: Dietary interventions, such as a PUFA-enriched HFD, may alleviate systemic inflammation, partially correct metabolic imbalances, and mitigate specific disease phenotypes in Leigh syndrome, warranting further investigation into the underlying mechanisms and broader therapeutic applications.

Keywords:  Flow cytometry; Ketogenic diet; Lipidomics; Metabolomics; Mitochondrial disease; Polyunsaturated fatty acids; mTOR

DOI:  https://doi.org/10.1016/j.bbadis.2025.167873
Neural Regen Res. 2025 Apr 29.

Regulation of synaptic function and lipid metabolism.

Tongtong Zhang, Yunsi Yin, Xinyi Xia, Xinwei Que, Xueyu Liu, Guodong Zhao, Jiahao Chen, Qiuyue Chen, Zhiqing Xu, Yi Tang, Qi Qin.

   ABSTRACT: Synapses are key structures involved in transmitting information in the nervous system, and their functions rely on the regulation of various lipids. Lipids play important roles in synapse formation, neurotransmitter release, and signal transmission, and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases. The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention, but their specific mechanisms remain to be fully understood. This review aims to explore how lipids regulate synaptic activity in the central nervous system, focusing on their roles in synapse formation, neurotransmitter release, and signal transmission. Additionally, it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation. This review shows that within the central nervous system, lipids are essential components of the cell membrane bilayer, playing critical roles in synaptic structure and function. They regulate presynaptic vesicular trafficking, postsynaptic signaling pathways, and glialneuronal interactions. Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts. Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles. Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis. Fatty acids are vital for energy metabolism and the synthesis of signaling molecules. Abnormalities in lipid metabolism may lead to impairments in synaptic function, affecting information transmission between neurons and the overall health of the nervous system. Therapeutic strategies targeting lipid metabolism, particularly through cholesterol modulation, show promise for treating these conditions. In neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, and amyotrophic lateral sclerosis, dysregulation of lipid metabolism is closely linked to synaptic dysfunction. Therefore, lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs. Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.

Keywords:  astrocyte; central nervous system; cholesterol; glycerophospholipids; lipid; microglia; neurodegenerative diseases; sphingolipids; synapse; therapy

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01412
iScience. 2025 May 16. 28(5): 112342

Astrocytic FABP5 mediates retrograde endocannabinoid transport at central synapses.

Saida Oubraim, Mohammad Fauzan, Keith Studholme, Chris Gordon, Sherrye T Glaser, Roh-Yu Shen, Iwao Ojima, Martin Kaczocha, Samir Haj-Dahmane.

  Endocannabinoids (eCBs) regulate synaptic function via cannabinoid receptors. While eCB signaling is well understood, the mechanisms underlying eCB synaptic transport are poorly characterized. Using 2-arachidonoylglycerol (2-AG)-mediated depolarization-induced suppression of inhibition (DSI) in the hippocampus as a readout of retrograde eCB signaling, we demonstrate that the deletion of fatty acid binding protein 5 (FABP5) impairs DSI. In FABP5 KO mice, DSI was rescued by re-expressing wild-type FABP5 but not an FABP5 mutant that does not bind 2-AG. Importantly, the deletion of astrocytic FABP5 blunted DSI, which was rescued by its re-expression in the astrocytes of FABP5 KO mice. Neuronal FABP5 was dispensable for 2-AG signaling. DSI was also rescued by expressing a secreted FABP5 variant but not by FABP7, an astrocytic FABP that does not undergo secretion. Our results demonstrate that extracellular FABP5 of astrocytic origin controls 2-AG transport and that FABP5 is adapted to coordinate intracellular and synaptic eCB transport.

Keywords:  Cell biology; Cellular neuroscience; Neuroscience; Specialized functions of cells

DOI:  https://doi.org/10.1016/j.isci.2025.112342
Cell Death Discov. 2025 Apr 30. 11(1): 213

The role of protein lactylation in brain health and disease: current advances and future directions.

Mingrui Han, Wenfeng He, Wengen Zhu, Linjuan Guo.

