bims-medebr 2025-07-06 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–07–06
25 papers selected by
Regina F. Fernández, Johns Hopkins University

Astrocytic Glucose Sensing Drives Synaptic Depression under Metabolic Stress.
Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
Triglycerides are an important fuel reserve for synapse function in the brain.
Lactate Dynamics Modulated by MCT1 and Glucose Oxidation Shifts in Age-Related Energy Decline in the Corpus Callosum.
Potential for flexible lactate shuttling between astrocytes and neurons to mitigate against diving-induced hypoxia.
Impairments in synaptic inhibition and glucose hypometabolism contribute to epileptogenesis in Wistar Audiogenic rats with cortical malformation.
Hyperglycemia selectively increases cerebral non-oxidative glucose consumption without affecting blood flow.
The anti-tumour role of ketogenic diet based on energy metabolism.
Brain glucose and ketone metabolism in first-episode psychosis: Neuroimaging and brain metabolism before and after antipsychotic treatment: The protocol for the CAST-ATP study.
Conformational dynamics and membrane insertion mechanism of B4GALNT1 in ganglioside synthesis.
Glucose Metabolism, Lactate, Lactylation and Alzheimer's Disease.
Sphingomyelin-induced glucocorticoid receptor alterations lead to impaired presynaptic plasticity in acid sphingomyelinase deficient neurons.
FABP7 is increased in progressive multiple sclerosis and induces a pro-inflammatory phenotype in monocytes through a glycolytic switch.
Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis.
Association of Reduced Brain Metabolism With Motor Function and Survival in Amyotrophic Lateral Sclerosis Patients With Neurofilament Heavy (NEFH) Gene Mutation.
Microgliosis, neuronal death, minor behavioral abnormalities and reduced endurance performance in alpha-ketoglutarate dehydrogenase complex deficient mice.
SerpinA3N inhibits mitochondrial complex I activity to prevent neuron ferroptosis following cerebral ischemic stroke.
"The role of cholesterol biosynthesis and metabolism causing medical complexity in patients with Smith-Lemli-Opitz Syndrome (SLOS)".
The Role of Fatty Acid Binding Proteins in Neuropsychiatric Diseases: A Narrative Review.
A High Omega-3, Low Omega-6 Diet Reduces Headache Frequency and Intensity in Persistent Post-Traumatic Headache: A Randomized Trial.
Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction.
Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction.
Molecular machineries and pathways of mitochondrial protein transport.
Neuromuscular pathology and mitochondrial dysfunction in sorbitol dehydrogenase gene-related distal hereditary motor neuropathies.
The role of cardiolipin in mitochondrial dynamics and quality control in neuronal ischemia/reperfusion injury.

Aging Dis. 2025 Jun 19.

Astrocytic Glucose Sensing Drives Synaptic Depression under Metabolic Stress.

Andrés M Baraibar, Carlos G Ardanaz, Susana Mato, Paulo Kofuji, Alfonso Araque, Maite Solas.

Glucose is the primary energy source for the brain, and its continuous supply is essential for neuronal function. Astrocytes play a pivotal role in brain energy metabolism by mediating glucose uptake, sensing metabolic fluctuations, and modulating synaptic activity. However, astrocyte responses to transient glucose deprivation remain incompletely understood. Here, we demonstrate that astrocytic glucose uptake is crucial for network adaptation to metabolic stress. Using electrophysiology and calcium imaging approaches, we show that glucose deprivation depresses hippocampal synaptic transmission through an astrocyte-dependent mechanism that involves decreased glucose transporter 1 (GLUT1)-facilitated extracellular glucose uptake, intracellular calcium elevations, and ATP/adenosine-mediated signaling, which leads to excitatory neurotransmission depression via A1 receptors. Moreover, astrocyte-specific GLUT1 depletion prevents astrocytic responses to glucose deprivation and precludes the effects of glucose deprivation on synaptic transmission, thereby indicating that GLUT1-dependent glucose uptake is involved in astrocyte-mediated modulation of synaptic function. These findings extend the concept of astrocytic metabolic regulation beyond regions canonically classified as glucose-sensing and establish astrocytes as key integrators of energy availability and synaptic function. Our study provides new insights into the role of astrocytes in brain energy homeostasis and identifies potential therapeutic targets for metabolic disorders affecting the nervous system.

DOI: https://doi.org/10.14336/AD.2025.0507
Trends Endocrinol Metab. 2025 Jul 02. pii: S1043-2760(25)00120-1. [Epub ahead of print]

Neuronal glycolysis meets mitophagy to govern organismal wellbeing.

Daniel Jimenez-Blasco, Rebeca Lapresa, Jesus Agulla, Angeles Almeida, Juan P Bolaños.

  Neurons are exceptionally energy-demanding cells but have limited energy storage, relying on a constant supply of fuel and oxygen. Although glucose is the brain's main energy source, neurons reduce glycolysis under normal conditions. This surprising strategy helps to protect mitochondria by preserving nicotinamide-adenine dinucleotide (NAD+), a vital cofactor consumed by glycolysis. NAD+ is needed for sirtuin-driven mitophagy, a process that removes damaged mitochondria. By saving NAD+, neurons can maintain healthy, energy-efficient mitochondria. These mitochondria then use alternative fuels such as lactate and ketone bodies from astrocytes. Here, we discuss the way in which this balance between reduced glycolysis and active mitophagy supports brain function and overall metabolic health, highlighting a sophisticated system that prioritizes mitochondrial quality for long-term cognitive performance and systemic homeostasis.

Keywords:  NAD; glycolysis; mitophay; neuron; organismal wellbeing

DOI:  https://doi.org/10.1016/j.tem.2025.05.005
Nat Metab. 2025 Jul 01.

Triglycerides are an important fuel reserve for synapse function in the brain.

Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L Pontius, Daehun Park, Rose E Witte, Rachel McAllister, Kallol Gupta, Kartik N Rajagopalan, Pietro De Camilli, Timothy A Ryan.

Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.

