bims-medebr 2024-12-29 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–12–29
thirteen papers selected by
Regina F. Fernández, Johns Hopkins University

Brain energy homeostasis: the evolution of the astrocyte-neuron lactate shuttle hypothesis.
Brain glucose metabolism: Role of nitric oxide.
Dysregulation of brain cholesterol biosynthetic pathway following hypoxia-ischemia in neonatal mice.
Effects of Aging on Glucose and Lipid Metabolism in Mice.
Instationary metabolic flux analysis reveals that NPC1 inhibition increases glycolysis and decreases mitochondrial metabolism in brain microvascular endothelial cells.
Lactate: Beyond a Mere Fuel in the Epileptic Brain.
PKM2 is a key factor to regulate neurogenesis and cognition by controlling lactate homeostasis.
BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson's disease.
Opposite Roles of Cholesterol and Lanosterol in Lipid Membrane on Amyloid-Beta 42 Peptide Nucleation and Fibril Formation.
White matter lipidome alterations in the schizophrenia brain.
Brain region and sex-dependent heterogeneity of PUFA/oxylipin profile, microglia morphology and their relationship.
Increased White Matter Aerobic Glycolysis in Multiple Sclerosis.
Mitochondrial-targeted therapies in traumatic brain injury: From bench to bedside.

Korean J Physiol Pharmacol. 2025 Jan 01. 29(1): 1-8

Brain energy homeostasis: the evolution of the astrocyte-neuron lactate shuttle hypothesis.

Yihyang Kim, Solomon Ergando Dube, Chan Bae Park.

  The brain's substantial metabolic requirements, consuming a substantial fraction of the body's total energy despite its relatively small mass, necessitate sophisticated metabolic mechanisms for efficient energy distribution and utilization. The astrocyte-neuron lactate shuttle (ANLS) hypothesis has emerged as a fundamental framework explaining the metabolic cooperation between astrocytes and neurons, whereby astrocyte-derived lactate serves as a crucial energy substrate for neurons. This review synthesizes current understanding of brain energy metabolism, focusing on the dual roles of lactate as both an energy substrate and a signaling molecule. We examine the molecular underpinnings of metabolic compartmentalization, particularly the differential expression of lactate dehydrogenase (LDH) isozymes between astrocytes and neurons, which facilitates directional lactate flux. Recent evidence has challenged aspects of the classical ANLS model, revealing greater metabolic flexibility in neurons than previously recognized, including substantial LDHA expression and direct glucose utilization capabilities. Our recent studies on LDHB-deficient neurons provide new insights into the compensatory mechanisms and limitations of neuronal lactate metabolism, suggesting a more nuanced understanding of the ANLS hypothesis. Furthermore, we discuss lactate's emerging role as a signaling molecule in synaptic plasticity, memory formation, and neuroprotection, particularly in ischemic conditions where elevated lactate levels correlate with enhanced neuronal survival through prostaglandin E2-mediated vasodilation. This comprehensive review integrates classical perspectives with recent advances, providing an updated framework for understanding brain lactate metabolism and its therapeutic implications in neurological disorders.

Keywords:  Brain; Energy metabolism; L-lactate dehydrogenase; Lactic acid; Neuron

DOI:  https://doi.org/10.4196/kjpp.24.388
Biochem Pharmacol. 2024 Dec 19. pii: S0006-2952(24)00729-9. [Epub ahead of print] 116728

Brain glucose metabolism: Role of nitric oxide.

Asghar Ghasemi, Sajad Jeddi, Khosrow Kashfi.