Lactate, the end product of glycolysis, plays a crucial role in cellular signaling and metabolism. The discovery of lactylation, a novel post-translational modification, has uncovered the role of lactate in regulating diseases, especially in the brain. Lactylation connects genetic encoding with protein function, thereby influencing key biological processes. Increasing evidence supports lactate-mediated lactylation as a critical modulator in neurological disorders. This review offers an overview of lactate metabolism and lactylation, highlighting recent advances in understanding the regulatory enzymes of lactylation and their role in the central nervous system. We investigate the impact of lactylation on brain dysfunctions, including neurodegenerative diseases, cerebrovascular disorders, neuroinflammation, brain tumors, and psychiatric conditions. Moreover, we highlight the therapeutic potential of targeting lactylation in treating brain disorders and outline key research gaps and future directions needed to advance this promising field.

DOI: https://doi.org/10.1038/s41420-025-02408-w
Curr Alzheimer Res. 2025 Apr 25.

Metabolic Regulation as a Potential Therapeutic Approach for Alzheimer's Disease.

Jinmiao Zhong, Jiaxin Sun, Bing Zhou.

  Lecanemab, a therapeutic antibody designed to target amyloid-beta (Aβ) clearance, has recently been approved by the FDA and introduced in multiple countries, representing a significant milestone in advancing Alzheimer's disease (AD) treatment. However, its limited clinical efficacy underscores the need for further investigation of disease pathogenesis. Emerging evidence suggests that glucose and lipid metabolism dysfunction plays a critical role in AD, with metabolic changes emerging as one of the most significantly altered pathways in the early stage of pathology. These findings highlight the therapeutic potential of targeting metabolic regulation as a strategy to address AD.

Keywords:  Alzheimer's disease (AD); Aβ.; glucose metabolism; glycolytic enzyme; lipid metabolism; mitochondrial dysfunction

DOI:  https://doi.org/10.2174/0115672050379410250421065857
Sci Rep. 2025 Apr 29. 15(1): 15051

ApoE4 requires lipidation enhancement to resolve cellular lipid and protein abnormalities following NPC1 inhibition.

Erika Di Biase, Kyle J Connolly, Ingrid Crumpton, Oliver Cooper, Penelope J Hallett, Ole Isacson.

  Apolipoprotein E (ApoE) variants are central to Alzheimer's disease (AD), Lewy body dementia (LBD) and Niemann-Pick disease type C (NPC). The ApoE4 variant elevates AD risk by 3-15-fold. ApoE's normal function in lipid transport is known. The question remains how different ApoE isoforms cause cellular pathogenesis. We determined the effects of ApoE isoforms on lipid accumulation induced by inhibiting the endo-lysosomal cholesterol transporter NPC1. In human fibroblasts and astrocytes, NPC1 inhibition caused a 4-fold cholesterol accumulation and mis-localization with altered cholesterol sensing and increased synthesis of cholesterol and triglycerides. Total APP, APP C-terminal fragments (CTF) and BACE1 levels increased 3-fold. Remarkably, the intracellular neutral lipids co-localized with APP and APP C-terminal fragments. ApoE2 and ApoE3, but not ApoE4, reduced intracellular cholesterol levels by 67% and 62%, respectively, normalized APP, BACE, CTF, and improved cell survival. ApoE4 combined with a synthetic lipopeptide, which increased the proportion of large lipidated ApoE4 particles, corrected these abnormalities. This highlights ApoE in lipid pathogenesis and targeting ApoE4 lipidation to restore ApoE4 function.

Keywords:  Alzheimer’s risk variant; Amyloid; ApoE; ApoE4 drug therapy; Astrocyte; Cholesterol; Fibroblast.; Human cellular platform; Lipid transport; NPC1; Triglycerides

DOI:  https://doi.org/10.1038/s41598-025-96531-4
Biomedicines. 2025 Mar 24. pii: 789. [Epub ahead of print]13(4):

Lactate Provides Metabolic Substrate Support and Attenuates Ischemic Brain Injury in Mice, Revealed by 1H-13C Nuclear Magnetic Resonance Metabolic Technique.

Kefan Wu, Yajing Liu, Yuxuan Wang, Jiabao Hou, Meng Jiang, Shaoqin Lei, Bo Zhao, Zhongyuan Xia.