DOI: https://doi.org/10.1038/s42255-025-01321-x
Free Radic Biol Med. 2025 Jun 28. pii: S0891-5849(25)00793-2. [Epub ahead of print]

Lactate Dynamics Modulated by MCT1 and Glucose Oxidation Shifts in Age-Related Energy Decline in the Corpus Callosum.

Gonzalo Mayorga-Weber, Pablo Alarcón, Gaspar Peña-Münzenmayer, Patricio Rojas, Rafael A Burgos, Francisco J Rivera, Maite A Castro.

  The global population is aging, as reported by the World Health Organization (WHO). The brain, an energy-dependent organ, experiences a significant decline in energy production as we age. The corpus callosum, a major white matter tract, undergoes changes in energy metabolism during aging that remain poorly understood. This study aimed to investigate axonal energy metabolism in the corpus callosum and the potential role of Monocarboxylate Transporter 1 (MCT1) in age-related metabolic alterations. We analyzed the corpus callosum of young (3-4 months) and aged (18-24 months) mice, focusing on metabolic changes. Metabolomic analysis by gas chromatography-mass spectroscopy (GC-MS) revealed lactate accumulation, reduced glucose levels, and oxidative stress in the aged corpus callosum. Neuronal stimulation experiments using SoNar fluorescent sensor demonstrated a reduced capacity for oxidative energy metabolism in aged axons, evidenced by a lower axonal NADH/NAD+ ratio during electrical stimulation. In young axons, oxidative energy metabolism is sustained by glycolysis, lactate production via lactate dehydrogenase (LDH), and lactate transport mediated by MCTs during electrical stimulation. However, these processes are significantly impaired in aged axons. Additionally, glucose oxidation shifted preferentially to the pentose phosphate pathway (PPP) during electrical stimulation, highlighting its role in mitigating oxidative stress in aging. We observed reduced lactate uptake and MCT1 expression in aging. This reduction likely disrupts lactate flux and oxidation, contributing to energy inefficiencies that may promote oxidative stress and axonal deterioration. Our findings emphasize the need for further investigation of the role of MCT1 and lactate metabolism as therapeutic targets to preserve white matter integrity and axonal function in the aging brain.

Keywords:  Brain aging; MCT1; monocarboxylate transporter; white matter

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.044
Front Neuroanat. 2025 ;19 1607396

Potential for flexible lactate shuttling between astrocytes and neurons to mitigate against diving-induced hypoxia.

Chiara Ciccone, Sari Elena Dötterer, Sigrid Vold Jensen, Cornelia Geßner, Alexander C West, Shona H Wood, David G Hazlerigg, Lars P Folkow.

  For most non-diving mammals, lack of O2 (hypoxia) has detrimental effects on brain function. Seals, however, display a series of systemic, cellular, and molecular adaptations that enable them to tolerate repeated episodes of severe hypoxia. One as yet unresolved question is whether seal neurons in part employ anaerobic metabolism during diving: the "reverse astrocyte-neuron lactate shuttle" (rANLS) hypothesis postulates that seal neurons, by shuttling lactate to the astrocytes, may be relieved (1) from the lactate burden and (2) from subsequent ROS-production as lactate is oxidized by astrocytes upon re-oxygenation after the dive. Here, we have investigated this possibility, through histological and functional comparisons of the metabolic characteristics of neocortical neurons and astrocytes from the deep-diving hooded seal (Cystophora cristata), using mice (Mus musculus) as a non-diving control. We found that seal astrocytes have higher mitochondrial density and larger mitochondria than seal neurons, and that seal neurons have an atypical and significantly higher representation of the monocarboxylate lactate exporter MCT4 compared to mouse neurons. Also, measurements of mitochondrial O2 consumption suggest that the aerobic capacity of primary seal astrocytes is at least equal to that of primary seal neurons. Transcriptomics data from seals vs. mice suggest that specific adaptations to the electron transport system in seals may contribute to enhance hypoxia tolerance. These observations are consistent with the rANLS hypothesis.

Keywords:  astrocyte; diving mammals; hooded seal; hypoxia; lactate shuttling; mitochondrial respiration; neuron

DOI:  https://doi.org/10.3389/fnana.2025.1607396
Neuroscience. 2025 Jun 29. pii: S0306-4522(25)00748-1. [Epub ahead of print]

Impairments in synaptic inhibition and glucose hypometabolism contribute to epileptogenesis in Wistar Audiogenic rats with cortical malformation.

Fernanda Marcelia Dos Santos, Thais Martins de Lima, Gabriela Lazzarotto, João Arthur Meyer, Gabriel Carvalho da Silva, José Antonio Cortes de Oliveira, Gianina Teribele Venturin, Jaderson Costa da Costa, Eduardo R Zimmer, Norberto Garcia-Cairasco, Maria Elisa Calcagnotto.

  Epilepsy associated with malformations of cortical development (MCD) is often characterized by impaired cortical inhibition and altered brain metabolism, both of which play a key role in epileptogenesis. Recently, we reported the Wistar Audiogenic Rat (WAR), an epileptic-prone strain with induced cortical microgyria, exhibited increased ictogenesis and enhanced local cortical network synchrony, making it a reliable model to study epileptogenesis during development. The present study aimed to evaluate synaptic inhibition and glucose metabolism in several brain regions of this two-hit model of epilepsy (WAR-MCD) during the development. Unilateral cortical microgyria was induced via freeze-lesion in male and female neonatal WARs. Spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) were recorded in cortical pyramidal neurons adjacent to, distant from the microgyria, and the contralateral hemisphere during the juvenile and adolescent periods. Additionally, in vivo brain glucose metabolism was assessed during the same periods using [18F]FDG Positron Emission Tomography (PET) imaging. We observed significant reductions in amplitude, frequency and altered kinetics of sIPSCs in pyramidal neurons of MCD rats during the juvenile period. Synaptic inhibition deficits in paramicrogyral and contralateral cortices were even more pronounced in the two-hit model during adolescence. Glucose hypometabolism was evident in several brain regions of WARs and was further intensified in the two-hit model. These findings suggest an age-dependent disruption of cortical inhibition and glucose metabolism associated with MCD, further exacerbated by pro-epileptic conditions, contributing to epileptogenesis.