  One possible reason for failure in achieving optimal glycemic control in patients with type 2 diabetes (T2D) is that less attention has been paid to the brain, a fundamental player in glucose homeostasis, that consumes about 25% of total glucose utilization. In addition, animal and human studies indicate that nitric oxide (NO) is a critical player in glucose metabolism. NO synthesis from L-arginine is lower in patients with T2D, and endothelial NO synthase (eNOS)-derived NO bioavailability is lower in T2D. NO in the nervous system plays a role in neurovascular coupling (NVC) and the hypothalamic control of glucose sensing and energy homeostasis, influencing glucose utilization. This review explores NO's role in the brain's glucose metabolism. Literature indicates that glucose metabolism is different between neurons and astrocytes. Unlike neurons, astrocytes have a higher rate of glycolysis and a greater ability for lactate production. Astrocytes produce a greater amount of NO than neurons. NO inhibits mitochondrial respiration in both neurons and astrocytes and decreases intracellular ATP. NO-induced inhibition of mitochondrial respiration in neurons is not accompanied by compensatory glycolysis because phosphofructokinase 2.3 (PFK2.3), the most potent activator of PFK1 and thus glycolysis, is subjected to ubiquitylation and proteasomal degradation by cadherin-1 (Cdh1)-activated anaphase-promoting complex/cyclosome (APC/C), which leads to a low glycolytic rate in neurons. In astrocytes, NO inhibits mitochondrial respiration, but astrocytes display compensatory glycolysis by activating the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway.

Keywords:  Astrocytes; Brain; Glucose; Neurons; Nitric oxide; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.bcp.2024.116728
Dev Neurosci. 2024 Dec 20. 1-24

Dysregulation of brain cholesterol biosynthetic pathway following hypoxia-ischemia in neonatal mice.

Fuxin Lu, Celeste Yen, Chase D Corley, Jeffrey G McDonald, Tiina Manninen, Nicholas R Stewart, Christina M Zhu, Donna M Ferriero, Xiangning Jiang.

INTRODUCTION: Brain cholesterol relies on de novo biosynthesis and is crucial for brain development. Cholesterol synthesis is a complex series of reactions that involves more than twenty enzymes to reach the final product and generates a large number of intermediate sterols along two alternate pathways. This is a highly regulated and oxygen-dependent process, and thus sensitive to hypoxia.
METHODS: Using the modified Vannucci procedure, a clinically relevant animal model of neonatal hypoxia-ischemia (HI), we characterized the profile of cholesterol and its sterol intermediates, along with the key enzymes on the cholesterol synthetic pathway over a time course of 5 days after HI in the postnatal day 10 mouse brain.
RESULTS: Although the total cholesterol levels in the injured cortices appeared to be minimally attenuated at 5 days following HI, there was an overall repression of brain cholesterol biosynthesis. Lanosterol and the downstream sterols in both the Bloch and Kandutsch-Russell (K-R) pathways were consistently reduced for up to 3 days except for desmosterol which was elevated. Correspondingly, protein expression of the controlling transcription factors sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1 was decreased at early time points (within 6 hours), in parallel with the downregulation of several substrate enzymes for up to 5 days post-HI. HMG-CoA reductase (HMGCR), the first rate-limiting enzyme, was upregulated in the first 24 hours after HI. The expression of 24-dehydrocholesterol reductase (DHCR24) that catalyzes the last step to produce cholesterol on the Bloch pathway and bridges the Bloch to K-R pathway was also augmented.
CONCLUSIONS: Our data suggest perturbed brain cholesterol biosynthesis following neonatal HI. As some sterol intermediates and enzymes have diverse functions in brain development and stress responses other than producing cholesterol, assessment of their dynamic changes after HI is important to understand the lipid responses in rodent HI models and to identify lipid-based targeted therapies in future studies.

DOI: https://doi.org/10.1159/000543254
Aging Cell. 2024 Dec 27. e14462

Effects of Aging on Glucose and Lipid Metabolism in Mice.

Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.

  Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.

Keywords:  NAD; aging; metabolic rate; mice

DOI:  https://doi.org/10.1111/acel.14462
Neurobiol Dis. 2024 Dec 18. pii: S0969-9961(24)00371-1. [Epub ahead of print]204 106769

Instationary metabolic flux analysis reveals that NPC1 inhibition increases glycolysis and decreases mitochondrial metabolism in brain microvascular endothelial cells.

