bims-medebr 2026-01-04 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–01–04
eighteen papers selected by
Regina F. Fernández, Johns Hopkins University

Mitochondria and Lipids in Cellular Signaling of the Brain: from Physiology to Neurodegeneration.
Proposed unified model of late-onset Alzheimer's disease: Chronic astrocytic and neuronal bioenergetic failure.
Plasma Membrane Lipid Composition and Turnover in Human Midbrain Neurons Investigated by Time-of-Flight Mass Spectrometry.
Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia.
Enduring Effects of Humanin on Mitochondrial Systems in TBI Pathology.
Maternal Exposure to Polypropylene Nanoplastics Disrupts Sex- and Region-Specific Lipid Metabolism in the Brains of C57BL/6N Mouse Offspring.
Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways.
Energy-Metabolic Imbalance of Oligodendrocytes in Multiple Sclerosis: Mechanisms, Network Coupling, and Advances in Metabolism-Targeted Therapies.
Choline transporters fueling the great myelin expansion.
The unanticipated role of the glial-associated glucose-6-phosphatase system in brain homeostasis.
Phosphatidylcholine with C26:0-moiety, a precursor of a diagnostic marker for X-ALD, is synthesized by LPLAT10/LPEAT2.
An Emerging Role for OGDHL: From Mitochondrial Energy Metabolism to Neurodevelopmental Disorders.
LCLAT1 regulates cardiolipin composition, mitochondrial phenotype, Lin28A, and oncogenic signaling networks in ETMR.
Associations of Plasma Lipids with Traumatic Brain Injury Outcomes: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study.
Stearoyl-CoA desaturase in development and disease.
Hippocampal cell- and circuit-specific differences in mitochondrial form and function.
Disturbances in Mitochondrial Network, Biogenesis, and Mitochondria-Mediated Inflammatory Responses in Selected Brain Structures of Rats Exposed to Lead (Pb) During Prenatal and Neonatal Development.
Unraveling sex differences in age-related hippocampal decline: differential mitochondrial dysfunction, Lonp1-dependent mitochondrial proteostasis and mtROS production in aged C57BL/6 mice.

Mol Cell Biol. 2026 Jan 02. 1-19

Mitochondria and Lipids in Cellular Signaling of the Brain: from Physiology to Neurodegeneration.

Plamena R Angelova, Lauren Millichap, Andrey Y Abramov.

  The brain is one of the most lipid-rich organs, reflecting the critical role of lipid metabolism in neuronal and glial cell function. While mitochondria are central to energy metabolism, calcium signaling, and cell death, they do not utilize lipid oxidation for energy but rely on lipids for membrane integrity and intracellular communication. Here we review the interactions between lipids and mitochondria in intracellular signaling within brain cells, examining their roles in normal physiology and the mechanisms underlying major neurodegenerative diseases. Alterations in lipid homeostasis and mitochondrial metabolism are implicated in neurodegeneration, highlighting the importance of lipid-mediated mitochondrial signaling pathways. Understanding these interactions provides insights into cellular dysfunction in neurodegenerative disorders and may inform future therapeutic strategies targeting lipid and mitochondrial pathways.

Keywords:  Lipid signaling; calcium signaling; lipid peroxidation; mitochondria; neurodegeneration

DOI:  https://doi.org/10.1080/10985549.2025.2607428
J Alzheimers Dis. 2025 Dec 29. 13872877251404970

Proposed unified model of late-onset Alzheimer's disease: Chronic astrocytic and neuronal bioenergetic failure.

James P Garrahy.

