bims-medebr 2024-12-22 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–12–22
twenty-six papers selected by
Regina F. Fernández, Johns Hopkins University

Role of Fatty Acids β-Oxidation in the Metabolic Interactions Between Organs.
Aging promotes an increase in mitochondrial fragmentation in astrocytes.
Multinuclear MRI Can Depict Metabolic and Energetic Changes in Mild Traumatic Brain Injury.
Brain glucose metabolism as a neuronal substrate of the abnormal behavioral response to stress in the mdx mouse, a model of Duchenne muscular dystrophy.
Intermittent fasting and neurodegenerative diseases: Molecular mechanisms and therapeutic potential.
Altered lipid profile and reduced neuronal support in human induced pluripotent stem cell-derived astrocytes from adrenoleukodystrophy patients.
The possible antioxidative effects of ketogenic diet by modifying brain klotho expression: a rat model study.
Increased ROS levels, antioxidant defense disturbances and bioenergetic disruption induced by thiosulfate administration in the brain of neonatal rats.
Omega-3 Fatty Acids and Traumatic Injury in the Adult and Immature Brain.
Astrocyte neuronal metabolic coupling in the anterior cingulate cortex of mice with inflammatory pain.
Metabolic reprogramming of astrocytes: emerging roles of lactate.
Diacylglycerol Kinases and Its Role in Lipid Metabolism and Related Diseases.
Lipids: Emerging Players of Microglial Biology.
Evolution of Lipid Metabolism in the Injured Mouse Spinal Cord.
Exploring the Role of SMPD3 in the lncRNA-miRNA-mRNA Regulatory Network in TBI Progression by Influencing Energy Metabolism.
Prohibitin 1 tethers lipid membranes and regulates OPA1-mediated membrane fusion.
Dynamic mitophagy trajectories hallmark brain aging.
Therapeutic Efficacy of a Synthetic Brain-Targeted H2S Donor Cross-Linked Nanomicelle in Autism Spectrum Disorder Rats through Aerobic Glycolysis.
Validation and Optimization of a Stable Isotope-Labeled Substrate Assay for Measuring AGAT Activity.
Targeting mitochondrial dynamics: A promising approach for intracerebral hemorrhage therapy.
Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50.
(Re)building the nervous system: A review of neuron-glia interactions from development to disease.
Fundamental Neurochemistry Review: Lipids across microglial states.
Altered metabolic function induced by Aβ-oligomers and PSEN1 mutations in iPSC-derived astrocytes.
Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
Carnitine supplementation in progressive supranuclear palsy.

Int J Mol Sci. 2024 Nov 27. pii: 12740. [Epub ahead of print]25(23):

Role of Fatty Acids β-Oxidation in the Metabolic Interactions Between Organs.

Alexander V Panov, Vladimir I Mayorov, Sergey I Dikalov.

  In recent decades, several discoveries have been made that force us to reconsider old ideas about mitochondria and energy metabolism in the light of these discoveries. In this review, we discuss metabolic interaction between various organs, the metabolic significance of the primary substrates and their metabolic pathways, namely aerobic glycolysis, lactate shuttling, and fatty acids β-oxidation. We rely on the new ideas about the supramolecular structure of the mitochondrial respiratory chain (respirasome), the necessity of supporting substrates for fatty acids β-oxidation, and the reverse electron transfer via succinate dehydrogenase during β-oxidation. We conclude that ATP production during fatty acid β-oxidation has its upper limits and thus cannot support high energy demands alone. Meanwhile, β-oxidation creates conditions that significantly accelerate the cycle: glucose-aerobic glycolysis-lactate-gluconeogenesis-glucose. Therefore, glycolytic ATP production becomes an important energy source in high energy demand. In addition, lactate serves as a mitochondrial substrate after converting to pyruvate + H+ by the mitochondrial lactate dehydrogenase. All coupled metabolic pathways are irreversible, and the enzymes are organized into multienzyme structures.

Keywords:  aerobic glycolysis; beta-oxidation; fatty acids; gluconeogenesis; lactate; metabolism; mitochondria; respirasome

DOI:  https://doi.org/10.3390/ijms252312740
Front Cell Neurosci. 2024 ;18 1496163

Aging promotes an increase in mitochondrial fragmentation in astrocytes.

Ana Paula Bergamo Araujo, Gabriele Vargas, Lívia de Sá Hayashide, Isadora Matias, Cherley Borba Vieira Andrade, Jorge José de Carvalho, Flávia Carvalho Alcantara Gomes, Luan Pereira Diniz.

   Introduction: Brain aging involves a complex interplay of cellular and molecular changes, including metabolic alterations and the accumulation of senescent cells. These changes frequently manifest as dysregulation in glucose metabolism and mitochondrial function, leading to reduced energy production, increased oxidative stress, and mitochondrial dysfunction-key contributors to age-related neurodegenerative diseases.
Methods: We conducted experiments on two models: young (3-4 months) and aged (over 18 months) mice, as well as cultures of senescent and control mouse astrocytes. Mitochondrial content and biogenesis were analyzed in astrocytes and neurons from aged and young animals. Cultured senescent astrocytes were examined for mitochondrial membrane potential and fragmentation. Quantitative PCR (qPCR) and immunocytochemistry were used to measure fusion- and fission-related protein levels. Additionally, transmission electron microscopy provided morphological data on mitochondria.
Results: Astrocytes and neurons from aged animals showed a significant reduction in mitochondrial content and a decrease in mitochondrial biogenesis. Senescent astrocytes in culture exhibited lower mitochondrial membrane potential and increased mitochondrial fragmentation. qPCR and immunocytochemistry analyses revealed a 68% increase in fusion-related proteins (mitofusin 1 and 2) and a 10-fold rise in DRP1, a key regulator of mitochondrial fission. Transmission electron microscopy showed reduced perimeter, area, and length-to-diameter ratio of mitochondria in astrocytes from aged mice, supported by elevated DRP1 phosphorylation in astrocytes of the cerebral cortex.
Discussion: Our findings provide novel evidence of increased mitochondrial fragmentation in astrocytes from aged animals. This study sheds light on mechanisms of astrocytic metabolic dysfunction and mitochondrial dysregulation in brain aging, highlighting mitochondrial fragmentation as a potential target for therapeutic interventions in age-related neurodegenerative diseases.