Keywords:  Brain glucose metabolism; Cortical synaptic inhibition; Epilepsy; Microgyria; Two-hit model; Wistar Audiogenic Rats

DOI:  https://doi.org/10.1016/j.neuroscience.2025.06.060
J Cereb Blood Flow Metab. 2025 Jul 01. 271678X251329714

Hyperglycemia selectively increases cerebral non-oxidative glucose consumption without affecting blood flow.

Tyler Blazey, John J Lee, Abraham Z Snyder, Manu S Goyal, Tamara Hershey, Ana Maria Arbeláez, Marcus E Raichle.

  Multiple studies have shown that hyperglycemia increases the cerebral metabolic rate of glucose (CMRglc) in subcortical white matter. This observation remains unexplained. Using positron emission tomography (PET) and pancreatic glucose clamps with basal insulin replacement in twenty-nine healthy young adults (34.5 years, SD = 10.1) we found that acute hyperglycemia increases non-oxidative CMRglc (i.e., aerobic glycolysis (AG)) in subcortical white mater as well as in medial temporal lobe structures, cerebellum and brainstem, all areas with low CMRglc during euglycemia. Surprisingly, hyperglycemia did not change regional cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2), or the blood-oxygen-level-dependent (BOLD) response. Correlation with existing regional gene expression data showed that brain regions where CMRglc increased have greater expression of hexokinase 2 (HK2). Simulations of glucose transport revealed that, unlike hexokinase 1, HK2 is not saturated at euglycemia, and thus can accommodate increased AG during hyperglycemia.

Keywords:  Energy metabolism; diabetes; glucose; hyperglycemia; white matter/oligodendrocytes

DOI:  https://doi.org/10.1177/0271678X251329714
Clin Nutr. 2025 Jun 13. pii: S0261-5614(25)00160-8. [Epub ahead of print]51 174-186

The anti-tumour role of ketogenic diet based on energy metabolism.

Jiasheng Wu, Xinyu Sun, Hanmou Luo, Xiaoqi Luo, Suxia Sun.

   BACKGROUND: Unlike the energy metabolism of normal cells, tumour cells favor aerobic glycolysis to meet their unique energy demands, while disrupting normal mitochondrial metabolism. This specialized energy metabolic pathway promotes tumour growth, proliferation, and metastasis. The ketogenic diet (KD) is a high-fat diet inducing ketone bodies (KBs) for energy metabolism by restricting carbohydrate intake and promoting fatty acid breakdown. Due to the unique energy metabolism of tumours, KD has the potential to counteract tumour energy metabolism.
METHODS: The current literature was reviewed for potential anti-tumour mechanisms of KD based on energy metabolism and the clinical evidence suggested for KD roles in tumours.
RESULTS: KD exerts anti-tumour effects by inhibiting tumour aerobic glycolysis, inducing KBs, activating AMP-activated protein kinase (AMPK), and regulating reactive oxygen species (ROS) levels.
CONCLUSION: This review groundbreakingly concludes that KD manifests the potential of anti-tumour effects based on energy metabolism. Furthermore, this study establishes a theoretical foundation for exploring the anti-cancer properties of KD and its potential as a adjunctive therapy for cancer.

Keywords:  Energy metabolism; Glycolysis; Ketogenic diet; Tumour

DOI:  https://doi.org/10.1016/j.clnu.2025.06.006
PLoS One. 2025 ;20(6): e0325489

Brain glucose and ketone metabolism in first-episode psychosis: Neuroimaging and brain metabolism before and after antipsychotic treatment: The protocol for the CAST-ATP study.

Kevin Zemmour, Guy-Olivier Samson, Mélanie Fortier, Eliot Parent, Alexandra Leus, Sylvain Grignon, Jean-Daniel Carrier, Kevin Whittingstall, Andreas Aalkjær Danielsen, Ole Köhler-Forsberg, Allan Kjeldsen Hansen, Sri Mahavir Agarwal, Anna Cristina Andreazza, Bjørn Hylsebeck Ebdrup, Margaret Hahn, Stephen Cunnane.

First episode of psychosis (FEP) has an early onset and is associated with significant functional impairment, loss of productivity and premature cardiovascular disease. Antipsychotics (AP) remain the cornerstone treatment of FEP yet they fail to improve key symptom domains and contribute to the metabolic burden of this disorder. A growing body of evidence suggests that a metabolic deficit in the brain, specifically of glucose, at the earliest stages of illness could represent an etiopathological phenotype of FEP. Correcting this metabolic deficit could improve outcomes and disease course. The acronym for this study is CAST-ATP for the collaboration between our clinical research sites in Copenhagen, Aarhus, Sherbrooke and Toronto, on the subject of Antipsychotic (AP) treatment, PET and Psychosis. The main aims of CAST-ATP are to evaluate the effect of 1) a diagnosis of FEP, and, 2) 4-6 weeks of AP treatment on brain energy metabolism measured by PET scans (uptake of ketones and glucose). The hypothesis is that (i) glucose metabolism will be impaired in AP-naïve patients as compared to healthy controls, and (ii) this defect will be worsened by AP. In contrast, across the two aims, brain ketone metabolism is predicted to not be significantly influenced by FEP or AP treatment. Participants on both sites will undergo an imaging protocol (PET scans + MRI) in addition to measures of psychopathology and related peripheral metabolic, inflammatory and hormonal markers. If our hypothesis is confirmed, it will reinforce the strategy to leverage ketone supplementation to improve symptoms, functioning and quality of life by bypassing the brain glucose deficit in FEP. As such, this should be a significant therapeutic development. To this last point, the pharmaceutical treatment of schizophrenia spectrum disorders has not progressed beyond currently available AP for over seven decades.

DOI: https://doi.org/10.1371/journal.pone.0325489
Nat Commun. 2025 Jul 01. 16(1): 5442

Conformational dynamics and membrane insertion mechanism of B4GALNT1 in ganglioside synthesis.

Jack W J Welland, Henry G Barrow, Phillip J Stansfeld, Janet E Deane.