Bilal Moiz, Matthew Walls, Viviana Alpizar Vargas, Anirudh Addepalli, Callie Weber, Andrew Li, Ganesh Sriram, Alisa Morss Clyne.

  Niemann Pick Disease Type C (NP-C), a rare neurogenetic disease with no known cure, is caused by mutations in the cholesterol trafficking protein NPC1. Brain microvascular endothelial cells (BMEC) are thought to play a critical role in the pathogenesis of several neurodegenerative diseases; however, little is known about how these cells are altered in NP-C. In this study, we investigated how NPC1 inhibition perturbs BMEC metabolism in human induced pluripotent stem cell-derived BMEC (hiBMEC). We incorporated extracellular metabolite and isotope labeling data into an instationary metabolic flux analysis (INST-MFA) model to estimate intracellular metabolic fluxes. We found that NPC1 inhibition significantly increased glycolysis and pentose phosphate pathway flux while decreasing mitochondrial metabolism. These changes may have been driven by gene expression changes due to increased cholesterol biosynthesis, in addition to mitochondrial cholesterol accumulation. We corroborated these findings in primary BMEC, an alternative in vitro human brain endothelial model. Finally, we found that co-treatment with hydroxypropyl-β cyclodextrin (HPβCD) partially restored metabolic phenotype in U18666A-treated BMECs, suggesting that this drug may have therapeutic effects on the brain endothelium in NP-C. Together, our data highlight the importance of NPC1 in BMEC metabolism and implicate brain endothelial dysfunction in NP-C pathogenesis.

Keywords:  Blood-brain barrier; Endothelial cells; Glycolysis; Metabolic flux analysis; Metabolism; NPC1; Niemann-pick disease type C; Oxidative respiration; Systems biology

DOI:  https://doi.org/10.1016/j.nbd.2024.106769
Neuropharmacology. 2024 Dec 22. pii: S0028-3908(24)00442-8. [Epub ahead of print] 110273

Lactate: Beyond a Mere Fuel in the Epileptic Brain.

Xiang Chen, Xinjian Zhu.

  Epilepsy, a prevalent neurological disorder characterized by spontaneous recurrent seizures, significantly impacts physiological and cognitive functions. Emerging evidence suggests a crucial role for metabolic factors, particularly lactate, in epilepsy. We discuss the applicability of the Astrocyte-Neuron Lactate Shuttle (ANLS) model during acute seizure events and examine lactate's metabolic adaptation in epilepsy progression. Additionally, the roles of lactate metabolism in microglia and oligodendrocytes are considered, aiming to supplement our understanding of neuro-glial metabolic interactions as extensions of the ANLS model. Additionally, lactate modulates neuronal excitability via its interaction with hydroxycarboxylic acid receptor 1 (HCAR1), alongside additional mechanisms involving acid-sensing ion channels (ASICs) and ATP-sensitive potassium (KATP) channels, which contribute as secondary modulatory pathways. In conclusion, we propose that lactate functions as more than a mere fuel source in the epileptic brain, offering potential insights into new therapeutic targets for seizure control.

Keywords:  Astrocyte-Neuron Lactate Shuttle; Epilepsy; Hydroxycarboxylic Acid Receptor 1; Lactate Metabolism; Neuronal Excitability

DOI:  https://doi.org/10.1016/j.neuropharm.2024.110273
Stem Cell Reports. 2024 Dec 12. pii: S2213-6711(24)00325-4. [Epub ahead of print] 102381

PKM2 is a key factor to regulate neurogenesis and cognition by controlling lactate homeostasis.

Pengyan He, Bingjun Zhang, Wei Jiang, Fan Zhu, Ziqi Liang, Lin Gao, Yuhong Zhang, Yuge Wang, Caixia Wu, Changyong Tang.