Keywords:  astrocytes; brain aging; mitochondrial biogenesis and neurodegeneration; mitochondrial dysfunction; mitochondrial fragmentation

DOI:  https://doi.org/10.3389/fncel.2024.1496163
NMR Biomed. 2025 Jan;38(1): e5306

Multinuclear MRI Can Depict Metabolic and Energetic Changes in Mild Traumatic Brain Injury.

Thomas M Thorsen, Nikolaj Bøgh, Lotte B Bertelsen, Esben S S Hansen, Christoffer Laustsen.

  Mild traumatic brain injuries (TBIs) are frequent in the European population. The pathophysiological changes after TBI include metabolic changes, but these are not observable using current clinical tools. We aimed to evaluate multinuclear MRI as a mean of assessing these changes. In our model, pigs were exposed to a controlled cortical impact (CCI) directly on the dura and scanned at 2 h and 2 days after injury. A multinuclear MRI protocol was used. It included hyperpolarized [1-13C]pyruvate MRI, which allows depiction of hyperpolarized carbon-13, through its metabolism from pyruvate to lactate or bicarbonate. At Day 2, cerebral microdialysis were performed, and tissue was obtained for analyses. At Day 0, the cerebral blood flow was reduced in the affected hemisphere (TBI: 31.7 mL/100 mL/min, contralateral: 35.6 mL/100 mL/min, p = 0.1227), and the impacted area showed reduced oxygenation (R2*, TBI: 33.11 s-1, contralateral: 22.20 s-1, p = 0.035). At both days, the lactate-to-pyruvate ratios (hyperpolarized [1-13C]pyruvate) were increased (Day 0: p = 0.023, Day 2: p = 0.022). However, this study can only evaluate the total injury and, thus, cannot differentiate effects from craniotomy and CCI. This metabolic difference was not found using cerebral microdialysis nor a lactate dehydrogenase (LDH) activity assay. The metabolic changes depicted in this study contributes to our understanding of mild TBI; however, the clinical potential of multinuclear MRI is yet to be determined.

Keywords:  MRI; TBI; lactate; metabolism; microdialysis

DOI:  https://doi.org/10.1002/nbm.5306
Neurobiol Dis. 2024 Dec 17. pii: S0969-9961(24)00373-5. [Epub ahead of print] 106771

Brain glucose metabolism as a neuronal substrate of the abnormal behavioral response to stress in the mdx mouse, a model of Duchenne muscular dystrophy.

Sébastien Goutal, Marion Lancien, François Rivier, Nicolas Tournier, Cyrille Vaillend.

  Duchenne muscular dystrophy (DMD) is associated with a range of cognitive and behavioral problems. Brain-related comorbidities show clinical heterogeneity depending on the position of the mutation within the multi-promoter dystrophin (DMD) gene, likely due to the differential impact of mutations on the expression of distinct brain dystrophins. A deficiency of the full-length brain dystrophin, Dp427, has been associated with enhanced stress reactivity, characterized by abnormal fear responses in both patients and mdx mouse model. However, the neural substrates of this phenotype are still unknown. Here, we undertook the first functional imaging study of the mdx mouse brain, following expression of the typical unconditioned fear response expressed by mdx mice after a short scruff restraint and one week later after recovery from stress. We compared the brain glucose metabolism in 12 brain structures of mdx and WT littermate male mice using [18F]FDG PET imaging. Restraint-stress induced a global decrease in [18F]FDG uptake in mdx mice, while no difference was found between genotypes when mice were tested one week later under non-stressful conditions. A subset of brain structures were particularly affected by stress in mdx mice, and we identified abnormal correlations between fear responses and metabolism in specific structures, and altered co-activation of the hypothalamus with several subcortical structures. Our data support the hypothesis that enhanced stress reactivity due to loss of brain Dp427 relies on abnormal activation of the brain fear circuit and deregulation of a hypothalamus-dependent pathway.

Keywords:  Duchenne muscular dystrophy; Dystrophin; Fear circuit; Functional brain imaging; Hypothalamus; Unconditioned fear

DOI:  https://doi.org/10.1016/j.nbd.2024.106771
Metabolism. 2024 Dec 12. pii: S0026-0495(24)00332-9. [Epub ahead of print] 156104

Intermittent fasting and neurodegenerative diseases: Molecular mechanisms and therapeutic potential.

Renjun Lv, Bin Liu, Ziying Jiang, Runfa Zhou, Xiaoxing Liu, Tangsheng Lu, Yanping Bao, Chunxia Huang, Guichang Zou, Zongyong Zhang, Lin Lu, Qingqing Yin.

  Neurodegenerative disorders are straining public health worldwide. During neurodegenerative disease progression, aberrant neuronal network activity, bioenergetic impairment, adaptive neural plasticity impairment, dysregulation of neuronal Ca2+ homeostasis, oxidative stress, and immune inflammation manifest as characteristic pathological changes in the cellular milieu of the brain. There is no drug for the treatment of neurodegenerative disorders, and therefore, strategies/treatments for the prevention or treatment of neurodegenerative disorders are urgently needed. Intermittent fasting (IF) is characterized as an eating pattern that alternates between periods of fasting and eating, requiring fasting durations that vary depending on the specific protocol implemented. During IF, depletion of liver glycogen stores leads to the production of ketone bodies from fatty acids derived from adipocytes, thereby inducing an altered metabolic state accompanied by cellular and molecular adaptive responses within neural networks in the brain. At the cellular level, adaptive responses can promote the generation of synapses and neurons. At the molecular level, IF triggers the activation of associated transcription factors, thereby eliciting the expression of protective proteins. Consequently, this regulatory process governs central and peripheral metabolism, oxidative stress, inflammation, mitochondrial function, autophagy, and the gut microbiota, all of which contribute to the amelioration of neurodegenerative disorders. Emerging evidence suggests that weight regulation significantly contributes to the neuroprotective effects of IF. By alleviating obesity-related factors such as blood-brain barrier dysfunction, neuroinflammation, and β-amyloid accumulation, IF enhances metabolic flexibility and insulin sensitivity, further supporting its potential in mitigating neurodegenerative disorders. The present review summarizes animal and human studies investigating the role and underlying mechanisms of IF in physiology and pathology, with an emphasis on its therapeutic potential. Furthermore, we provide an overview of the cellular and molecular mechanisms involved in regulating brain energy metabolism through IF, highlighting its potential applications in neurodegenerative disorders. Ultimately, our findings offer novel insights into the preventive and therapeutic applications of IF for neurodegenerative disorders.