  Background/Objectives: Lactate, classically considered a metabolic byproduct of anaerobic glycolysis, is implicated in ischemic acidosis and neuronal injury. The recent evidence highlights its potential role in sustaining metabolic networks and neuroprotection. This study investigates lactate's compensatory mechanisms in ischemic brain injury by analyzing post-ischemic metabolic enrichments and inter-regional metabolite correlations. Methods: Dynamic metabolic profiling was conducted using 13C-labeled glucose combined with 1H-13C NMR spectroscopy to quantify the metabolite enrichment changes in a murine cerebral ischemia model (n = 8). In vivo validation included intracerebroventricular pH-neutral lactate infusion in ischemic mice to assess the behavioral, electrophysiological, and mitochondrial outcomes. In vitro, HT22 hippocampal neurons underwent oxygen-glucose deprivation (OGD) with pH-controlled lactate supplementation (1 mM), followed by the evaluation of neuronal survival, mitochondrial membrane potential, and glycolytic enzyme expression. Results: NMR spectroscopy revealed a 30-50% reduction in most cerebral metabolites post-ischemia (p < 0.05), while the quantities of lactate and the related three-carbon intermediates remained stable or increased. Correlation analyses demonstrated significantly diminished inter-metabolite coordination post-ischemia, yet lactate and glutamate maintained high metabolic activity levels (r > 0.80, p < 0.01). Lactate exhibited superior cross-regional metabolic mobility compared to those of the other three-carbon intermediates. In vivo, lactate infusion improved the behavioral/electrophysiological outcomes and reduced mitochondrial damage. In the OGD-treated neurons, pH-neutral lactate (7.4) reduced mortality (p < 0.05), preserved the mitochondrial membrane potential (p < 0.05), and downregulated the glycolytic enzymes (HK, PFK, and PKM; p < 0.01), thereby attenuating H+ production. Conclusions: Under ischemic metabolic crisis, lactate and the three-carbon intermediates stabilize as critical substrates, compensating for global metabolite depletion. pH-neutral lactate restores energy flux, modulates the glycolytic pathways, and provides neuroprotection by mitigating acidotoxicity.

Keywords:  NMR; cerebral ischemia; glycolytic; lactate

DOI:  https://doi.org/10.3390/biomedicines13040789
Mol Neurobiol. 2025 Apr 28.

Ceramides may Play a Central Role in the Pathogenesis of Alzheimer's Disease: a Review of Evidence and Horizons for Discovery.

Hans O Kalkman, Lukasz Smigielski.

  While several hypotheses have been proposed to explain the underlying mechanisms of Alzheimer's disease, none have been entirely satisfactory. Both genetic and non-genetic risk factors, such as infections, metabolic disorders and psychological stress, contribute to this debilitating disease. Multiple lines of evidence indicate that ceramides may be central to the pathogenesis of Alzheimer's disease. Tumor necrosis factor-α, saturated fatty acids and cortisol elevate the brain levels of ceramides, while genetic risk factors, such as mutations in APP, presenilin, TREM2 and APOE ε4, also elevate ceramide synthesis. Importantly, ceramides displace sphingomyelin and cholesterol from lipid raft-like membrane patches that connect the endoplasmic reticulum and mitochondria, disturbing mitochondrial oxidative phosphorylation and energy production. As a consequence, the flattening of lipid rafts alters the function of γ-secretase, leading to increased production of Aβ42. Moreover, ceramides inhibit the insulin-signaling cascade via at least three mechanisms, resulting in the activation of glycogen synthase kinase-3 β. Activation of this kinase has multiple consequences, as it further deteriorates insulin resistance, promotes the transcription of BACE1, causes hyperphosphorylation of tau and inhibits the transcription factor Nrf2. Functional Nrf2 prevents apoptosis, mediates anti-inflammatory activity and improves blood-brain barrier function. Thus, various seemingly unrelated Alzheimer's disease risk factors converge on ceramide production, whereas the elevated levels of ceramides give rise to the well-known pathological features of Alzheimer's disease. Understanding and targeting these mechanisms may provide a promising foundation for the development of novel preventive and therapeutic strategies.

Keywords:  De novo ceramide synthesis; Glycogen synthase kinase-3 β; Mitochondrion-associated endoplasmic reticulum membrane; Saturated fatty acids; Sphingomyelinase

DOI:  https://doi.org/10.1007/s12035-025-04989-0
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Apr 28. pii: S0278-5846(25)00141-1. [Epub ahead of print] 111387

Sex-dependent upregulation in oxylipins involved in inflammation resolution in the cerebellum of Niemann-pick disease C1 mice.