Glycosphingolipids (GSLs) are crucial membrane components involved in essential cellular pathways. Complex GSLs, known as gangliosides, are synthesised by glycosyltransferase enzymes and imbalances in GSL metabolism cause severe neurological diseases. B4GALNT1 synthesises the precursors to the major brain gangliosides. Loss of B4GALNT1 function causes hereditary spastic paraplegia, while its overexpression is linked to cancers including childhood neuroblastoma. Here, we present crystal structures of the human homodimeric B4GALNT1 enzyme demonstrating dynamic remodelling of the substrate binding site during catalysis. We show that processing of lipid substrates by B4GALNT1 is severely compromised when surface loops flanking the active site are mutated from hydrophobic residues to polar. Molecular dynamics simulations support that these loops can insert into the lipid bilayer explaining how B4GALNT1 accesses and processes lipid substrates. By combining structure prediction and molecular simulations we propose that this mechanism of dynamic membrane insertion is exploited by other, structurally distinct GSL synthesising enzymes.

DOI: https://doi.org/10.1038/s41467-025-60593-9
Aging Dis. 2025 Jun 25.

Glucose Metabolism, Lactate, Lactylation and Alzheimer's Disease.

Shuangshuang Hai, Yadan Hou, Meiyan Zhang, Xiaoyan Gao, Tuo Yang, Xiuli Shang, Xiaohong Sun.

Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline; however, its pathogenesis remains incompletely understood. In recent years, the role of lactate metabolism and its derived lactylation modifications in AD has received increasing attention. As a product of glycolysis, lactate is not only a key molecule in energy metabolism but also regulates gene expression and protein function through lactylation modifications. Studies have shown that in the brains of AD patients, glucose metabolism is significantly reduced, while glycolysis is upregulated, and lactate levels are elevated. Nevertheless, the research regarding the relationship between lactylation and AD remains limited. Building on recent advances in understanding lactylation in neurodegenerative diseases and related conditions, we analyze and explore the potential relationships between lactylation and AD from the perspectives of β-amyloid (Aβ) deposition, tau protein pathology, and neuroinflammation. In summary, lactylation, as a novel post-translational modification holds significant promise in elucidating the pathological mechanisms and advancing the treatment of AD. A deeper investigation into its molecular mechanisms and regulatory networks may open new avenues for the diagnosis and treatment of AD.

DOI: https://doi.org/10.14336/AD.2025.0338
Neurobiol Dis. 2025 Jul 01. pii: S0969-9961(25)00232-3. [Epub ahead of print]213 107016

Sphingomyelin-induced glucocorticoid receptor alterations lead to impaired presynaptic plasticity in acid sphingomyelinase deficient neurons.

Sara Naya-Forcano, Ángel Gaudioso, Beatriz Soto-Huelin, Celia García-Vilela, César Venero, Edward H Schuchman, José A Esteban, María Dolores Ledesma.

  Acid sphingomyelinase deficiency (ASMD) is a rare disease caused by mutations in the gene encoding ASM, an enzyme that degrades sphingomyelin (SM). In addition to SM accumulation, neuroinflammation and cognitive impairment are pathological hallmarks of neurovisceral ASMD. Since the glucocorticoid system may influence these features, we have characterized it in ASM knockout (ASMko) mice that mimic this form of the disease. While plasma corticosterone levels are not altered in these mice, brain levels of the α, but not the β, isoform of glucocorticoid receptors (GR) are reduced. The reduction is evident in neurons and is due to the accumulation of SM. As a consequence, the expression of the protein, synapsin I, is low in ASMko neurons, leading to the disorganization of synaptic vesicles and to impaired presynaptic plasticity. Treatment with the glucocorticoid hydrocortisone diminished SM levels, increased synapsin I expression, and improved presynaptic function in neuronal cultures and hippocampal slices of ASMko mice. These findings establish, for the first time, a link between the glucocorticoid system and brain pathology in ASMD, highlighting the GR as a potential therapeutic target for this devastating disease.

Keywords:  Acid sphingomyelinase deficiency; Glucocorticoid receptors; Hydrocortisone; Sphingomyelin; Synapsin

DOI:  https://doi.org/10.1016/j.nbd.2025.107016
Nat Commun. 2025 Jul 01. 16(1): 6049

FABP7 is increased in progressive multiple sclerosis and induces a pro-inflammatory phenotype in monocytes through a glycolytic switch.

Rohit Patel, Devin King, Brenna LaBarre, Hrishikesh Lokhande, Danielle Caefer, Johnna F Varghese, Keturah Warner, Marc A Bouffard, Shrishti Saxena, Alena Zhirova, Rohit Bakshi, Tanuja Chitnis.

Multiple sclerosis (MS) involves dysregulation of innate immune cells including monocytes, especially in progressive MS. Fatty acid binding proteins (FABP) are essential for fatty acid transport and metabolism in multiple cell types. FABP7, a brain-FABP, maintains metabolic function in astrocytes and neural stem cells, but the effect of FABP7 on monocytes is unknown. Here we find elevated levels of FABP7 in the serum and cerebrospinal fluid of patients with secondary progressive MS. Elevated serum FABP7 levels positively correlate with higher disability scores, brain lesion volumes, and lower brain volumes. FABP7 levels are increased in astrocytes from MS postmortem brain lesion. Mechanistically, in vitro treatment of FABP7 induces CD16, CD80 and IL-1β expression in monocytes via increased glycolysis. FABP7-induced gene expression reflects enhanced inflammation, chemotaxis and glucose metabolism in monocytes. In conclusion, we find that FABP7 induces pro-inflammatory profiles in monocytes, correlates with disability and represents a potential biomarker and therapeutic target for progressive MS.

DOI: https://doi.org/10.1038/s41467-025-60747-9
Mov Disord. 2025 Jul 01.

Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis.