Keywords:  Brain metabolism; Brain-related diseases; Cognition; Intermittent fasting; Ketone bodies; Neurodegeneration

DOI:  https://doi.org/10.1016/j.metabol.2024.156104
J Inherit Metab Dis. 2025 Jan;48(1): e12832

Altered lipid profile and reduced neuronal support in human induced pluripotent stem cell-derived astrocytes from adrenoleukodystrophy patients.

Roberto Montoro Ferrer, Yorrick R J Jaspers, Inge M E Dijkstra, Nicole Breeuwsma, Jan-Bert van Klinken, Cato Romero, Marc Engelen, Stephan Kemp, Vivi M Heine.

  X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder resulting from pathogenic variants in the ABCD1 gene that primarily affects the nervous system and is characterized by progressive axonal degeneration in the spinal cord and peripheral nerves and leukodystrophy. Dysfunction of peroxisomal very long-chain fatty acid (VLCFA) degradation has been implicated in ALD pathology, but the impact on astrocytes, which critically support neuronal function, remains poorly understood. Fibroblasts from four ALD patients were reprogrammed to generate human-induced pluripotent stem cells (hiPSC). hiPSC-derived astrocytes were generated to study the impact of ALD on astrocytic fatty acid homeostasis. Our study reveals significant changes in the lipidome of ALD hiPSC-derived astrocytes, characterized by an enrichment of VLCFAs across multiple lipid classes, including triacylglycerols, cholesteryl esters, and phosphatidylcholines. Importantly, ALD hiPSC-derived astrocytes not only exhibit intrinsic lipid dysregulation but also affect the dendritic tree complexity of neurons in co-culture systems. These findings highlight the cell-autonomous effects of pathogenic variants in the ABCD1 protein on astrocytes and their microenvironment, shed light on potential mechanisms underlying ALD neuropathology, and underscore the critical role of astrocytes in neuronal health.

Keywords:  ABCD1 gene; X‐linked adrenoleukodystrophy; astrocytes; human‐induced pluripotent stem cells; lipid homeostasis; peroxisome

DOI:  https://doi.org/10.1002/jimd.12832
Nutr Neurosci. 2024 Dec 15. 1-7

The possible antioxidative effects of ketogenic diet by modifying brain klotho expression: a rat model study.

Nasrin Ranjbar, Bahador Ebrahimi Behnam, Mehran Mesgari Abbasi, Mahsa Esmaeili, Fatemeh Jolfaei, Jamal Mohammadian, Nadereh Rashtchizadeh, Amir Ghorbanihaghjo, Sina Raeisi.

  Objectives: The ketogenic diet (KD) has long been used as an alternative nonpharmacological therapy to manage pharmacoresistant epilepsy. The anticonvulsant mechanisms of KD have yet to be fully elucidated. The present study explored whether a KD could exert antioxidative effects by altering brain Klotho (Kl) gene expression.Methods: Thirty male rats were divided into three groups: the normal diet (ND) group received standard rat chow; the calorie-restricted diet (CRD) group was maintained at 90% of the calculated energy need; and the KD group received a diet composed of 8% protein, 2% carbohydrates, and 90% fat (per calorie macronutrient). The levels of β-hydroxybutyrate (BHB) in the serum, Kl gene expression in the brain, and Kl protein, malondialdehyde (MDA), and protein carbonyl (PC) levels in the serum and brain were evaluated by standard methods.Results: The serum BHB levels in the KD group were significantly greater than those in the ND and CRD groups (p < 0.001). The Kl expression in the brain was significantly greater in the KD group than in the ND group (p = 0.028). The brain MDA levels in the KD group were significantly lower than those in the ND group (p = 0.006). Elevated BHB was positively correlated with brain Kl expression (r = 0.668, p < 0.001). The brain MDA levels were negatively correlated with brain Kl expression (r = -0.531, p = 0.003) and serum BHB levels (r = 0.472, p = 0.020).Discussion: KD might exert antioxidative effects by increasing BHB and upregulating Kl in the brain. This could be considered a possible anticonvulsant mechanism of KD.

Keywords:  Animal model; epilepsy; ketogenic diet; klotho; oxidative stress

DOI:  https://doi.org/10.1080/1028415X.2024.2436817
Metab Brain Dis. 2024 Dec 20. 40(1): 73

Increased ROS levels, antioxidant defense disturbances and bioenergetic disruption induced by thiosulfate administration in the brain of neonatal rats.

Nícolas Manzke Glänzel, Nevton Teixeira da Rosa-Junior, Marian F Signori, Josyane de Andrade Silveira, Camila Vieira Pinheiro, Manuela Bianchin Marcuzzo, Cristina Campos-Carraro, Alex Sander da Rosa Araujo, Helgi B Schiöth, Moacir Wajner, Guilhian Leipnitz.

  Sulfite oxidase deficiencies, either caused by deficiency of the apoenzyme or the molybdenum cofactor, and ethylmalonic encephalopathy are inherited disorders that impact sulfur metabolism. These patients present with severe neurodeterioration accompanied by cerebral cortex and cerebellum abnormalities, and high thiosulfate levels in plasma and tissues, including the brain. We aimed to clarify the mechanisms of such abnormalities, so we assessed the ex vivo effects of thiosulfate administration on energetic status and oxidative stress markers in cortical and cerebellar tissues of newborn rats. Thiosulfate (0.5 µmol/g) or PBS (vehicle) was injected into the fourth ventricle of rat pups. Thirty minutes after the injection, animals were euthanized and the brain structures were utilized for the experiments. Our data showed that thiosulfate decreased the reduced glutathione (GSH) concentrations, and superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) activities in the cortical structure. Thiosulfate also increased DCFH oxidation, hydrogen peroxide generation and glutathione reductase activity. In the cerebellum, thiosulfate reduced SOD and glutathione peroxidase activities but increased GST and CAT activities as well as DCFH oxidation. Regarding energy metabolism, thiosulfate specifically decreased complex IV activity in the cortex, whereas it increased cerebellar complex I and creatine kinase activities, indicating bioenergetic disturbances. The results suggest that the accumulation of thiosulfate causing redox disruption and bioenergetic alterations has a prominent role in the pathogenesis of sulfur metabolism deficiencies.