  Adult hippocampal neurogenesis (AHN), the process of generating new neurons from adult neural stem/progenitor cells (NSPCs), is crucial for cognitive functions and is influenced by numerous factors, including metabolic processes. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, catalyzes the production of pyruvate, which undergoes either oxidative phosphorylation or anaerobic oxidation. We observed that PKM2 is highly expressed in NSPCs, but its significance remains unclear for AHN and cognition. Using knockdown or knockout strategies, we discovered that PKM2 deficiency led to reduced AHN and impaired cognitive functions. Furthermore, we observed that knockout of PKM2 resulted in lower L-lactate levels, and supplementing L-lactate in PKM2 knockout mice improved AHN and cognitive functions. Mechanistically, L-lactate restored neurogenesis via monocarboxylate transporter 2 (MCT2), but not hydroxycarboxylic acid receptor 1. In summary, our findings demonstrate that PKM2 is essential for AHN, and lactate supplementation can restore neurogenesis in an MCT2-dependent manner.

Keywords:  PKM2; cognitive function; lactate homeostasis; neural stem cells

DOI:  https://doi.org/10.1016/j.stemcr.2024.11.011
Acta Neuropathol Commun. 2024 Dec 21. 12(1): 198

BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson's disease.

Aya Jishi, Di Hu, Yutong Shang, Rihua Wang, Steven A Gunzler, Xin Qi.

Mitochondrial dysfunction and α-synuclein (αSyn) aggregation are key contributors to Parkinson's Disease (PD). While genetic and environmental risk factors, including mutations in mitochondrial-associated genes, are implicated in PD, the precise mechanisms linking mitochondrial defects to αSyn pathology remain incompletely understood, hindering the development of effective therapeutic interventions. Here, we identify the loss of branched chain ketoacid dehydrogenase kinase (BCKDK) as a mitochondrial risk factor that exacerbates αSyn pathology by disrupting Complex I function. Our findings reveal a consistent downregulation of BCKDK in dopaminergic (DA) neurons from A53T-αSyn mouse models, PD patient-derived induced pluripotent stem (iPS) cells, and postmortem brain tissues. BCKDK deficiency leads to mitochondrial dysfunction, including reduced membrane potential and increased reactive oxygen species (ROS) production upon administration of a stressor, which in turn promotes αSyn oligomerization. Mechanistically, BCKDK interacts with the NDUFS1 subunit of Complex I to stabilize its function. Loss of BCKDK disrupts this interaction, leading to Complex I destabilization and enhanced αSyn aggregation. Notably, restoring BCKDK expression in neuron-like cells rescues mitochondrial integrity and restores Complex I activity. Similarly, in patient-derived iPS cells differentiated to form dopaminergic neurons, NDUFS1 and phosphorylated aSyn levels are partially restored upon BCKDK expression. These findings establish a mechanistic link between BCKDK deficiency, mitochondrial dysfunction, and αSyn pathology in PD, positioning BCKDK as a potential therapeutic target to mitigate mitochondrial impairment and neurodegeneration in PD.

DOI: https://doi.org/10.1186/s40478-024-01915-8
ACS Chem Neurosci. 2024 Dec 21.

Opposite Roles of Cholesterol and Lanosterol in Lipid Membrane on Amyloid-Beta 42 Peptide Nucleation and Fibril Formation.

Kyohei Akiho, Akane Iida-Adachi, Hideki Nabika.

  Molecular self-assembly of amyloid-beta peptides to form fibrillar aggregates is a known cause of Alzheimer's disease. Although homogeneous nucleation of amyloid-beta is unfavorable, heterogeneous nucleation of amyloid-beta in cell membranes plays a key role in fibril formation. We observed these opposite roles in the effects of cholesterol and lanosterol, the precursor of cholesterol in the brain, on nucleation. As previously reported, cholesterol accelerated nucleation, whereas lanosterol decelerated it when mixed with dioleoyl-phosphatidylcholine at 20%. The observed opposite effects of cholesterol and lanosterol on nucleation do not correlate with the differences in the mechanical and thermodynamic nature of mixed membranes. However, the affinity of amyloid-beta to the inner membrane seems to be related to the opposite effects on nucleation kinetics. Cholesterol reduced the insertion of amyloid-beta into the lipid membrane, whereas lanosterol promoted the insertion of amyloid-beta into the membrane, which would make amyloid-beta more tightly bound by lipid molecules and reduce its diffusivity in the membrane and consequently inhibit nucleation. Our study provides insights into the effects of sterol compounds other than the well-investigated cholesterol on the self-assembly of amyloid-beta to clarify the molecular basis underlying Alzheimer's disease pathology and to develop targeted therapeutic strategies.