Keit Men Wong, Reza Maroofian, Kolja Meier, Susann Diegmann, Tinatin Tkemaladze, Javeria Raza Alvi, Behnoosh Tasharrofi, Stephanie Efthymiou, Alexander Munchau, G Christoph Korenke, Naif Almontashiri, Wafaa Eyaid, Amna Kashgari, Modhi Alotaibi, Jutta Gärtner, Brenda Huppke, Mostafa Asadollahi, Gocha Chikvinidze, Mohammad Keramatipour, Tipu Sultan, Holger Thiele, Peter Nürnberg, Markus H Gräler, Henry Houlden, Peter Huppke.

   BACKGROUND: Very long chain fatty acids (VLCFAs) are an integral component of myelin and the epidermal water barrier. Variants in genes encoding enzymes responsible for catalyzing the first and rate limiting step in the production of VLCFAs, elongation of VLCFAs (ELOVLs), underlie a novel group of metabolic disorders.
OBJECTIVES: The goal was to describe the clinical phenotype and disturbance in VLCFA metabolism associated with variants in the ELOV1 gene.
METHODS: The following methods were employed: Exome sequencing, clinical phenotyping, magnetic resonance imaging (MRI), metabolomics, liquid chromatography-tandem mass spectrometry, fatty acid elongation assay.
RESULTS: We, here, describe seven patients with autosomal recessive variants in ELOVL1. Common clinical features included ichthyosis (5/7), developmental delay (7/7), progressive spasticity (7/7), nystagmus (5/6), and a complex movement disorder characterized by pronounced head tremor (7/7), myoclonus (6/7), and dysarthria (6/6). Brain MRI revealed non-progressive hypomyelination (6/6) and hypoplasia of the corpus callosum (5/6). Plasma VLCFA analysis in one patient showed reduced concentrations of C24:0 and C26:0. Biochemical analysis of fibroblasts from this patient revealed elongation defects in VLCFA synthesis and dysregulation of other ELOVL enzymes.
CONCLUSIONS: We show that biallelic variants in ELOVL1 are associated with a unique and recognizable phenotype of hypomyelinating leukodystrophy, ichthyosis, and a complex movement disorder including progressive spasticity, head tremor, and myoclonus. Biochemical analyses confirmed a defect in VLCFA synthesis. Variants in genes encoding enzymes involved in the elongation of VLCFAs are a novel group of metabolic disorders with overlapping symptoms. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  ELOVL1; head tremor; ichthyosis; leukodystrophy; myoclonus

DOI:  https://doi.org/10.1002/mds.30258
Eur J Neurol. 2025 Jul;32(7): e70261

Association of Reduced Brain Metabolism With Motor Function and Survival in Amyotrophic Lateral Sclerosis Patients With Neurofilament Heavy (NEFH) Gene Mutation.

Xinyu Song, Xueying Wang, Fan Hu, Pan Liu, Ziqin Liu, Jiping Yi, Renxu Xu, Wenfeng Cao, Yuanchao Zhang, Junling Wang, Alessandro Grecucci, Xiaoping Yi, Bihong T Chen.

   BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that impairs both upper and lower motor neurons. Mutations in the neurofilament heavy (NEFH) gene are associated with a higher risk for ALS. This study aimed to evaluate the brain metabolism in patients with ALS and NEFH gene mutations (NEFH-ALS) and assess its correlation with emotional and cognitive changes.
METHODS: This prospective study enrolled 119 patients with ALS and 128 age- and gender-matched health controls. Study assessments included demographic data collection, questionnaires for motor function, cognition, and depression, and brain F-18 FDG PET/CT (18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT)) scan. Correlation between brain metabolism and clinical questionnaire scores was performed. Chain-mediation model analysis for the NEFH-ALS group was conducted. Cox regression and Kaplan-Meier survival analysis were also performed.
RESULTS: There were 26 NEFH-ALS patients. Patients with NEFH-ALS showed brain glucose hypometabolism in the cortex-striatum/limbic system-brainstem circuit when compared with healthy controls (p < 0.05). Decreased brain glucose metabolism was correlated with impairments of motor function (r = 0.477, p = 0.014, FDR corrected p = 0.014), cognitive scores (r = 0.549, p = 0.004, FDR corrected p = 0.009), and depression (r = -0.523, p = 0.009, FDR corrected p = 0.009). This study showed that brain glucose hypometabolism could lead to impairment of motor function, which was mediated by cognition and depression. Survival analysis showed that brain glucose metabolism was an independent prognostic factor for patients with ALS.
CONCLUSIONS: Reduced brain glucose metabolism in the cortex-striatum/limbic system-brainstem circuit may potentially serve as an independent prognostic factor for patients with ALS and NEFH mutation.

Keywords:  18F‐FDG‐PET/CT 18F‐fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT); amyotrophic lateral sclerosis; brain glucose metabolism; mediation effect; neurofilament heavy (NEFH) gene

DOI:  https://doi.org/10.1111/ene.70261
Redox Biol. 2025 Jun 27. pii: S2213-2317(25)00256-3. [Epub ahead of print]85 103743

Microgliosis, neuronal death, minor behavioral abnormalities and reduced endurance performance in alpha-ketoglutarate dehydrogenase complex deficient mice.

Márton Kokas, András Budai, Andrea Kádár, Soroosh Mozaffaritabar, Lei Zhou, Tímea Téglás, Rebeka Sára Orova, Dániel Gáspár, Kristóf Németh, Daniel Marton Toth, Nabil V Sayour, Csenger Kovácsházi, Andrea Xue, Réka Zsuzsanna Szatmári, Beáta Törőcsik, Domokos Máthé, Noémi Kovács, Krisztián Szigeti, Péter Nagy, Ildikó Szatmári, Csaba Fekete, Tamás Arányi, Zoltán V Varga, Péter Ferdinandy, Zsolt Radák, Andrey V Kozlov, László Tretter, Tímea Komlódi, Attila Ambrus.