Keywords:  Antioxidant defenses; Cerebellum; Cerebral cortex; Energy metabolism; Neonatal rats; Oxidative stress; Thiosulfate

DOI:  https://doi.org/10.1007/s11011-024-01510-9
Nutrients. 2024 Nov 30. pii: 4175. [Epub ahead of print]16(23):

Omega-3 Fatty Acids and Traumatic Injury in the Adult and Immature Brain.

Ester Valero-Hernandez, Jordi L Tremoleda, Adina T Michael-Titus.

  Background/Objectives: Traumatic brain injury (TBI) can lead to substantial disability and health loss. Despite its importance and impact worldwide, no treatment options are currently available to help protect or preserve brain structure and function following injury. In this review, we discuss the potential benefits of using omega-3 polyunsaturated fatty acids (O3 PUFAs) as therapeutic agents in the context of TBI in the paediatric and adult populations. Methods: Preclinical and clinical research reports investigating the effects of O3 PUFA-based interventions on the consequences of TBI were retrieved and reviewed, and the evidence presented and discussed. Results: A range of animal models of TBI, types of injury, and O3 PUFA dosing regimens and administration protocols have been used in different strategies to investigate the effects of O3 PUFAs in TBI. Most evidence comes from preclinical studies, with limited clinical data available thus far. Overall, research indicates that high O3 PUFA levels help lessen the harmful effects of TBI by reducing tissue damage and cell loss, decreasing associated neuroinflammation and the immune response, which in turn moderates the severity of the associated neurological dysfunction. Conclusions: Data from the studies reviewed here indicate that O3 PUFAs could substantially alleviate the impact of traumatic injuries in the central nervous system, protect structure and help restore function in both the immature and adult brains.

Keywords:  docosahexaenoic acid; eicosapentaenoic acid; neuroprotection; omega-3 polyunsaturated fatty acids; traumatic brain injury

DOI:  https://doi.org/10.3390/nu16234175
Brain Behav Immun. 2024 Dec 16. pii: S0889-1591(24)00751-7. [Epub ahead of print]

Astrocyte neuronal metabolic coupling in the anterior cingulate cortex of mice with inflammatory pain.

Paige Reid, Kaitlin Scherer, Danielle Halasz, Ana Leticia Simal, James Tang, Fariya Zaheer, Jaime Tuling, Gabriel Levine, Jana Michaud, Andrea L Clark, Giannina Descalzi.

  Chronic pain is a major global concern, with at least 1 in 5 people suffering from chronic pain worldwide. Mounting evidence indicates that neuroplasticity of the anterior cingulate cortex (ACC) is a critical step in the development of chronic pain. Previously, we found that chronic pain and fear learning are both associated with enhanced neuronal excitability and cause similar neuroplasticity-related gene expression changes in the ACC of male mice. However, neuroplasticity, imposes large metabolic demands. In the brain, neurons have the highest energy needs and interact with astrocytes, which extract glucose from blood, mobilize glycogen, and release lactate in response to neuronal activity. Here, we use chronic and continuous inflammatory pain models in female and male mice to investigate the involvement of astrocyte-neuronal lactate shuttling (ANLS) in the ACC of female and male mice experiencing inflammatory pain. We found that ANLS in the mouse ACC promotes the development of chronic inflammatory pain, and expresses sex specific patterns of activation. Specifically, whereas both male and female mice show similar levels of chronic pain hypersensitivity, only male mice show sustained increases in lactate levels. Accordingly, chronic pain alters the expression levels of proteins involved in lactate metabolism and shuttling in a sexually dimorphic manner. We found that disrupting astrocyte-neuronal lactate shuttling in the ACC prior to inflammatory injury prevents the development of pain hypersensitivity in female and male mice, but only reduces temporary pain in male mice. Furthermore, using a transgenic mouse model (itga1-null mice) that displays a naturally occurring form of spontaneous osteoarthritis (OA), a painful inflammatory pain condition, we found that whereas both female and male mice develop OA, only male mice show increases in mechanisms involved in astrocyte-neuronal lactate shuttling. Our findings thus indicate that there are sex differences in astrocyte-neuronal metabolic coupling in the mouse ACC during chronic pain development.

Keywords:  ACC; ANLS; Astrocyte-neuronal lactate shuttle; CFA; Cingulate cortex; Inflammatory pain; Mouse models; Osteoarthritis; Sex differences

DOI:  https://doi.org/10.1016/j.bbi.2024.12.025
Neural Regen Res. 2024 Dec 16.

Metabolic reprogramming of astrocytes: emerging roles of lactate.

Zeyu Liu, Yijian Guo, Ying Zhang, Yulei Gao, Bin Ning.

ABSTRACT: Lactate serves as a key energy metabolite in the central nervous system, facilitating essential brain functions, including energy supply, signaling, and epigenetic modulation. Moreover, it links epigenetic modifications with metabolic reprogramming. Nonetheless, the specific mechanisms and roles of this connection in astrocytes remain unclear. Therefore, this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system. The close relationship between epigenetic modifications and metabolic reprogramming was discussed. Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases. In the nervous system, lactate plays an essential role. However, its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation. The involvement of lactate in epigenetic modifications is currently a hot research topic, especially in lactylation modification, a key determinant in this process. Lactate also indirectly regulates various epigenetic modifications, such as N6-methyladenosine, acetylation, ubiquitination, and phosphorylation modifications, which are closely linked to several neurological disorders.In addition, exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00776
Int J Mol Sci. 2024 Dec 09. pii: 13207. [Epub ahead of print]25(23):

Diacylglycerol Kinases and Its Role in Lipid Metabolism and Related Diseases.

Yishi Liu, Zehui Yang, Xiaoman Zhou, Zijie Li, Nakanishi Hideki.

  Lipids are essential components of eukaryotic membranes, playing crucial roles in membrane structure, energy storage, and signaling. They are predominantly synthesized in the endoplasmic reticulum (ER) and subsequently transported to other organelles. Diacylglycerol kinases (DGKs) are a conserved enzyme family that phosphorylate diacylglycerol (DAG) to produce phosphatidic acid (PA), both of which are key intermediates in lipid metabolism and second messengers involved in numerous cellular processes. Dysregulation of DGK activity is associated with several diseases, including cancer and metabolic disorders. In this review, we provide a comprehensive overview of DGK types, functions, cellular localization, and their potential as therapeutic targets. We also discuss DGKs' roles in lipid metabolism and their physiological functions and related diseases.