Keywords:  Alzheimer’s disease; amyloid-beta peptides; cholesterol; fibril formation; lanosterol; nucleation

DOI:  https://doi.org/10.1021/acschemneuro.4c00707
Schizophrenia (Heidelb). 2024 Dec 26. 10(1): 123

White matter lipidome alterations in the schizophrenia brain.

Dmitry Senko, Olga Efimova, Maria Osetrova, Nikolay Anikanov, Maria Boyko, Maksim Sharaev, Anna Morozova, Yana Zorkina, Maksim Kislov, Georgiy Kostyuk, Elena Stekolshchikova, Philipp Khaitovich.

Numerous brain imaging studies have reported white matter alterations in schizophrenia, but the lipidome analysis of the corresponding tissue remains incomplete. In this study, we investigated the lipidome composition of six subcortical white matter regions corresponding to major axonal tracks in both control subjects and schizophrenia patients. All six regions exhibited a consistent pattern of quantitative lipidome alterations in schizophrenia, involving myelin-forming and mitochondria associated lipid classes. While alteration levels of myelin-forming lipids, particularly sphingolipids, aligned with the extent of the myelin changes reported in structural brain imaging studies, a significant decrease of mitochondria in the white matter, indicated by the lipidome alterations, was not previously investigated. To verify this effect, we performed lipidome analysis in a larger set of individuals and in the mitochondria-enriched membrane fraction, as well as directly quantified mitochondrial content. Our results suggest a substantial reduction of the mitochondrial quotient accompanied by the imbalance in myelin lipids in schizophrenia white matter.

DOI: https://doi.org/10.1038/s41537-024-00542-5
Prostaglandins Leukot Essent Fatty Acids. 2024 Dec 16. pii: S0952-3278(24)00056-5. [Epub ahead of print]204 102662

Brain region and sex-dependent heterogeneity of PUFA/oxylipin profile, microglia morphology and their relationship.

J Geertsema, M A Franßen, F Barban, L Šarauskytė, M Giera, G Kooij, A Korosi.

  Lipid dyshomeostasis and neuroinflammation are key hallmarks of neuropsychiatric and neurodegenerative disorders, including major depressive disorder and Alzheimer's disease. In particular, polyunsaturated fatty acids (PUFAs) and their derivatives called oxylipins gained specific interest in this context, especially considering their capacity to orchestrate neuroinflammatory responses via direct modulation of microglia. The hippocampus and hypothalamus are crucial brain regions for regulating mood and cognition that are implicated in a variety of neuropsychiatric and neurodegenerative disorders and there is ample evidence for the sex-bias in risks for the development as well as sex-bias in the presentation of such psychiatric diseases, including the neuroinflammatory response. To better understand the local PUFA/oxylipin profiles and microglia responses in disease, we here assessed their brain region and sex-dependent profiles in homeostatic brains. In 2-month-old male and female mice, we measured non-esterified (free) PUFA/oxylipin profiles using liquid chromatography-tandem mass spectrometry and characterized microglia morphology via immunohistochemistry. The hypothalamus and hippocampus exhibit a different free PUFA/oxylipin profile, independent of sex. The hippocampus was characterized by a higher density of complex Iba1+ microglial cells than the hypothalamus, without sex effects. Hypothalamic microglial morphology correlated more strongly with free PUFA- and oxylipin species than hippocampal microglia, correlating with species from both the N-3 and N-6 PUFA metabolization pathways, while hippocampal microglial parameters correlated only with N-6 pathway-related species. Our findings provide a basis for future studies to investigate the relationship between PUFAs, their derivatives and neuroinflammation in the context of diseases.