  The alpha-ketoglutarate dehydrogenase complex (KGDHc), also known as the 2-oxoglutarate dehydrogenase complex, plays a crucial role in oxidative metabolism. It catalyzes a key step in the tricarboxylic acid (TCA) cycle, producing NADH (primarily for oxidative phosphorylation) and succinyl-CoA (for substrate-level phosphorylation, among others). Additionally, KGDHc is also capable of generating reactive oxygen species, which contribute to mitochondrial oxidative stress. Hence, the KGDHc and its dysfunction are implicated in various pathological conditions, including selected neurodegenerative diseases. The pathological roles of KGDHc in these diseases are generally still obscure. The aim of this study was to assess whether the mitochondrial malfunctions observed in the dihydrolipoamide succinyltransferase (DLST) and dihydrolipoamide dehydrogenase (DLD) double-heterozygous knockout (DLST+/-DLD+/-, DKO) mice are associated with neuronal and/or metabolic abnormalities. In the DKO animals, the mitochondrial O2 consumption and ATP production rates both decreased in a substrate-specific manner. Reduced H2O2 production was also observed, either due to Complex I inhibition with α-ketoglutarate or reverse electron transfer with succinate, which is significant in ischaemia-reperfusion injury. Middle-aged DKO mice exhibited minor cognitive decline, associated with microgliosis in the cerebral cortex and neuronal death in the Cornu Ammonis subfield 1 (CA1) of the hippocampus, indicating neuroinflammation. This was supported by increased levels of dynamin-related protein 1 (Drp1) and reduced levels of mitofusin 2 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in DKO mice. Observations on activity, food and oxygen consumption, and blood amino acid and acylcarnitine profiles revealed no significant differences. However, middle-aged DKO animals showed decreased performance in the treadmill fatigue-endurance test as compared to wild-type animals, accompanied by subtle resting cardiac impairment, but not skeletal muscle fibrosis. In conclusion, DKO animals compensate well the double-heterozygous knockout condition at the whole-body level with no major phenotypic changes under resting physiological conditions. However, under high energy demand, middle-aged DKO mice exhibited reduced performance, suggesting a decline in metabolic compensation. Additionally, microgliosis, neuronal death, decreased mitochondrial biogenesis, and altered mitochondrial dynamics were observed in DKO animals, resulting in minor cognitive decline. This is the first study to highlight the in vivo changes of this combined genetic modification. It demonstrates that unlike single knockout rodents, double knockout mice exhibit phenotypical alterations that worsen under stress situations.

Keywords:  Alpha-ketoglutarate dehydrogenase complex; Cognitive decline; Dihydrolipoyl dehydrogenase; Dihydrolipoyl succinyltransferase; Fatigue test; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2025.103743
Exp Neurol. 2025 Jul 02. pii: S0014-4886(25)00234-1. [Epub ahead of print] 115370

SerpinA3N inhibits mitochondrial complex I activity to prevent neuron ferroptosis following cerebral ischemic stroke.

Xiansheng Liu, Gan Li, Yunlu Guo, Ruqi Li, Shilin Yi, Shenghao Ding, Jieqing Wan.

  SerpinA3N, a serine protease inhibitor, plays emerging roles in programmed cell death regulation, yet its intracellular function in neuronal ferroptosis remains unexplored. Using the multi-omic integrative analyses of the neurons from middle cerebral artery occlusion (MCAO) challenged mouse model, we found that Serpina3n-deficient mice exhibited significantly dysregulated ferroptosis signaling networks characterized by mitochondrial lipid peroxidation amplification and redox homeostasis collapse as compared to wide type mice. An arginine mutation at position 90 of Ndufs3, the catalytic core subunit of mitochondrial complex I, in HT-22 cells impaired the binding of Ndufs3 with SerpinA3N and potentiated ferroptosis of HT-22 cells following oxygen glucose deprivation/reperfusion (OGD/R). Furthermore, neuron-specific Isl1 overexpression in wide type mice or intraperitoneal injected zinc robustly upregulated the expression of SerpinA3N in neurons following MCAO. We further found that both the overexpression of Isl1 in neurons and zinc treatment could reduce infarct volume, and improve sensorimotor recovery post-stroke. These findings collectively suggest SerpinA3N as a key mitochondrial redox regulator and reveals zinc-Isl1 signaling as a promising neuroprotective target. These findings not only identified a novel role for SerpinA3N in ferroptosis but also indicated that zinc ion may be a valuable candidate for the development of a potential therapeutic approach.

Keywords:  Complex I; Ferroptosis; Ischemic stroke; Mitochondria; SerpinA3N

DOI:  https://doi.org/10.1016/j.expneurol.2025.115370
J Steroid Biochem Mol Biol. 2025 Jul 01. pii: S0960-0760(25)00150-5. [Epub ahead of print] 106822

"The role of cholesterol biosynthesis and metabolism causing medical complexity in patients with Smith-Lemli-Opitz Syndrome (SLOS)".

Ellen Roy Elias.

  Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive genetic disorder associated with complex anatomic abnormalities, accompanied by medical, developmental and behavioral challenges. It was the first human disorder identified to be caused by an error in the complex cholesterol biosynthetic pathway, more than thirty years ago. This review will cover the clinical and developmental phenotype of patients with SLOS, and the understanding of how cholesterol deficiency, accumulation of the cholesterol precursors 7- and 8-dehydrocholesterol (7-DHC and 8-DHC), and the oxidation of these precursors into toxic oxysterols, are now known to cause this complex phenotype. There is a wide range of severity in patients with SLOS. The most severely affected babies may be miscarried or die in the newborn period due to lethal congenital anomalies. The most mildly impacted patients may show few anatomic abnormalities other than 2-3 toe syndactyly, but still display cognitive and behavioral challenges along the autism spectrum. The review will also cover the medical evaluation and interventions which are recommended in caring for patients with SLOS. There is no cure for this devastating disease, but certain interventions can lead to an improved quality of life, and stabilization of progressive problems for these complex patients.

Keywords:  7-dehydrocholesterol (7-DHC); 8-dehydrrocholesterol (8-DHC); Bile acids; Cholesterol; Oxysterols; Retinal disease; Smith-Lemli-Opitz Syndrome (SLOS)

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106822
Front Biosci (Landmark Ed). 2025 Jun 17. 30(6): 26812

The Role of Fatty Acid Binding Proteins in Neuropsychiatric Diseases: A Narrative Review.