Keywords:  diacylglycerol kinase; lipid; phosphatidic acid; phosphorylate diacylglycerol

DOI:  https://doi.org/10.3390/ijms252313207
Glia. 2024 Dec 17.

Lipids: Emerging Players of Microglial Biology.

Priya Prakash, Caitlin E Randolph, Katherine A Walker, Gaurav Chopra.

  Lipids are small molecule immunomodulators that play critical roles in maintaining cellular health and function. Microglia, the resident immune cells of the central nervous system, regulate lipid metabolism both in the extracellular environment and within intracellular compartments through various mechanisms. For instance, glycerophospholipids and fatty acids interact with protein receptors on the microglial surface, such as the Triggering Receptor Expressed on Myeloid Cells 2, influencing cellular functions like phagocytosis and migration. Moreover, cholesterol is essential not only for microglial survival but, along with other lipids such as fatty acids, is crucial for the formation, function, and accumulation of lipid droplets, which modulate microglial activity in inflammatory diseases. Other lipids, including acylcarnitines and ceramides, participate in various signaling pathways within microglia. Despite the complexity of the microglial lipidome, only a few studies have investigated the effects of specific lipid classes on microglial biology. In this review, we focus on major lipid classes and their roles in modulating microglial function. We also discuss novel analytical techniques for characterizing the microglial lipidome and highlight gaps in current knowledge, suggesting new directions for future research on microglial lipid biology.

Keywords:  fatty acids; inflammation; lipid droplets; lipidomics; lipids; microglia; phospholipids

DOI:  https://doi.org/10.1002/glia.24654
J Neurotrauma. 2024 Dec 17.

Evolution of Lipid Metabolism in the Injured Mouse Spinal Cord.

Natalie E Scholpa, Epiphani C Simmons, Justin M Snider, Kelsey Barrett, Lauren G Buss, Rick G Schnellmann.

  Following spinal cord injury (SCI), there is a short-lived recovery phase that ultimately plateaus. Understanding changes within the spinal cord over time may facilitate targeted approaches to prevent and/or reverse this plateau and allow for continued recovery. Untargeted metabolomics revealed distinct metabolic profiles within the injured cord during recovery (7 days postinjury [DPI]) and plateau (21 DPI) periods in a mouse model of severe contusion SCI. Alterations in lipid metabolites, particularly those involved in phospholipid (PL) metabolism, largely contributed to overall differences. PLs are hydrolyzed by phospholipases A2 (PLA2s), yielding lysophospholipids (LPLs) and fatty acids (FAs). PL metabolites decreased between 7 and 21 DPI, whereas LPLs increased at 21 DPI, suggesting amplified PL metabolism during the plateau phase. Expression of various PLA2s also differed between the two time points, further supporting dysregulation of PL metabolism during the two phases of injury. FAs, which can promote inflammation, mitochondrial dysfunction, and neuronal damage, were increased regardless of time point. Carnitine can bind with FAs to form acylcarnitines, lessening FA-induced toxicity. In contrast to FAs, carnitine and acylcarnitines were increased at 7 DPI, but decreased at 21 DPI, suggesting a loss of carnitine-mediated mitigation of FA toxicity at the later time point, which may contribute to the cessation of recovery post-SCI. Alterations in oxidative phosphorylation and tricarboxylic acid cycle metabolites were also observed, indicating persistent although dissimilar disruptions in mitochondrial function. These data aid in increasing our understanding of lipid metabolism following SCI and have the potential to lead to new biomarkers and/or therapeutic strategies.

Keywords:  carnitine; lipids; metabolomics; phospholipids; spinal cord injury

DOI:  https://doi.org/10.1089/neu.2024.0385
J Inflamm Res. 2024 ;17 10835-10848

Exploring the Role of SMPD3 in the lncRNA-miRNA-mRNA Regulatory Network in TBI Progression by Influencing Energy Metabolism.

Changmeng Cui, Biao Xu, Hui Liu, Changshui Wang, Tao Zhang, Pei Jiang, Lei Feng.

   Background: Traumatic brain injury (TBI) is associated with disturbances in energy metabolism. This study aimed to construct a lncRNA-miRNA-mRNA network through bioinformatics methods to explore energy metabolism-related genes in the pathogenesis of TBI.
Methods: Data from datasets GSE171718, GSE131695, and GSE223245 obtained from the Gene Expression Omnibus, were analyzed to identify differentially expressed (DE) genes. Regulatory relationships were investigated through miRDB, miRTarBase, and TargetScan, thereby forming a lncRNA-miRNA-mRNA network. The Molecular Signatures Database (MSigDB) was utilized to identify energy metabolism-related genes, and a protein-protein interaction (PPI) network was established through the STRING database. Functional annotation and enrichment analysis were conducted using GO and KEGG. The TBI mouse model was established to detect the expression levels of GOLGA8B, ZNF367, and SMPD3 in brain tissues.
Results: SMPD3 emerged as the key DE gene linked to energy metabolism in TBI, demonstrating a negative correlation with miR-218-5p and being associated with moderate unconsciousness and female patients. The PPI network revealed SMPD3 interactions with proteins associated with cell death, sphingolipid metabolism, and neurodegenerative diseases such as Alzheimer's disease. In vivo, GOLGA8B, ZNF367, and SMPD3 mRNA levels were significantly lower in TBI mice.
Conclusion: In summary, SMPD3 represents a crucial metabolic gene in the progression of TBI. It potentially provides a new therapeutic target for metabolic disorders caused by traumatic brain injury (TBI) and holds significant theoretical value for further research.

Keywords:  SMPD3; bioinformatics analysis; energy metabolism; lncRNA-miRNA-mRNA network; traumatic brain injury

DOI:  https://doi.org/10.2147/JIR.S491290
J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02578-X. [Epub ahead of print] 108076

Prohibitin 1 tethers lipid membranes and regulates OPA1-mediated membrane fusion.

Tadato Ban, Kimiya Kuroda, Mitsuhiro Nishigori, Keisuke Yamashita, Keisuke Ohta, Takumi Koshiba.