Sandra M Camunas-Alberca, Maria Moran-Garrido, Ángel Gaudioso, Felipe da Costa Souza, Ana Gradillas, Maria Dolores Ledesma, Coral Barbas, Ameer Y Taha.

  Unresolved inflammation in the cerebellum is implicated in motor and cognitive decline in Niemann-Pick Disease type C (NPC), a neurodegenerative lysosomal storage disorder caused by pathogenic mutations in the Npc1 gene, encoding a cholesterol transporter protein. It is unclear whether unresolved inflammation in NPC stems from impairments in lipid-mediated resolution. For this reason, free lipid mediators (i.e., oxylipins) and esterified lipid mediators, which regulate free oxylipins bioavailability, were quantified using Reverse-Phase Ultra-High Performance Liquid Chromatography coupled to negative Electrospray Ionization and Triple Quadrupole Tandem Mass Spectrometry (RP-UPLC-ESI(-)-QqQ-MS/MS) in Npc1 knock-in (NPC1ki) and Wildtype (WT) mice. Total cholesterol and fatty acids including polyunsaturated fatty acids (PUFA) precursors to oxylipins, were quantified using Gas Chromatography coupled to Flame Ionization Detection (GC-FID). Compared to WT mice, female NPC1ki mice, but not males, exhibited significantly elevated levels of free pro-resolving fatty acid epoxides (EpETrE and EpDPE) from the cytochrome P450 (CYP) pathway. Esterified mono- and dihydroxy lipid mediators from the lipoxygenase (LOX) and soluble epoxide hydrolase (sEH) pathways were mainly increased in NPC1ki females, suggesting enhanced sequestration of pro-inflammatory LOX and sEH metabolites. While PUFA and total cholesterol levels were not significantly different between groups, myristic (C14:0) and palmitoleic acid (C16:1n-7) were significantly elevated in NPC1ki females. These findings suggest sex-specific adaptations in inflammation resolution pathways in NPC, with females exhibiting distinct inflammatory responses that may drive sex-related differences in disease pathogenesis. Our findings underscore the need for sex-specific therapeutic approaches to improve NPC treatment outcomes.

Keywords:  Esterified oxylipins; Free oxylipins; Lipid mediators; Lysosomal storage disorders; Neuroinflammation; Niemann-pick disease type C (NPC); Tandem mass spectrometry

DOI:  https://doi.org/10.1016/j.pnpbp.2025.111387
NMR Biomed. 2025 Jun;38(6): e70055

In Vivo Quantification of Creatine Kinase Kinetics in Mouse Brain Using 31P-MRS at 7 T.

Mohamed Tachrount, Sean Smart, Jason Lerch, Antoine Cherix.

  31P-MRS is a method of choice for studying neuroenergetics in vivo, but its application in the mouse brain has been limited, often restricted to ultrahigh field (> 7 T) MRI scanners. Establishing its feasibility on more readily available preclinical 7-T scanners would create new opportunities to study metabolism and physiology in murine models of brain disorders. Here, we demonstrate that the apparent forward rate constant (kf) of creatine kinase (CK) can be accurately quantified using a progressive saturation-transfer approach in the mouse brain at 7 T. We also find that a 20% reduction in respiration of anesthetized mice can lead to 36% increase in kf attributable to a drop in cellular pH and mitochondrial ATP production. To achieve this, we used a test-retest analysis to assess the reliability and repeatability of 31P-MRS acquisition, analysis, and experimental design protocols. We report that many 31P-containing metabolites can be reliably measured using a localized 3D-ISIS sequence, which showed highest SNR amplitude, SNR consistency, and minimal T2 relaxation signal loss. Our study identifies key physiological factors influencing mouse brain energy homeostasis in vivo and provides a methodological basis to guide future studies interested in implementing 31P-MRS on preclinical 7-T scanners.

Keywords:  31P‐magnetic resonance spectroscopy; 7 T; brain; creatin kinase; mouse; saturation transfer

DOI:  https://doi.org/10.1002/nbm.70055
Biomolecules. 2025 Apr 14. pii: 580. [Epub ahead of print]15(4):

Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.

Varshini V Suresh, Sathish Sivaprakasam, Yangzom D Bhutia, Puttur D Prasad, Muthusamy Thangaraju, Vadivel Ganapathy.

  Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by "keto" diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease.