  Late-onset Alzheimer's disease (LOAD) is framed here as progressive astrocyte-neuronal metabolic and neurovascular uncoupling initiated by astrocytic bioenergetic collapse. In genetically or environmentally predisposed brains, a self-reinforcing loop of lipid accumulation, inflammation, vascular impairment, glucose-handling defects, and mitochondrial dysfunction erodes astrocytic functional capacity. Subsequent cerebrovascular dysfunction and loss of blood-brain barrier (BBB) integrity perpetuate the neuroinflammatory response and drive amyloid-β deposition. Astrocytic failure then disrupts astrocyte-neuron metabolic and neurovascular coupling, compromising lactate shuttling, glycogen mobilization, glutamate uptake, potassium buffering, antioxidant support, lipid handling, and demand-perfusion matching. Neurons deprived of this support enter chronic energy stress with sustained AMPK activation, which enhances tau hyperphosphorylation, perturbs proteostasis, and reduces tau O-GlcNAc protection, fostering pathological tau assembly. Amyloid-β deposits are enriched with heparan sulphate proteoglycans that provide a polyanionic scaffold which, together with persistent AMPK and inflammatory signaling, concentrates and misfolds tau into paired helical filaments. Tau-mediated mitochondrial injury further amplifies neuronal energy failure and feeds back via inflammatory pathways to worsen astrocytic dysfunction, closing the loop. Failure of the astrocyte-neuron lactate shuttle is identified as a key bridge between astrocytic and neuronal bioenergetic failure, where reduced lactate shuttling is proposed to impair long-term potentiation, thus accounting for the typical amnestic presentation of LOAD. Astrocytic bioenergetic load is predicted to peak in default-mode network hubs and other cortices with high resting aerobic glycolysis, reflecting reliance on astrocytic glycolysis for lactate shuttling and thereby accounting for the regional vulnerability observed in LOAD. This bioenergetic failure model integrates amyloid-β, tau, vascular, metabolic, and inflammatory findings into a single framework that accounts for genetic risk factors such as APOE and TREM2. Falsifiable temporal sequencing predictions for LOAD and specific forms of early-onset Alzheimer's disease are generated from the model.

Keywords:  Alzheimer's disease; amyloid-β; astrocytes; cerebrovascular disease; lipid metabolism; microglia; mitochondria; neurons; tau; tauopathies

DOI:  https://doi.org/10.1177/13872877251404970
Biomolecules. 2025 Nov 24. pii: 1650. [Epub ahead of print]15(12):

Plasma Membrane Lipid Composition and Turnover in Human Midbrain Neurons Investigated by Time-of-Flight Mass Spectrometry.

Emmanuel Berlin, Alicia A Lork, Carl Ernst, John S Fletcher, Nhu T N Phan.

  The molecular structure and dynamics of the neuronal plasma membrane are essential for neuronal biology and function. We employed time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging to investigate the lipid composition and turnover at the plasma membrane of single human midbrain neurons. The results showed that the profile of lipid turnover was heavily influenced by the types of precursors incorporated into the membrane lipids. In addition, there was a high prevalence of phosphatidylcholines, phosphatidylserines, and ceramides in the human midbrain neurons, and a preference for incorporating stearic acid into membrane lipids compared to other precursors. These features indicate a direct link between the membrane lipids to the biological state and functions of midbrain neurons. This is among a very few studies using mass spectrometry imaging to provide an insight into the native membrane lipid organization and lipid turnover using various lipid precursors in human neurons at a single cell level, illustrating their biological relevance in neuronal functions.

Keywords:  lipid turnover; lipid(s); midbrain; neuron(s); plasma membrane; secondary ion mass spectrometry imaging; time-of-flight mass spectrometry

DOI:  https://doi.org/10.3390/biom15121650
Elife. 2025 Dec 29. pii: RP100129. [Epub ahead of print]13

Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia.

Naidi Sun, Yu-Yo Sun, Rui Cao, Hong-Ru Chen, Yiming Wang, Elizabeth Fugate, Marchelle R Smucker, Yi-Min Kuo, Ellen P Grant, Diana M Lindquist, Chia-Yi Kuan, Song Hu.

  Hypoxia-ischemia (HI), which disrupts the oxygen supply-demand balance in the brain by impairing blood oxygen supply and the cerebral metabolic rate of oxygen (CMRO2), is a leading cause of neonatal brain injury. However, it is unclear how post-HI hypothermia helps to restore the balance, as cooling reduces CMRO2. Also, how transient HI leads to secondary energy failure (SEF) in neonatal brains remains elusive. Using photoacoustic microscopy, we examined the effects of HI on CMRO2 in awake 10-day-old mice, supplemented by bioenergetic analysis of purified cortical mitochondria. Our results show that while HI suppresses ipsilateral CMRO2, it sparks a prolonged CMRO2-surge post-HI, associated with increased mitochondrial oxygen consumption, superoxide emission, and reduced mitochondrial membrane potential necessary for ATP synthesis-indicating oxidative phosphorylation (OXPHOS) uncoupling. Post-HI hypothermia prevents the CMRO2-surge by constraining oxygen extraction fraction, reduces mitochondrial oxidative stress, and maintains ATP and N-acetylaspartate levels, resulting in attenuated infarction at 24 hr post-HI. Our findings suggest that OXPHOS-uncoupling induced by the post-HI CMRO2-surge underlies SEF and blocking the surge is a key mechanism of hypothermia protection. Also, our study highlights the potential of optical CMRO2 measurements for detecting neonatal HI brain injury and guiding the titration of therapeutic hypothermia at the bedside.