Aidan Powell, Noa Yamaguchi, Huy Lu, Ojas Pareek, Igor Elman, Mark S Gold, Albert Pinhasov, Kenneth Blum, Panayotis K Thanos.

  Fatty acid binding proteins (FABPs) transport lipids in the brain and may be involved in the course of various neuropsychiatric syndromes, e.g., major depressive disorder (MDD), anxiety, schizophrenia, neurodegenerative disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and substance use disorders (SUDs). However, the nature of this link is not sufficiently elucidated. To that end, we performed a comprehensive literature search on the role of FABPs in neuropsychiatric disorders. Literature searches were conducted from Medline/PubMed electronic databases utilizing the search terms ("fatty acid binding protein" OR "FABP") AND ("psychiatry" OR "ADHD" OR "autism" OR "schizophrenia" OR "substance abuse" OR "substance use disorder" OR "addiction" OR "cocaine" OR "ethanol" OR "tetrahydrocannabinol (THC)" OR "nicotine" OR "anxiety" OR "depression" OR "major depressive disorder", OR "neurodegenerative" OR "Alzheimer" OR "Parkinson" OR "dementia"). Of the 1281 publications found, 90 met the inclusion criteria. FABP alterations were found to be involved in pathology and/or associated with the severity of all conditions examined. Elevated levels of FABP2 and FABP7 were found in patients with MDD and ASD, while FABP3 is implicated in dopamine receptor regulation linked to ADHD and SUDs. Moreover, FABPs' involvement in neuroinflammation and lipid metabolism could shed light on new therapeutic strategies. Alterations in FABP expression may contribute to the increased prevalence and severity of certain neuropsychiatric conditions. Our findings, albeit pending further validation via prospective clinical trials, call for further research into the mechanisms by which FABPs affect neurophysiopathology and highlight the therapeutic potential of FABP inhibitors in mitigating such illnesses.

Keywords:  anxiety; attention-deficit (hyperactivity) disorder; autism spectrum disorder; fatty acid binding protein; major depressive disorder; neurodegeneration; schizophrenia; substance use disorders

DOI:  https://doi.org/10.31083/FBL26812
J Neurotrauma. 2025 Jul 02.

A High Omega-3, Low Omega-6 Diet Reduces Headache Frequency and Intensity in Persistent Post-Traumatic Headache: A Randomized Trial.

Daisy Zamora, Kimbra Kenney, Mark Horowitz, Wesley R Cole, Beth A MacIntosh, Jacques P Arrieux, Margaret Dunlap, Olafur S Palsson, Cora Davis, Carol B Moore, Wanda Rivera, J Kent Werner, Ramon Diaz-Arrastia, Anthony F Domenichiello, Pranavi Nara, Ameer Y Taha, Duncan A Sylvestre, Chris E Ramsden, Keturah R Faurot.

  Targeted manipulation of dietary omega-3 and omega-6 fatty acids has previously been shown to decrease nontraumatic headaches in controlled trials. This study assessed the effects of a diet high in omega-3 fatty acids and low in omega-6 linoleic acid (H3L6 diet) on headache frequency and severity, headache impact, and plasma nociceptive mediators in a persistent post-traumatic headache (pPTH) population. One hundred and twenty-two participants with pPTH were randomized 1:1 to 12 weeks of either the H3L6 (n = 62) or a control (n = 60) diet. A priori primary end-points were the plasma levels of the antinociceptive docosahexaenoic acid (DHA) derivative 17-hydroxy-DHA and the Headache Impact Test (HIT-6) score. Secondary end-points included headache days/month and average daily headache pain intensity (0-10 scale). Statistical analyses followed intention-to-treat principles and were adjusted for baseline values. Relative to the control group, the H3L6 group significantly reduced headache days/month (-2.1, 95% confidence interval [CI]: -3.5 to -0.8, p = 0.002) and average headache intensity (-0.9, 95% CI: -1.2 to -0.5, p < 0.001) and increased circulating 17-hydroxy-DHA (nanograms/milliliter; difference 0.07, 95% CI: 0.02-0.11, p = 0.003), although it did not significantly improve HIT-6 scores (-1.6, 95% CI: -4.0 to 0.8, p = 0.18). In conclusion, the H3L6 diet reduced headache pain and increased antinociceptive mediators, supporting its potential as an adjunct nonpharmacological pPTH therapy.

Keywords:  clinical trial; omega-3 fatty acids; omega-6 fatty acids; oxylipins; persistent post-traumatic headaches; traumatic brain injury

DOI:  https://doi.org/10.1089/neu.2025.0126
PLoS Biol. 2025 Jul 03. 23(7): e3003265

Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction.

Alex S Nicholson, David A Priestman, Robin Antrobus, James C Williamson, Reuben Bush, Shannon J McKie, Henry G Barrow, Emily Smith, Kostantin Dobrenis, Nicholas A Bright, Frances M Platt, Janet E Deane.

Glycosphingolipids (GSL) are important bioactive membrane components. GSLs containing sialic acids, known as gangliosides, are highly abundant in the brain and diseases of ganglioside metabolism cause severe early-onset neurodegeneration. The ganglioside GM2 is processed by β-hexosaminidase A and when non-functional GM2 accumulates causing Tay-Sachs and Sandhoff diseases. We have developed i3Neuron-based disease models demonstrating storage of GM2 and severe endolysosomal dysfunction. Additionally, the plasma membrane (PM) is significantly altered in its lipid and protein composition. These changes are driven in part by lysosomal exocytosis causing inappropriate accumulation of lysosomal proteins on the cell surface. There are also significant changes in synaptic protein abundances with direct functional impact on neuronal activity. Lysosomal proteins are also enriched at the PM in GM1 gangliosidosis supporting that lysosomal exocytosis is a conserved mechanism of PM proteome change in these diseases. This work provides mechanistic insights into neuronal dysfunction in gangliosidoses highlighting that these are severe PM disorders with implications for other lysosomal and neurodegenerative diseases.

