bims-medebr 2024-03-03 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–03–03
29 papers selected by
Regina F. Fernández, Johns Hopkins University

Nutritional ketosis as treatment for alcohol withdrawal symptoms in female C57BL/6J mice.
Assessment of a one-week ketogenic diet on brain glycolytic metabolism and on the status epilepticus stage of a lithium-pilocarpine rat model.
Glycerophospholipids dysregulation after traumatic brain injury.
Data-driven analysis of regional brain metabolism in behavioral frontotemporal dementia and late-onset primary psychiatric diseases with frontal lobe syndrome: A PET/MRI study.
Metabolic dynamics in astrocytes and microglia during post-natal development and their implications for autism spectrum disorders.
Lipotype acquisition during neural development is not recapitulated in stem cell-derived neurons.
Cerebral lactate uptake following half-molar sodium lactate therapy in traumatic brain injury : a brief report.
Lactate/Hydroxycarboxylic Acid Receptor 1 in Alzheimer's Disease: Mechanisms and Therapeutic Implications-Exercise Perspective.
Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency.
Metabolic rescue of α-synuclein-induced neurodegeneration through propionate supplementation and intestine-neuron signaling in C. elegans.
Hypothermia promotes tunneling nanotube formation and the transfer of astrocytic mitochondria into oxygen-glucose deprivation/reoxygenation-injured neurons.
Most axonal mitochondria in cortical pyramidal neurons lack mitochondrial DNA and consume ATP.
High-Throughput Lipidomic and Metabolomic Profiling for Brain Tissue and Biofluid Samples in Neurodegenerative Disorders.
AMP-activated protein kinase as a mediator of mitochondrial dysfunction of multiple sclerosis in animal models: A systematic review.
Fatty acid-binding proteins 3, 7, and 8 bind cholesterol and facilitate its egress from lysosomes.
ER Membrane Lipid Composition and Metabolism: Lipidomic Analysis.
APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model.
Lack of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile-onset brainstem neurodegenerative disease with early lethality.
A metabolome-wide Mendelian randomization study identifies dysregulated arachidonic acid synthesis as a potential causal risk factor for bipolar disorder.
Sirtuin dysregulation in Parkinson's disease: Implications of acetylation and deacetylation processes.
Brain function in classic galactosemia, a galactosemia network (GalNet) members review.
Promises of Lipid-Based Nanocarriers for Delivery of Dimethyl Fumarate to Multiple Sclerosis Brain.
Mitochondrial dysfunction in lipid processing and gastrointestinal disorders.
The effect of Ferroptosis -related Mitochondrial Dysfunction in the Development of Temporal Lobe Epilepsy.
Chemical inhibition of phosphatidylcholine biogenesis reveals its role in mitochondrial division.
No Effects of Decanoic Acid on Locomotor Activity and Antioxidant Defences in an Experimental Animal Model of Attention-Deficit/Hyperactivity Disorder.
The 3-hydroxyacyl-CoA dehydratase 1/2 form complex with trans-2-enoyl-CoA reductase involved in substrates transfer in very long chain fatty acid elongation.
High-Resolution Respirometry for Mitochondrial Function in Rodent Brain.
Optimized combination of MALDI MSI and immunofluorescence for neuroimaging of lipids within cellular microenvironments.

Sci Rep. 2024 Mar 01. 14(1): 5092

Nutritional ketosis as treatment for alcohol withdrawal symptoms in female C57BL/6J mice.

Simone Tonetto, Pia Weikop, Morgan Thomsen.

Upon both acute and prolonged alcohol intake, the brain undergoes a metabolic shift associated with increased acetate metabolism and reduced glucose metabolism, which persists during abstinence, putatively leading to energy depletion in the brain. This study evaluates the efficacy of ketogenic treatments to rescue psychiatric and neurochemical alterations during long-term alcohol withdrawal. Female mice were intermittently exposed to alcohol vapor or air for three weeks, during which mice were introduced to either a ketogenic diet (KD), control diet supplemented with ketone ester (KE) or remained on control diet (CD). Withdrawal symptoms were assessed over a period of four weeks followed by re-exposure using several behavioral and biochemical tests. Alcohol-exposed mice fed CD displayed long-lasting depressive-like symptoms measured by saccharin preference and tail suspension, as well as decreased norepinephrine levels and serotonin turnover in the hippocampus. Both KD and KE rescued anhedonia for up to three weeks of abstinence. KD mice showed higher latency to first immobility in the tail suspension test, as well as lower plasma cholesterol levels. Our findings show promising effects of nutritional ketosis in ameliorating alcohol withdrawal symptoms in mice. KD seemed to better rescue these symptoms compared to KE.

DOI: https://doi.org/10.1038/s41598-024-55310-3
Sci Rep. 2024 Mar 01. 14(1): 5063

Assessment of a one-week ketogenic diet on brain glycolytic metabolism and on the status epilepticus stage of a lithium-pilocarpine rat model.

Matthieu Doyen, Clémentine Lambert, Emilie Roeder, Henri Boutley, Bailiang Chen, Julien Pierson, Antoine Verger, Emmanuel Raffo, Gilles Karcher, Pierre-Yves Marie, Fatiha Maskali.