Keywords:  CMRO2; OXPHOS; cerebral metabolic rate of oxygen; hypothermia; medicine; mouse; neonatal hypoxia-ischemia; neuroscience; oxidative phosphorylation; photoacoustic microscopy

DOI:  https://doi.org/10.7554/eLife.100129
Biomolecules. 2025 Dec 06. pii: 1705. [Epub ahead of print]15(12):

Enduring Effects of Humanin on Mitochondrial Systems in TBI Pathology.

Pavan Thapak, Zhe Ying, Fernando Gomez-Pinilla.

  Traumatic brain injury has long-term detrimental effects on neurological function and general quality of life of affected individuals. Bioenergetic failure is a primary mechanism for cellular dysfunction. We used the mitochondrial activator humanin (HN) to try to normalize the disruptive action of TBI on cellular bioenergetics in the hippocampus. We found that HN supplied right after the injury counteracted the action of TBI on metabolic sensing proteins (LKB1, AMPK, and AKT). HN also counteracted cognitive function and restored the synaptic proteins (Synapsin I and PSD-95) at three weeks post-injury. Moreover, HN normalized the disruptive action of TBI on mitochondrial functioning and dynamics (fusion, fission, and mitophagy). In addition, HN treatment counteracted TBI's effects on mitochondrial biogenesis (PGC-1α), antioxidant (SOD2), and apoptotic marker (CC3). Furthermore, HN intervention in injured animals counteracted the gene expression linked with inflammation (Itgax, SALL1, GFAP, and NLRP3), synaptic plasticity (HDAC2), and bioenergetics (mtND2, TFAM, SIRT1, and SIRT3). These observations emphasize the therapeutic potential of HN by normalizing the fundamental aspects of TBI pathogenesis central to cellular bioenergetics and synaptic plasticity.

Keywords:  cellular energy; cognition; inflammation; mitochondrial dynamics; traumatic brain injury

DOI:  https://doi.org/10.3390/biom15121705
Toxicology. 2025 Dec 31. pii: S0300-483X(25)00351-8. [Epub ahead of print] 154392

Maternal Exposure to Polypropylene Nanoplastics Disrupts Sex- and Region-Specific Lipid Metabolism in the Brains of C57BL/6N Mouse Offspring.

Jangjae Lee, Subin Park, Da Yong Lee, Sung-Hee Cho.

  Polypropylene nanoplastics (PPNPs), produced through the degradation of widely used plastic products, are increasingly recognized as emerging environmental contaminants with potential neurodevelopmental toxicity. However, the long-term biochemical consequences of prenatal PPNP exposure on brain development remain poorly understood. In this study, we performed a region- and sex-specific targeted lipidomic analysis to examine how maternal oral exposure to PPNPs during pregnancy and lactation alters brain lipid composition in offspring at postnatal day 21. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we profiled lipid classes in the hippocampus (HP), cortex (CTX), cerebellum (CB), and dorsal raphe nucleus (DR) of both male and female mice. Our findings revealed distinct, region-specific lipid remodeling patterns in response to PPNP exposure. Females exhibited consistent reductions in neuroprotective lipids, including lysophosphatidylethanolamines (LPEs) and plasmalogens, most prominently in the hippocampus. Males, in contrast, displayed elevated triglyceride levels and region-specific alterations in phospholipid composition, such as reduced phosphatidylcholines in the hippocampus and dorsal raphe. These results indicate that maternal nanoplastic exposure, even without postnatal contact, can cause persistent, sex-specific disturbances in brain lipid metabolism. To our knowledge, this study provides the first targeted lipidomic characterization of offspring brains following maternal PPNP exposure and highlights the importance of brain region-specific lipid analysis for identifying localized disruptions in neurodevelopment caused by environmental pollutants.

Keywords:  Brain lipidomics analysis; Neurodevelopmental toxicity; Polypropylene nanoplastics (PPNP); Prenatal exposure; Sex-specific brain effects

DOI:  https://doi.org/10.1016/j.tox.2025.154392
Exp Neurol. 2025 Dec 30. pii: S0014-4886(25)00494-7. [Epub ahead of print] 115629

Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways.

Elika Z Moallem, Hemendra J Vekaria, Teresa Macheda, Margaret R Hawkins, Kelly N Roberts, Samir P Patel, Patrick G Sullivan, Adam D Bachstetter.