DOI: https://doi.org/10.1371/journal.pbio.3003265
Nat Metab. 2025 Jun 30.

Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction.

Sudipta Bar, Kenneth A Wilson, Tyler A U Hilsabeck, Sydney Alderfer, Eric B Dammer, Jordan B Burton, Samah Shah, Anja Holtz, Enrique M Carrera, Jennifer N Beck, Jackson H Chen, Grant Kauwe, Fatemeh Seifar, Ananth Shantaraman, Tara E Tracy, Nicholas T Seyfried, Birgit Schilling, Lisa M Ellerby, Pankaj Kapahi.

Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), for which there are currently no successful treatments. Here, we show impaired glycogen metabolism in the brain of a tauopathy Drosophila melanogaster model and people with AD, indicating a link between tauopathies and glycogen metabolism. We demonstrate that the breakdown of neuronal glycogen ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC)-derived neurons from people with FTLD-tau. Glycogen breakdown redirects glucose flux to the pentose phosphate pathway and alleviates oxidative stress. Our findings uncover a critical role for the neuroprotective effects of dietary restriction (DR) by increasing glycogen breakdown. Mechanistically, we show a potential interaction between tau protein and glycogen, suggesting a vicious cycle in which tau binding promotes glycogen accumulation in neurons, which in turn exacerbates tau accumulation which further disrupts cellular homeostasis. Our studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy and other neurodegenerative diseases.

DOI: https://doi.org/10.1038/s42255-025-01314-w
Nat Rev Mol Cell Biol. 2025 Jul 03.

Molecular machineries and pathways of mitochondrial protein transport.

Toshiya Endo, Nils Wiedemann.

Mitochondria contain about 1,000-1,500 different proteins, most of which are encoded by the nuclear genome and synthesized in the cytosol, although a handful are specified by the mitochondrial DNA and translated within mitochondria. The coordinated transport of nucleus-encoded proteins into mitochondria, followed by their proper folding, assembly and/or integration into mitochondrial membranes, is central to mitochondrial biogenesis. In this Review, we describe the pathways and machineries for protein transport across and insertion into the inner and outer mitochondrial membranes, as well as the targeting and sorting signals, and energy requirements for these processes. These machineries include the TOM and SAM complexes in the outer membrane and the TIM complexes in the inner membrane, and some components in the intermembrane space. We emphasize recent developments in our understanding of the protein structures of the transport machineries and discuss mechanisms for the shift of protein localization and correction of mislocalization.

DOI: https://doi.org/10.1038/s41580-025-00865-w
J Neuropathol Exp Neurol. 2025 Jun 21. pii: nlaf070. [Epub ahead of print]

Neuromuscular pathology and mitochondrial dysfunction in sorbitol dehydrogenase gene-related distal hereditary motor neuropathies.

Zhenyu Li, Xujun Chu, Yize Li, Zhiying Xie, Meng Yu, Jianwen Deng, He Lv, Wei Zhang, Qiang Gang, Zhaoxia Wang, Lingchao Meng, Yun Yuan.

  Biallelic variants in sorbitol dehydrogenase (SORD) have been reported to be a major cause of autosomal recessive distal hereditary motor neuropathy (dHMN). In this study, the clinical and pathological features of 10 patients with SORD gene-related dHMN are reported. Homozygous c.757delG variant was detected in 6 patients while c.757delG, c.786 + 1G>A, c.218C>T, and a novel c.104T>A compound heterozygous variants were observed in the others. Serum sorbitol, xylitol, and D-arabinitol were measured by gas chromatography-mass spectrometry; increased sorbitol and xylitol, and decreased D-arabinitol were identified. Sural nerve biopsies showed mild loss of large, myelinated fibers, and a few thin myelinated fibers. Skeletal muscle biopsies exhibited a neurogenic pattern with vacuoles, tubular aggregates, and abnormal mitochondria. Proteomic analyses of muscle tissue were performed to explore potential mechanisms. Complex I deficiency was dominant in the proteomic analysis and the malic acid/oxaloacetic acid ratio was significantly higher in the patients than in controls. In summary, SORD gene-related dHMN is a systemic disorder of carbohydrate metabolism with subclinical myopathologic changes, including tubular aggregates and vacuoles. Mitochondrial complex I deficiency, may be a key mechanism in SORD gene-related dHMN.

Keywords:  SORD; carbohydrate metabolism; distal hereditary motor neuropathy; mitochondria; tubular aggregate

DOI:  https://doi.org/10.1093/jnen/nlaf070
Cell Death Dis. 2025 Jul 05. 16(1): 494

The role of cardiolipin in mitochondrial dynamics and quality control in neuronal ischemia/reperfusion injury.

Katlynn J Emaus, Garrett M Fogo, Joseph M Wider, Thomas H Sanderson.

Stroke and cardiac arrest claim the lives of millions worldwide each year emphasizing the importance of understanding this injury cascade. These pathologies present as a 'two hit' injury termed ischemia/reperfusion (I/R) injury. The primary injury is the initial disruption of blood flow and ischemic state while the secondary injury, paradoxically, being the return of blood flow and oxygen availability. The injury caused by reperfusion presents a viable window for therapeutic intervention, stressing the importance of understanding this injury pathology. Constantly undergoing fission and fusion, mitochondria are dynamic organelles that play a vital role in maintaining cell health and are highly susceptible to I/R injury. Following I/R injury, disrupted mitochondrial dynamics and quality control ultimately lead to a dysfunctional mitochondrial network, energy depletion and eventually cell death. While mitochondrial dynamics and quality control have been studied extensively in the realm of I/R injuries, the role of mitochondrial lipids is emerging as an important component of injury progression. The inner mitochondrial membrane lipid, cardiolipin has been demonstrated to play an integral role in maintaining mitochondrial quality control, dynamics and energy production. In response to oxidative stress, cardiolipin has been shown to interact with several important proteins involved in mitochondrial dynamics while also contributing to integral signaling cascades. This review will highlight the role of cardiolipin in mitochondrial dynamics and quality control in response to neuronal I/R injury.

DOI: https://doi.org/10.1038/s41419-025-07786-8