  Prohibitins (PHBs) are ubiquitously expressed proteins in the mitochondrial inner membrane (MIM) that provide membrane scaffolds for both mitochondrial proteins and phospholipids. Eukaryotic PHB complexes contain two highly homologous PHB subunits, PHB1 and PHB2, which are involved in various cellular processes, including metabolic control through the regulation of mitochondrial dynamics and integrity. Their mechanistic actions at the molecular level, however, particularly those of PHB1, remain poorly understood. To gain insight into the mechanistic actions of PHB1, we established an overexpression system for the full-length recombinant protein using silkworm larvae and characterized its biophysical properties in vitro. Using recombinant PHB1 proteoliposomes reconstituted into MIM-mimicking phospholipids, we found that PHB1 forms an oligomer via its carboxy-terminal coiled-coil region. A proline substitution into the PHB1 coiled-coil collapsed its well-ordered oligomeric state, and its destabilization correlated with mitochondrial morphologic defects. Negative-staining electron microscopy revealed that homotypic PHB1-PHB1 interactions via the coiled-coil also induced liposome tethering with remodeling of the lipid membrane structure. We clarified that PHB1 promotes membrane fusion mediated by optic atrophy 1 (OPA1), a key regulator of MIM fusion. Additionally, the presence of PHB1 reduces the dependency of lipids and OPA1 for completing the fusion process. Our in vitro study provides structural insight into how the mitochondrial scaffold plays a crucial role in regulating mitochondrial dynamics. Modulating the structure and/or function of PHB1 may offer new therapeutic potential, not only for mitochondrial dysfunction but also for other cell-related disorders.

Keywords:  Coiled-coil; Prohibitin 1; membrane fusion; mitochondria; proteoliposomes

DOI:  https://doi.org/10.1016/j.jbc.2024.108076
Autophagy. 2024 Dec 19. 1-3

Dynamic mitophagy trajectories hallmark brain aging.

Anna Rappe, Thomas G McWilliams.

  Studies using mitophagy reporter mice have established steady-state landscapes of mitochondrial destruction in mammalian tissues, sparking intense interest in basal mitophagy. Yet how basal mitophagy is modified by healthy aging in diverse brain cell types has remained a mystery. We present a comprehensive spatiotemporal analysis of mitophagy and macroautophagy dynamics in the aging mammalian brain, reporting critical region- and cell-specific turnover trajectories in a longitudinal study. We demonstrate that the physiological regulation of mitophagy in the mammalian brain is cell-specific, dynamic and complex. Mitophagy increases significantly in the cerebellum and hippocampus during midlife, while remaining unchanged in the prefrontal cortex (PFC). Conversely, macroautophagy decreases in the hippocampus and PFC, but remains stable in the cerebellum. We also describe emergent lysosomal heterogeneity, with subsets of differential acidified lysosomes accumulating in the aging brain. We further establish midlife as a critical inflection point for autophagy regulation, which may be important for region-specific vulnerability and resilience to aging. By mapping in vivo autophagy dynamics at the single cell level within projection neurons, interneurons and microglia, to astrocytes and secretory cells, we provide a new framework for understanding brain aging and offer potential targets and timepoints for further study and intervention in neurodegenerative diseases.

Keywords:  Aging; autophagy; brain; mitochondria; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2426115
ACS Appl Mater Interfaces. 2024 Dec 18.

Therapeutic Efficacy of a Synthetic Brain-Targeted H2S Donor Cross-Linked Nanomicelle in Autism Spectrum Disorder Rats through Aerobic Glycolysis.

Changmei Zhang, Lingyuan Yang, Feng Wang, Mingyuan Liu, Zehui Liu, Mingyang Zou, Lijie Wu.

  Autism spectrum disorder (ASD) is characterized by cognitive inflexibility and social deficits, with a notably limited range of brain-targeted medications, particularly in the field of nanomedicine. Herein, we introduce the brain-targeted H2S donor cross-linked nanomicelle, named mannose-PEG600-lipoic acid (Man-LA). Man-LA demonstrates enhanced stability and precise brain delivery by interacting with glucose transporter 1 (GLUT1) in astrocytes, facilitating a gradual release of H2S that is modulated by glutathione (GSH). In vivo, studies suggest that Man-LA alleviates symptoms of ASD, correlating with increased expression of aerobic glycolysis enzymes, elevated lactate production, and higher H2S levels, while preventing damage to hippocampal neurons. In vitro, Man-LA tightly binds to aldehyde dehydrogenase family 3 member B1 (Aldh3b1) in astrocytes, upregulating its expression. This interaction promotes aerobic glycolysis and enhances lactate production. These findings suggest a connection between ASD deficits and the dysregulation of astrocytic aerobic glycolysis, underscoring the role of H2S. Identifying the Aldh3b1 gene within aerobic glycolysis pathways provides a promising target for ASD treatment.

Keywords:  Aerobic glycolysis; Astrocytes; Autism spectrum disorder; Cross-linked nanomicelle; Hydrogen sulfide

DOI:  https://doi.org/10.1021/acsami.4c11663
Int J Mol Sci. 2024 Nov 21. pii: 12490. [Epub ahead of print]25(23):

Validation and Optimization of a Stable Isotope-Labeled Substrate Assay for Measuring AGAT Activity.

Alex Lee, Lucas Anderson, Ilona Tkachyova, Michael B Tropak, Dahai Wang, Andreas Schulze.