  Cerebral hypometabolism occurs in both traumatic brain injury (TBI) and Alzheimer's disease (AD), but whether these conditions act through distinct or overlapping mechanisms is unclear. TBI disrupts cerebral metabolism via blood-brain barrier damage, altered glucose transporter expression, calcium buffering abnormalities, and oxidative damage to metabolic enzymes. AD-related hypometabolism is linked to amyloid-β (Aβ) effects on mitochondria, including impaired respiration, oxidative stress, and altered mitophagy, fusion, and fission. We tested whether TBI-induced mitochondrial dysfunction exacerbates Aβ-mediated impairment using a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice. Injuries were delivered at 4-5 months of age, before plaque formation and mitochondrial deficits in KI mice. Bioenergetics were measured at 1, 4, and 8 months post-injury in hippocampus and cortex using Seahorse assays on isolated mitochondria. At 1 month, genotype-by-injury interactions revealed greater dysfunction in KI mice than either condition alone, with males more vulnerable than females. At 4-8 months, amyloid-mediated effects predominated, while TBI-specific changes were no longer apparent, suggesting recovery or convergence onto shared mechanisms. These results indicate that TBI can temporarily worsen mitochondrial dysfunction in the context of early amyloidosis, with sex influencing vulnerability. Findings provide insight into the temporal relationship between TBI and amyloid-induced mitochondrial deficits and support the importance of sex as a biological variable in neurodegenerative disease progression.

Keywords:  Amyloid; Bioenergetics; Neurodegeneration; Neurotrauma; Sex differences

DOI:  https://doi.org/10.1016/j.expneurol.2025.115629
Biomedicines. 2025 Nov 26. pii: 2880. [Epub ahead of print]13(12):

Energy-Metabolic Imbalance of Oligodendrocytes in Multiple Sclerosis: Mechanisms, Network Coupling, and Advances in Metabolism-Targeted Therapies.

Zhimian Zhang, Jihe Kang, Xudong Guo, Taotao Jiang, Xiaoling Li.

  Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system (CNS), are principal targets of autoimmune attack in multiple sclerosis (MS), resulting in demyelination and impaired neural conduction. Recent studies indicate that white matter in patients with MS exhibits increased aerobic glycolysis alongside reduced oxygen consumption-a metabolic mismatch between glucose utilization and oxygen consumption-that correlates with disability accumulation. Dysregulated energy metabolism is also a central mechanism limiting remyelination in MS. In MS, this dysregulation is characterized primarily by abnormal availability of metabolic substrates entering the CNS; in turn, it disrupts glucose and lipid metabolism within OLs, leading to mitochondrial dysfunction and a diminished capacity for myelin repair. Pharmacological studies employing metabolic intermediates as interventions have shown that correcting energy-metabolism disturbances in OLs can promote remyelination and mitigate MS symptoms, highlighting the metabolic-epigenetic axis as a potential therapeutic target. Clinical and translational research further suggests that modulation of metabolic pathways may enhance remyelination and improve brain energy homeostasis. Future work should integrate metabolomics, multimodal imaging, and multi-omics approaches to map neuron-glia metabolic-coupling networks with precision and to test, in high-quality randomized controlled trials, the efficacy and safety of metabolism-targeted therapies.

Keywords:  demyelination; energy metabolism; multiple sclerosis; oligodendrocytes

DOI:  https://doi.org/10.3390/biomedicines13122880
Trends Neurosci. 2025 Dec 31. pii: S0166-2236(25)00258-9. [Epub ahead of print]

Choline transporters fueling the great myelin expansion.

Aksheev Bhambri, Lu O Sun.

  Myelin formation involves massive lipid production, which requires extensive choline uptake and metabolism. Highlighting two recent studies conducted by Liu et al. and Chen et al., we discuss the identification of Slc44a1 as the primary oligodendrocyte choline transporter. These findings establish choline import as an evolutionarily conserved checkpoint for oligodendrocyte differentiation and central nervous system myelination.

Keywords:  choline metabolism; lipid metabolism; neurodevelopment; oligodendrocytes; white matter

DOI:  https://doi.org/10.1016/j.tins.2025.12.001
iScience. 2025 Dec 19. 28(12): 114235

The unanticipated role of the glial-associated glucose-6-phosphatase system in brain homeostasis.

María José Barahona, Katterine Salazar, Francisco Nualart.

  The glucose-6-phosphatase (G6Pase) system is a multiprotein complex within the endoplasmic reticulum that enables glucose export during high energy demand. Although traditionally studied in peripheral tissues such as the liver, recent studies highlight its relevance in the central nervous system, particularly in astrocytes and specialized glial cells called tanycytes. This review explores emerging functions of the G6Pase system in cerebral glial cells and its putative role in the regulation of brain bioenergetics and energy balance. In astrocytes, G6Pase expression supports glucose uptake, ATP production, and endoplasmic reticulum Ca2+ accumulation, contributing to cognitive processes and the counterregulatory response to hypoglycemia. In tanycytes, G6Pase is essential for promoting food intake and maintaining body weight. Collectively, these findings emphasize the importance of the G6Pase system in sustaining brain homeostasis.