Keywords:  Hippocampus; Hypothalamus; Microglia; Oxylipins; PUFA

DOI:  https://doi.org/10.1016/j.plefa.2024.102662
Ann Neurol. 2024 Dec 23.

Increased White Matter Aerobic Glycolysis in Multiple Sclerosis.

Matthew R Brier, Bradley Judge, Chunwei Ying, Amber Salter, Hongyu An, Aakash Patel, Qing Wang, Yong Wang, Anne H Cross, Robert T Naismith, Tammie Ls Benzinger, Manu S Goyal.

OBJECTIVE: Despite treatments which reduce relapses in multiple sclerosis (MS), many patients continue to experience progressive disability accumulation. MS is associated with metabolic disruptions and cerebral metabolic stress predisposes to tissue injury and possibly impaired remyelination. Additionally, myelin homeostasis is metabolically expensive and reliant on glycolysis. We investigated cerebral metabolic changes in MS and when in the disease course they occurred, and assessed their relationship with microstructural changes.
METHODS: This study used combined fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) to measure cerebral metabolic rate of glucose and oxygen, thereby quantifying glycolysis. Twelve healthy controls, 20 patients with relapsing MS, and 13 patients with non-relapsing MS were studied. Relapsing patients with MS were treatment naïve and scanned pre- and post-initiation of high efficacy disease modifying therapy.
RESULTS: In normal appearing white matter, we observed increased glucose utilization and reduced oxygen utilization in newly diagnosed MS, consistent with increased glycolysis. Increased glycolysis was greater in patients with a longer disease duration course and higher disability. Among newly diagnosed patients, different treatments had differential impacts on glucose utilization. Last, whereas hypermetabolism within lesions was clearly associated with inflammation, no such relationship was found within normal appearing white matter.
INTERPRETATION: Increased white matter glycolysis is a prominent feature of cerebral metabolism in MS. It begins early in the disease course, increases with disease duration and is independent of microstructural evidence of inflammation in normal appearing white matter. Optimization of the metabolic environment may be an important component of therapies designed to reduce progressive disability. ANN NEUROL 2024.

DOI: https://doi.org/10.1002/ana.27165
Neurotherapeutics. 2024 Dec 24. pii: S1878-7479(24)00202-2. [Epub ahead of print] e00515

Mitochondrial-targeted therapies in traumatic brain injury: From bench to bedside.

Sidra Tabassum, Silin Wu, Chang-Hun Lee, Bosco Seong Kyu Yang, Aaron M Gusdon, Huimahn A Choi, Xuefang S Ren.

  Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with limited effective therapeutic options currently available. Recent research has highlighted the pivotal role of mitochondrial dysfunction in the pathophysiology of TBI, making mitochondria an attractive target for therapeutic intervention. This review comprehensively examines advancements in mitochondrial-targeted therapies for TBI, bridging the gap from basic research to clinical applications. We discuss the underlying mechanisms of mitochondrial damage in TBI, including oxidative stress, impaired bioenergetics, mitochondrial dynamics, and apoptotic pathways. Furthermore, we highlight the complex interplay between mitochondrial dysfunction, inflammation, and blood-brain barrier (BBB) integrity, elucidating how these interactions exacerbate injury and impede recovery. We also evaluate various preclinical studies exploring pharmacological agents, gene therapy, and novel drug delivery systems designed to protect and restore mitochondrial function. Clinical trials and their outcomes are assessed to evaluate the translational potential of mitochondrial-targeted therapies in TBI. By integrating findings from bench to bedside, this review emphasizes promising therapeutic avenues and addresses remaining challenges. It also provides guidance for future research to pave the way for innovative treatments that improve patient outcomes in TBI.

Keywords:  Mitochondrial dysfunction; Novel drug delivery system; Therapeutic interventions; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.neurot.2024.e00515