  L-arginine: glycine amidinotransferase (AGAT) gained academic interest as the rate-limiting enzyme in creatine biosynthesis and its role in the regulation of creatine homeostasis. Of clinical relevance is the diagnosis of patients with AGAT deficiency but also the potential role of AGAT as therapeutic target for the treatment of another creatine deficiency syndrome, guanidinoacetate N-methyltransferase (GAMT) deficiency. Applying a stable isotope-labeled substrate method, we utilized ARG 15N2 (ARG-δ2) and GLY 13C215N (GLY-δ3) to determine the rate of 1,2-13C2,15N3 guanidinoacetate (GAA-δ5) formation to assess AGAT activity in various mouse tissue samples and human-derived cells. Following modification and optimization of the assay, we analyzed AGAT activity in several mouse organs. The Km and Vmax of AGAT in mouse kidney for GLY-δ3 were 2.06 mM and 6.48 ± 0.26 pmol/min/mg kidney, and those for ARG-δ2, they were 2.67 mM and 2.17 ± 0.49 pmol/min/mg kidney, respectively. Our results showed that mouse kidneys had the highest levels of enzymatic activity, followed by brain and liver, with 4.6, 1.8, and 0.4 pmol/min/mg tissue, respectively. Both the heart and muscle had no detectable levels of AGAT activity. We noted that due to interference with arginase in the liver, performing the enzyme assay in liver homogenates required the addition of Nor-NOHA, an arginase inhibitor. In immortalized human cell lines, we found the highest levels of AGAT activity in RH30 cells, followed by HepaRG, HAP1, and HeLa cells. AGAT activity was readily detectable in lymphoblasts and leukocytes from healthy controls. In our assay, AGAT activity was not detectable in HEK293 cells, in human fibroblasts, and in the lymphoblasts of a patient with AGAT deficiency. Our results demonstrate that this enzyme assay is capable of accurately quantifying AGAT activity from both tissues and cells for diagnostic purposes and research.

Keywords:  AGAT activity; creatine deficiency syndromes; enzyme assay; isotope-labeled

DOI:  https://doi.org/10.3390/ijms252312490
Life Sci. 2024 Dec 12. pii: S0024-3205(24)00907-X. [Epub ahead of print] 123317

Targeting mitochondrial dynamics: A promising approach for intracerebral hemorrhage therapy.

Mengnan Liu, Binru Li, Zhixue Yin, Lu Yin, Ye Luo, Qi Zeng, Dechou Zhang, Anguo Wu, Li Chen.

  Intracerebral hemorrhage (ICH) is a major global health issue with high mortality and disability rates. Following ICH, the hematoma exerts direct pressure on brain tissue, and blood entering the brain directly damages neurons and the blood-brain barrier. Subsequently, oxidative stress, inflammatory responses, apoptosis, brain edema, excitotoxicity, iron toxicity, and metabolic dysfunction around the hematoma further exacerbate brain tissue damage, leading to secondary brain injury (SBI). Mitochondria, essential for energy production and the regulation of oxidative stress, are damaged after ICH, resulting in impaired ATP production, excessive reactive oxygen species (ROS) generation, and disrupted calcium homeostasis, all of which contribute to SBI. Therefore, a central factor in SBI is mitochondrial dysfunction. Mitochondrial dynamics regulate the shape, size, distribution, and quantity of mitochondria through fusion and fission, both of which are crucial for maintaining their function. Fusion repairs damaged mitochondria and preserves their health, while fission helps mitochondria adapt to cellular stress and removes damaged mitochondria through mitophagy. When this balance is disrupted following ICH, mitochondrial dysfunction worsens, oxidative stress and metabolic failure are exacerbated, ultimately contributing to SBI. Targeting mitochondrial dynamics offers a promising therapeutic approach to restoring mitochondrial function, reducing cellular damage, and improving recovery. This review explores the latest research on modulating mitochondrial dynamics and highlights its potential to enhance outcomes in ICH patients.

Keywords:  Intracerebral hemorrhage; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Neuroprotection strategies; Secondary brain injury

DOI:  https://doi.org/10.1016/j.lfs.2024.123317
Elife. 2024 Dec 16. pii: RP99914. [Epub ahead of print]13

Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50.

Eyal Paz, Sahil Jain, Irit Gottfried, Orna Staretz-Chacham, Muhammad Mahajnah, Pritha Bagchi, Nicholas T Seyfried, Uri Ashery, Abdussalam Azem.

  TIMM50, an essential TIM23 complex subunit, is suggested to facilitate the import of ~60% of the mitochondrial proteome. In this study, we characterized a TIMM50 disease-causing mutation in human fibroblasts and noted significant decreases in TIM23 core protein levels (TIMM50, TIMM17A/B, and TIMM23). Strikingly, TIMM50 deficiency had no impact on the steady-state levels of most of its putative substrates, suggesting that even low levels of a functional TIM23 complex are sufficient to maintain the majority of TIM23 complex-dependent mitochondrial proteome. As TIMM50 mutations have been linked to severe neurological phenotypes, we aimed to characterize TIMM50 defects in manipulated mammalian neurons. TIMM50 knockdown in mouse neurons had a minor effect on the steady state level of most of the mitochondrial proteome, supporting the results observed in patient fibroblasts. Amongst the few affected TIM23 substrates, a decrease in the steady state level of components of the intricate oxidative phosphorylation and mitochondrial ribosome complexes was evident. This led to declined respiration rates in fibroblasts and neurons, reduced cellular ATP levels, and defective mitochondrial trafficking in neuronal processes, possibly contributing to the developmental defects observed in patients with TIMM50 disease. Finally, increased electrical activity was observed in TIMM50 deficient mice neuronal cells, which correlated with reduced levels of KCNJ10 and KCNA2 plasma membrane potassium channels, likely underlying the patients' epileptic phenotype.

Keywords:  Action potential; TIM23; TIMM50; TIMM50 disease; biochemistry; chemical biology; human; import disease; mitochondria; mitochondrial protein import; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.99914
J Neurochem. 2025 Jan;169(1): e16258

(Re)building the nervous system: A review of neuron-glia interactions from development to disease.

Matthew D Demmings, Luana da Silva Chagas, Marianela E Traetta, Rui S Rodrigues, Maria Florencia Acutain, Evgeny Barykin, Ashok Kumar Datusalia, Liliana German-Castelan, Vanesa S Mattera, Pedzisai Mazengenya, Cecilia Skoug, Hisashi Umemori.

  Neuron-glia interactions are fundamental to the development and function of the nervous system. During development, glia, including astrocytes, microglia, and oligodendrocytes, influence neuronal differentiation and migration, synapse formation and refinement, and myelination. In the mature brain, glia are crucial for maintaining neural homeostasis, modulating synaptic activity, and supporting metabolic functions. Neurons, inherently vulnerable to various stressors, rely on glia for protection and repair. However, glia, in their reactive state, can also promote neuronal damage, which contributes to neurodegenerative and neuropsychiatric diseases. Understanding the dual role of glia-as both protectors and potential aggressors-sheds light on their complex contributions to disease etiology and pathology. By appropriately modulating glial activity, it may be possible to mitigate neurodegeneration and restore neuronal function. In this review, which originated from the International Society for Neurochemistry (ISN) Advanced School in 2019 held in Montreal, Canada, we first describe the critical importance of glia in the development and maintenance of a healthy nervous system as well as their contributions to neuronal damage and neurological disorders. We then discuss potential strategies to modulate glial activity during disease to protect and promote a properly functioning nervous system. We propose that targeting glial cells presents a promising therapeutic avenue for rebuilding the nervous system.