Keywords:  Cellular physiology; Glycobiology; Neuroscience; Specialized functions of cells

DOI:  https://doi.org/10.1016/j.isci.2025.114235
J Lipid Res. 2025 Dec 30. pii: S0022-2275(25)00236-6. [Epub ahead of print] 100973

Phosphatidylcholine with C26:0-moiety, a precursor of a diagnostic marker for X-ALD, is synthesized by LPLAT10/LPEAT2.

Kotaro Hama, Yuko Fujiwara, Koko Imai, Yoshio Kusakabe, Yasuhiro Hayashi, Shigeo Takashima, Shohei Azuma, Masaru Kondo, Atsushi Yamashita, Ryo Takita, Nobuyuki Shimozawa, Kazuaki Yokoyama.

  X-linked adrenoleukodystrophy (X-ALD) is a congenital metabolic disorder characterized mainly by inflammatory demyelination and adrenal insufficiency. Newborn screening using hexacosanoyl lysophosphatidylcholine (C26:0-LPC) in dried blood spots as a diagnostic marker can successfully identify potential patients with X-ALD and prevent disease onset. C26:0-LPC accumulates in patients with X-ALD, although the machinery synthesizing it has remained unclear. In this study, we focused on phosphatidylcholine (PC) with C26:0-moiety as a precursor of C26:0-LPC. We identified that lysophospholipid acyltransferase 10 (LPLAT10)/LPCAT4/LPEAT2/AGPAT7 is the responsible lysophospholipid acyltransferase that produces PC with C26:0-moiety by transferring C26:0-CoA into 2-acyl-LPC. We also found that LPLAT10 deficiency decreased the amount of C26:0-LPC in fibroblasts from X-ALD patients. Mechanistically, LPLAT10 introduced saturated fatty acids-CoA of various chain lengths as substrates into the sn-1 position of LPC, but did not transfer C26:0-CoA other lysophospholipid classes such as lysophosphatidylethanolamine. Structural analysis revealed that a trimethylamine group of PC was placed between two tryptophan residues (W242 and W244), forming a W-X-W motif, possibly through cation-π interaction. Finally, it was shown that exogenously administered C26:0 free fatty acid-d4 was preferentially incorporated into sphingolipids in the absence of LPLAT10. These results suggest that C26:0-LPC is produced through acyl-chain remodeling of PC catalyzed by LPLAT10 and accumulates in the plasma from X-ALD patients.

Keywords:  C26:0-lysophosphatidylcholine; Fatty acid/Transport; Glycerophospholipids; Lipolysis and fatty acid metabolism; Lysophospholipid acyltransferase; Newborn screening; Peroxisome; Phospholipids/Metabolism; Phospholipids/Phosphatidylcholine; Very long-chain fatty acid

DOI:  https://doi.org/10.1016/j.jlr.2025.100973
Biology (Basel). 2025 Dec 12. pii: 1777. [Epub ahead of print]14(12):

An Emerging Role for OGDHL: From Mitochondrial Energy Metabolism to Neurodevelopmental Disorders.

Xian Liu, Guicheng Zhang, Decai Yu, Junhai Han.

  The oxoglutarate dehydrogenase-like (OGDHL) gene encodes a brain-enriched, rate-limiting enzyme in the tricarboxylic acid cycle, playing an essential role in mitochondrial energy metabolism. Mutations in OGDHL are linked to a broad spectrum of neurodevelopmental disorders, characterized by developmental delay, intellectual disability, epilepsy, corpus callosum dysgenesis, and sensory deficits. This mini-review systematically summarizes the discovery, structural features, and molecular functions of OGDHL, and provides a comprehensive catalog of all reported pathogenic mutations and their clinical phenotypes. By linking mitochondrial energy metabolism and neural pathogenesis, this work positions OGDHL as a potential key regulator in neural development and function. Ultimately, this review aims to advance further research on OGDHL in the nervous system, enhance the understanding of metabolic regulation in neurodevelopment, and lay the groundwork for elucidating the mechanisms underlying OGDHL-related neurological diseases.

Keywords:  mitochondrial metabolism; neurodevelopment disorders; oxoglutarate dehydrogenase L; tricarboxylic acid cycle

DOI:  https://doi.org/10.3390/biology14121777
Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf228

LCLAT1 regulates cardiolipin composition, mitochondrial phenotype, Lin28A, and oncogenic signaling networks in ETMR.