Keywords:  GPR109A; HMGCS2; cancer; epigenetic modification; inflammation; ketoacidosis; ketone body transporters; loss-of-function mutations; neurodegeneration; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/biom15040580
Cell. 2025 Apr 25. pii: S0092-8674(25)00405-2. [Epub ahead of print]

Regional differences in progenitor metabolism shape brain growth during development.

Natalia Baumann, Robin J Wagener, Awais Javed, Eleonora Conti, Philipp Abe, Andrea Lopes, Roberto Sansevrino, Adrien Lavalley, Elia Magrinelli, Timea Szalai, Daniel Fuciec, Clothilde Ferreira, Sabine Fièvre, Andreane Fouassier, Davide D'Amico, Oliver Harschnitz, Denis Jabaudon.

  Mammals have particularly large forebrains compared with other brain parts, yet the developmental mechanisms underlying this regional expansion remain poorly understood. Here, we provide a single-cell-resolution birthdate atlas of the mouse brain (www.neurobirth.org), which reveals that while hindbrain neurogenesis is transient and restricted to early development, forebrain neurogenesis is temporally sustained through reduced consumptive divisions of ventricular zone progenitors. This atlas additionally reveals region-specific patterns of direct and indirect neurogenesis. Using single-cell RNA sequencing, we identify evolutionarily conserved cell-cycle programs and metabolism-related molecular pathways that control regional temporal windows of proliferation. We identify the late neocortex-enriched mitochondrial protein FAM210B as a key regulator using in vivo gain- and loss-of-function experiments. FAM210B elongates mitochondria and increases lactate production, which promotes progenitor self-replicative divisions and, ultimately, the larger clonal size of their progeny. Together, these findings indicate that spatiotemporal heterogeneity in mitochondrial function regulates regional progenitor cycling behavior and associated clonal neuronal production during brain development.

Keywords:  brain development; metabolism; mitochondria dynamics; progenitor diversity

DOI:  https://doi.org/10.1016/j.cell.2025.04.003
Neural Regen Res. 2025 Apr 29.

Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.

Min Zhou, Min Zheng, Siyao Liang, Maomao Li, Jiarui Ma, Shiyu Zhang, Xinyao Song, Yonglin Hu, Yuhong Lyu, Xingkun Ou, Changwu Yue.

   ABSTRACT: The cure rate for chronic neurodegenerative diseases remains low, creating an urgent need for improved intervention methods. Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases. This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases, aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options. We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy, inhibiting mitochondrial fission, enhancing mitochondrial biogenesis, applying mitochondria-targeting antioxidants, and transplanting mitochondria. Each method has unique advantages and potential limitations, making them suitable for various therapeutic situations. Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression, especially in the early stages. In contrast, those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism. Mitochondrial transplantation, while still experimental, holds great promise for restoring the function of damaged cells. Future research should focus on exploring the mechanisms and effects of these intervention strategies, particularly regarding their safety and efficacy in clinical settings. Additionally, the development of innovative mitochondria-targeting approaches, such as gene editing and nanotechnology, may provide new solutions for treating chronic neurodegenerative diseases. Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; calcium homeostasis; intervention strategy; mitochondria; mitochondrial dysfunction; mitochondrial membrane permeability transition pore; mitophagy; neurodegenerative diseases; oxidative stress; targeted therapy

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01507
J Cell Sci. 2025 May 01. pii: jcs263403. [Epub ahead of print]138(9):

Mitochondria - the CEO of the cell.

Laurie P Lee-Glover, Martin Picard, Timothy E Shutt.

  As we have learned more about mitochondria over the past decades, including about their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at the whim of the cell. Rather, mitochondria are dynamic information and energy processors that play crucial roles in directing dozens of cellular processes and behaviors. They provide instructions to enact programs that regulate various cellular operations, such as complex metabolic networks, signaling and innate immunity, and even control cell fate, dictating when cells should divide, differentiate or die. To help current and future generations of cell biologists incorporate the dynamic, multifaceted nature of mitochondria and assimilate modern discoveries into their scientific framework, mitochondria need a 21st century 'rebranding'. In this Opinion article, we argue that mitochondria should be considered as the 'Chief Executive Organelle' - the CEO - of the cell.

Keywords:  Mitochondria; Organelle; mtDNA

DOI:  https://doi.org/10.1242/jcs.263403