Keywords:  astrocyte; brain development and function; glial dysfunction; microglia; neurodegenerative and neuropsychiatric disorders; oligodendrocyte

DOI:  https://doi.org/10.1111/jnc.16258
J Neurochem. 2025 Jan;169(1): e16259

Fundamental Neurochemistry Review: Lipids across microglial states.

Marianela E Traetta, Haley A Vecchiarelli, Marie-Ève Tremblay.

  The capacity of immune cells to alter their function based on their metabolism is the basis of the emerging field of immunometabolism. Microglia are the resident innate immune cells of the central nervous system, and it is a current focus of the field to investigate how alterations in their metabolism impact these cells. Microglia have the ability to utilize lipids, such as fatty acids, as energy sources, but also alterations in lipids can impact microglial form and function. Recent studies highlighting different microglial states and transcriptional signatures have highlighted modifications in lipid processing as defining these states. This review highlights these recent studies and uses these altered pathways to discuss the current understanding of lipid biology in microglia. The studies highlighted here review how lipids may alter microglial phagocytic functioning or alter their pro- and anti-inflammatory balance. These studies provide a foundation by which lipid supplementation or diet alterations could influence microglial states and function. Furthermore, targets modulating microglial lipid metabolism may provide new treatment avenues.

Keywords:  immunometabolism; lipid; microglia; microglial states

DOI:  https://doi.org/10.1111/jnc.16259
J Neurochem. 2025 Jan;169(1): e16267

Altered metabolic function induced by Aβ-oligomers and PSEN1 mutations in iPSC-derived astrocytes.

Richard J Elsworthy, Mattea J Finelli, Sarah Aqattan, Connor Dunleavy, Marianne King, Adele Ludlam, Marta A Tarczyluk, Sophie L Allen, Sophie Prosser, Rui Chen, Sandra Martinez Jarquin, Dong H Kim, James Brown, H R Parri, Sarah Aldred, Eric J Hill.

  Altered energy metabolism in Alzheimer's disease (AD) is a major pathological hallmark implicated in the early stages of the disease process. Astrocytes play a central role in brain homeostasis and are implicated in multiple neurodegenerative diseases. Although numerous studies have investigated global changes in brain metabolism, redox status, gene expression and epigenetic markers in AD, the intricate interplay between different metabolic processes, particularly in astrocytes, remains poorly understood. Numerous studies have implicated amyloid-β and the amyloid-β precursor in the development and progression of AD. To determine the effects of amyloid-β peptides or the impact of amyloid-β precursor protein processing on astrocyte metabolism, we differentiated astrocytes from induced pluripotent stem cells derived from people with early onset familial AD and controls. This study demonstrates that familial AD-derived astrocytes exhibit significantly more changes in their metabolism including glucose uptake, glutamate uptake and lactate release, with increases in oxidative and glycolytic metabolism compared to acute amyloid-β exposure. In addition to changes in major metabolic pathways including glutamate, purine and arginine metabolism and the citric acid cycle, we demonstrate evidence of gliosis in familial AD astrocytes highlighting a potential pathological hallmark. This suggests that chronic alterations in metabolism may occur very early in the disease process and present significant risk factors for disease progression for patients with early onset AD. These findings may also reveal important drivers of disease in late onset dementia and highlights key targets for potential diagnostic features and therapeutic agents in the future.

Keywords:  Alzheimer's; astrocytes; gliosis; inflammation; metabolism; stem cells

DOI:  https://doi.org/10.1111/jnc.16267
Nat Metab. 2024 Dec;6(12): 2319-2337

Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.

Lena E Høyland, Magali R VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K N Pettersen, Karl J Tronstad, Svein A Mjøs, Faisal Hayat, Mikhail V Makarov, Marie E Migaud, Ines Heiland, Mathias Ziegler.

The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.

DOI: https://doi.org/10.1038/s42255-024-01174-w
Nutr Clin Pract. 2024 Dec 15.

Carnitine supplementation in progressive supranuclear palsy.

Devika Dixit, Yang Zhao, Olgert Bardhi, Arvin Daneshmand, Jonathan Phillips, Trina Bala, Martin Rosenthal, Alicia Mohr, Prem Kandiah, Amir Y Kamel.

  Mitochondrial dysfunction has been implicated in the pathogenesis of several neurodegenerative disorders, including progressive supranuclear palsy (PSP). PSP is a Parkinsonian syndrome characterized by a rapidly progressive state that manifests itself as tremors, bradykinesia, and supranuclear gaze palsy. Carnitine plays an essential role in mitochondrial function by transporting fatty acids across the mitochondrial membrane to be used in energy production. Mitochondrial dysfunction can bring about rapid neuronal depolarization and a calcium-mediated cellular apoptosis owing to a loss of oxidative metabolism, likely contributing to the PSP disease process. A White man aged 65 years with PSP presented with small bowel obstruction and severe malnutrition as a result of prior gastrointestinal surgeries for which a gastrostomy tube was placed. During his hospitalization, the patient was found to be deficient in both free and total carnitine. He was treated with levocarnitine supplementation and exhibited marked improvement in tremors, fatigue, and physical therapy activities. Posthospitalization follow-up showed sustained improvement in symptoms with continued levocarnitine supplementation. Treatment of PSP remains largely supportive in nature. No studies have investigated the role of carnitine supplementation in PSP. To our knowledge, this is the first case report to identify improvement in PSP symptoms after carnitine repletion and supportive care. Numerous animal studies have reported on carnitine supplementation in the context of mitochondrial dysfunction associated with neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. Further investigation is necessary to elucidate the precise role of carnitine and other nutrition supplements in the pathophysiology of PSP.

Keywords:  adult; carnitine deficiency; enteral access; enteral formulas; enteral nutrition; gastroenterology; minerals/trace elements; nutrition support teams; parenteral nutrition

DOI:  https://doi.org/10.1002/ncp.11262