Evangelos Liapis, Allison Maas, Kelly C O'Neill, Adele Ponzoni, Tara Lozy, Annapurna Pamreddy, Francesca M Cozzi, Brent T Harris, Derek Hanson, Claire L Carter.

   Abstract: BackgroundEmbryonal tumor with multilayered rosettes (ETMR) is an aggressive pediatric brain tumor that carries a poor prognosis, and there is currently no standard of care. Dysregulated mitochondrial bioenergetics and dynamics have been associated with the progression of diverse cancers. Cardiolipins are mitochondrial-specific lipids, and their fatty acid composition has been shown to regulate mitochondrial structure and function. Despite the known functional significance of cardiolipins, their structure-specific accumulation in relation to mitochondrial phenotypes in ETMR remains ill-defined.
Methods: Spatial lipidomic profiles in patient samples and 3D models were determined using mass spectrometry imaging. Cell proliferation and mitochondrial bioenergetics and dynamics were characterized using immunohistochemistry, transmission electron microscopy, Western blotting, and metabolic assays. LCLAT1 KD was carried out using siRNA.
Results: We detected a structure-specific accumulation of cardiolipins and increased expression of the cardiolipin acyl chain remodeling enzyme, lysocardiolipin acyltransferase 1 (LCLAT1), within proliferating tumor cells in patient samples and the 3D tumorspheres. Orthogonal imaging techniques correlated the structure-specific accumulation of cardiolipin with fragmented mitochondria displaying aberrant cristae structure, altered mitochondrial dynamics, decreased expression of respiratory chain enzymes, and a more glycolytic phenotype. LCLAT1 KD altered cardiolipin profiles, reduced growth and proliferation, decreased Sox2 and N-Myc expression, increased p53 and p21 expression, and increased LIN28A and Dcx expression. Additional therapeutic targeting of the fragmented mitochondrial phenotype identified also resulted in selective inhibition of ETMR growth and viability.
Conclusions: Our findings provide novel insight into ETMR biology based on mitochondrial phenotypes and the fatty acid composition of the multifunctional mitochondrial-specific lipid, cardiolipin.

Keywords:  ETMR; LCLAT1; cardiolipins; mitochondrial dynamics and bioenergetics; pediatric brain tumors

DOI:  https://doi.org/10.1093/noajnl/vdaf228
Neurotrauma Rep. 2025 ;6(1): 1014-1023

Associations of Plasma Lipids with Traumatic Brain Injury Outcomes: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study.

TRACK-TBI Study Investigators

  Hypocholesterolemia has been observed in acute trauma, but less is known about lipid levels in acute traumatic brain injury (TBI). Our objectives were to (1) compare day 1 post-injury lipid levels from individuals with acute TBI to orthopedic trauma and healthy controls and (2) investigate associations of day 1 post-TBI lipid levels with clinical outcomes over the first-year post-injury. A subset of 266 participants with TBI, 68 orthopedic trauma controls, and 58 healthy controls from the Transforming Research and Clinical Knowledge in TBI Study were included in analyses. Plasma total cholesterol and triglycerides were measured using the enzymatic colorimetric method, and high-density lipoprotein (HDL) was measured via direct homogeneous/enzymatic colorimetric methods. Low-density lipoprotein (LDL) values were calculated using the Friedewald formula. The primary TBI outcome was the Glasgow Outcome Scale-Extended (dichotomized as favorable [score = 5-8] versus unfavorable [score = 1-4] outcome and complete [score = 8] versus incomplete [score = 1-7] recovery; administered at 2 weeks, 3 months, 6 months, and 1-year post-injury). Age- and sex-adjusted total cholesterol and LDL cholesterol were lower among participants with TBI compared with orthopedic trauma and healthy controls (total cholesterol: 116.7 mg/dL [95% confidence interval or CI = 112.1-121.3] versus 137.8 mg/dL [95% CI = 129.1-146.5] and 130.2 mg/dL [95% CI = 120.6-139.9]; LDL cholesterol: 59.3 mg/dL [95% CI = 55.8-62.9] versus 77.7 mg/dL [95% CI = 71.1-84.3] and 72.4 mg/dL [95% CI = 65.1-79.7]). Adjusted levels of HDL cholesterol and triglycerides were similar by group. Among participants with TBI, higher day 1 post-injury total cholesterol, LDL, and triglyceride levels were associated with greater adjusted odds of favorable versus unfavorable outcome after injury. In conclusion, our study found that day 1 post-injury levels of total and LDL cholesterol were lower among individuals with TBI compared with both orthopedic trauma and healthy controls. Furthermore, our results suggest that individuals who did not have acutely low total cholesterol and LDL cholesterol, and, to a lesser extent, triglycerides, had better functional outcomes over the first-year post-TBI.

Keywords:  TBI; cholesterol; lipids; outcomes

DOI:  https://doi.org/10.1177/2689288X251395462
Prog Lipid Res. 2025 Dec 29. pii: S0163-7827(25)00056-6. [Epub ahead of print] 101374

Stearoyl-CoA desaturase in development and disease.

Sampurna Ghosh, Roman Caceres, Sunny Congrove, James M Ntambi, Biplab Dasgupta.

The conversion of straight chain saturated fatty acids to their bent, unsaturated counterparts significantly increases their structural and functional complexity. Desaturation of fatty acids, where double bonds are introduced is an enzymatic reaction. Exploring 56 eukaryotic genomes, 275 desaturase homologs have been identified. Membrane-bound desaturases are the dominant form and are ubiquitous in bacteria and eukaryotes. Four subfamilies of desaturases introduce double bonds at distinct locations. Among them, the First Desaturase subfamily introduces the first double bond among which the stearoyl-CoA desaturases (SCDs) are the most predominant. SCD is a rate-limiting enzyme that generates monounsaturated fatty acids (MUFA) from saturated fatty acids (SFA) at the endoplasmic reticulum membrane, where SCD is localized. The MUFAs are utilized to produce a variety of cell membrane components including triglycerides, phospholipids, and cholesterol esters which play important roles in membrane fluidity, organelle function, and signal transduction. SCD activity is a critical regulator of SFA to MUFA ratio and, therefore, of overall cell function, growth, and survival. In this review, we will provide the latest updates on the expected as well as unanticipated roles of SCD in development, metabolism and disease with a focus on cancer and the central nervous system.

DOI: https://doi.org/10.1016/j.plipres.2025.101374
bioRxiv. 2025 Dec 17. pii: 2025.12.16.694759. [Epub ahead of print]

Hippocampal cell- and circuit-specific differences in mitochondrial form and function.

Mayd Alsalman, Lucy Turner, Katy Pannoni, Renesa Tarannum, Rutvi Desai, Sharon A Swanger, Shannon Farris.

Mitochondrial morphology varies by neuronal cell type and subcellular compartment; however, the functional significance of these differences is unclear. Hippocampal CA2 neurons are enriched for genes encoding mitochondrial proteins compared to CA1 neurons, suggesting a difference in metabolic demand across hippocampal circuits. However, whether CA2 neuron mitochondria are structurally or functionally distinct to support circuit-specific energy demands is unknown. Here we compared mitochondrial morphology, protein expression, and calcium levels across CA1 and CA2 circuits. We found mitochondria in CA2 dendrites were larger than mitochondria in CA1 dendrites. However, both subregions harbored larger mitochondria in the entorhinal cortex (EC)-contacting distal dendrites compared to CA3-contacting proximal dendrites. Together, these data demonstrate both cell type- and input-specific regulation of mitochondrial morphology that likely influences the function of these distinct circuits. To determine whether differences in mitochondrial fission or fusion account for cell and/or layer specific differences in morphology, we immunostained for OPA1 and MFF, which showed a general enrichment in distal dendrites relative to proximal dendrites, and an unexpected increase in CA1 distal dendrites compared to CA2 distal dendrites. To show whether these morphological differences result in functionally distinct mitochondria, we measured mitochondrial calcium levels in live slices. We found a striking enrichment of mitochondrial calcium levels in CA2 distal dendrites relative to proximal dendrites, and this layer-specific effect was significantly different from that in CA1 dendrites at baseline and after activity. Collectively, these findings reveal discrete morphological and functional differences in mitochondria across hippocampal subregions and dendritic layers, which likely confer unique circuit properties and/or vulnerabilities to disease.

DOI: https://doi.org/10.64898/2025.12.16.694759
Int J Mol Sci. 2025 Dec 10. pii: 11907. [Epub ahead of print]26(24):

Disturbances in Mitochondrial Network, Biogenesis, and Mitochondria-Mediated Inflammatory Responses in Selected Brain Structures of Rats Exposed to Lead (Pb) During Prenatal and Neonatal Development.

Mikołaj Chlubek, Magdalena Gąssowska-Dobrowolska, Agnieszka Kolasa, Maciej Tarnowski, Patrycja Tomasiak, Agnieszka Maruszewska, Katarzyna Barczak, Irena Baranowska-Bosiacka.

  Lead (Pb) disrupts mitochondrial function, but its impact on the mitochondrial dynamics and biogenesis during early brain development remains insufficiently understood. This study aimed to investigate the effects of pre- and neonatal Pb exposure on the processes involved in mitochondrial network formation in the brains of rat offspring, simulating environmental exposure. We quantified mRNA expression (qRT-PCR) and protein levels (ELISA) of key mitochondrial fusion (Mfn1, Mfn2, Opa1), fission (Drp1, Fis1) regulators, as well as biogenesis markers (PGC-1α, TFAM, NRF1) in the hippocampus, forebrain cortex, and cerebellum of rats exposed to Pb. Mitochondrial ultrastructure was evaluated using transmission electron microscopy (TEM), and the expression of mitochondrial electron transport chain (ETC) genes was analysed (qRT-PCR). Furthermore, to examine the involvement of the cGAS-STING pathway in Pb-induced neuroinflammation, we measured the expression of ISGs (qRT-PCR), TBK1 phosphorylation (Western blot), and 2',3'-cGAMP synthesis (ELISA). Our results showed that Pb exposure markedly reduced PGC-1α and region-specific NRF1 levels, broadly supressed fusion proteins (Mfn1, Mfn2, Opa1), increased Fis1, and depleted Drp1. ETC gene expression (mtNd1, mtCyb and mtCo1) were upregulated in a brain-structure-dependent manner. These molecular changes were accompanied by pronounced mitochondrial morphological abnormalities. Despite upregulation of Mx1, Ifi44, and Sting1, along with synthesis of 2'3'-cGAMP, TBK1 activation was not detected. All these findings demonstrate that early-life Pb exposure, even low-dose, disrupts mitochondrial biogenesis and the fusion-fission machinery, thus impairs brain energy homeostasis, and implicates mitochondria as central mediators of Pb-induced neuroinflammation and neurodevelopmental toxicity.

Keywords:  cGAS-STING pathway; developmental lead exposure; lead neurotoxicity; mitochondrial biogenesis; mitochondrial fission/fusion; rat brain

DOI:  https://doi.org/10.3390/ijms262411907
Cell Death Dis. 2025 Dec 30.

Unraveling sex differences in age-related hippocampal decline: differential mitochondrial dysfunction, Lonp1-dependent mitochondrial proteostasis and mtROS production in aged C57BL/6 mice.

Karina A Cicali, Claudia Jara, Daniela Cortés-Díaz, Matías Lira, Ítalo Fuentes, Alejandra Catenaccio, Josefa Arnaíz, Micaela Ricca, Sebastián Valenzuela, Carolina A Oliva, Daniela S Rivera, Cheril Tapia-Rojas.

Aging is a progressive process characterized by cellular and molecular damage leading to mitochondrial dysfunction and cognitive decline. Mitochondrial dysfunction is a critical factor in memory impairment in aging and neurodegenerative diseases. While sex differences in aging have been observed across various species, the underlying cellular and molecular mechanisms remain poorly understood, mainly focused on mitochondrial proteostasis. This study examined hippocampal-dependent cognitive decline and mitochondrial dysfunction in aged male and female C57BL/6 J mice. Our results reveal sex-dependent differences in cognitive impairment, with aged males exhibiting more significant deficits in spatial and localization memory, while aged females show impairments in recognition memory. Additionally, aged males display increased oxidative stress and exacerbated mitochondrial superoxide production, leading to more severe bioenergetic deficiencies. Conversely, aged females exhibit heightened mitochondrial permeability transition pore (mPTP) activity, suggesting a distinct mechanism of mitochondrial dysfunction, which could explain, almost in part, the cognitive differences in aging. Investigating possible mechanisms responsible for this mitochondrial dysfunction, we found that mitochondrial proteostasis is more prone to failure in aged males, with a significant decrease in the protease activity of Lonp1, a key matrix mitochondrial protease degrading >50% of the mitochondrial proteome. To further reinforce these findings, we replicated key experiments in SAMP8 mice, a model of accelerated aging, obtaining consistent results that strengthen the robustness and generalization of our conclusions. These findings suggest that sex influences hippocampal aging at multiple levels, highlighting the need to consider sexual dimorphism in aging research. This study also emphasizes the critical role of mitochondrial proteostasis in maintaining mitochondrial function in aging in a sex-dependent manner. Understanding these differences could facilitate the development of sex-specific strategies to mitigate age-related cognitive decline and neurodegeneration.

DOI: https://doi.org/10.1038/s41419-025-08360-y