The ketogenic diet (KD) has been shown to be effective in refractory epilepsy after long-term administration. However, its interference with short-term brain metabolism and its involvement in the early process leading to epilepsy remain poorly understood. This study aimed to assess the effect of a short-term ketogenic diet on cerebral glucose metabolic changes, before and after status epilepticus (SE) in rats, by using [18F]-FDG PET. Thirty-nine rats were subjected to a one-week KD (KD-rats, n = 24) or to a standard diet (SD-rats, n = 15) before the induction of a status epilepticus (SE) by lithium-pilocarpine administrations. Brain [18F]-FDG PET scans were performed before and 4 h after this induction. Morphological MRIs were acquired and used to spatially normalize the PET images which were then analyzed voxel-wisely using a statistical parametric-based method. Twenty-six rats were analyzed (KD-rats, n = 15; SD-rats, n = 11). The 7 days of the KD were associated with significant increases in the plasma β-hydroxybutyrate level, but with an unchanged glycemia. The PET images, recorded after the KD and before SE induction, showed an increased metabolism within sites involved in the appetitive behaviors: hypothalamic areas and periaqueductal gray, whereas no area of decreased metabolism was observed. At the 4th hour following the SE induction, large metabolism increases were observed in the KD- and SD-rats in areas known to be involved in the epileptogenesis process late-i.e., the hippocampus, parahippocampic, thalamic and hypothalamic areas, the periaqueductal gray, and the limbic structures (and in the motor cortex for the KD-rats only). However, no statistically significant difference was observed when comparing SD and KD groups at the 4th hour following the SE induction. A one-week ketogenic diet does not prevent the status epilepticus (SE) and associated metabolic brain abnormalities in the lithium-pilocarpine rat model. Further explorations are needed to determine whether a significant prevention could be achieved by more prolonged ketogenic diets and by testing this diet in less severe experimental models, and moreover, to analyze the diet effects on the later and chronic stages leading to epileptogenesis.

DOI: https://doi.org/10.1038/s41598-024-53824-4
Neurochem Int. 2024 Feb 28. pii: S0197-0186(24)00028-7. [Epub ahead of print] 105701

Glycerophospholipids dysregulation after traumatic brain injury.

Chinmoy Sarkar, Marta M Lipinski.

Brain tissue is highly enriched in lipids, the majority of which are glycerophospholipids (GPLs). Glycerophospholipids are the major constituents of cellular membranes and play an important role in maintaining integrity and function of cellular and subcellular structures. Any changes in glycerophospholipids homeostasis can adversely affect brain functions. Traumatic brain injury (TBI), an acquired injury caused by the impact of external forces to the brain, triggers activation of secondary biochemical events that include perturbation of lipid homeostasis. Several studies have demonstrated glycerophospholipid dysregulation in the brain and circulation after TBI. This includes spatial and temporal changes in abundance and distribution of glycerophospholipids in the injured brain. This is at least in part mediated by TBI-induced oxidative stress and by activation of lipid metabolism pathways involved in tissue repairing. In this review, we discuss current advances in understanding of the mechanisms and implications of glycerophospholipids dysregulation following TBI.

DOI: https://doi.org/10.1016/j.neuint.2024.105701
Neurobiol Aging. 2024 Feb 03. pii: S0197-4580(24)00027-7. [Epub ahead of print]137 47-54

Data-driven analysis of regional brain metabolism in behavioral frontotemporal dementia and late-onset primary psychiatric diseases with frontal lobe syndrome: A PET/MRI study.

Annachiara Cagnin, Giorgio Pigato, Ilaria Pettenuzzo, Giovanni Zorzi, Beatrice Roiter, Maria Giulia Anglani, Cinzia Bussè, Stefano Mozzetta, Carlo Gabelli, Cristina Campi, Diego Cecchin.

  Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose metabolism in bvFTD and late-onset PPD and investigate the metabolic correlates of cognitive and behavioral disturbances through FDG-PET/MRI. We studied 37 bvFTD and 20 late-onset PPD with a mean clinical follow-up of three years. At baseline evaluation, metabolism of the dorsolateral, ventrolateral, orbitofrontal regions and caudate could classify the patients with a diagnostic accuracy of 91% (95% CI: 0.81-0.98%). 45% of PPD showed low-grade hypometabolism in the anterior cingulate and/or parietal regions. Frontal lobe metabolism was normal in 32% of genetic bvFTD and bvFTD with motor neuron signs. Hypometabolism of the frontal and caudate regions could help in distinguishing bvFTD from PPD, except in cases with motor neuron signs and/or genetic bvFTD for which brain metabolism may be less informative.

Keywords:  Frontotemporal dementia; Frontotemporal lobar degeneration; Metabolism; PET; Phenocopy; Psychiatric diseases

DOI:  https://doi.org/10.1016/j.neurobiolaging.2024.01.015
Front Cell Neurosci. 2024 ;18 1354259

Metabolic dynamics in astrocytes and microglia during post-natal development and their implications for autism spectrum disorders.

Iva Cantando, Cristiana Centofanti, Giuseppina D'Alessandro, Cristina Limatola, Paola Bezzi.

  Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by elusive underlying mechanisms. Recent attention has focused on the involvement of astrocytes and microglia in ASD pathology. These glial cells play pivotal roles in maintaining neuronal homeostasis, including the regulation of metabolism. Emerging evidence suggests a potential association between ASD and inborn errors of metabolism. Therefore, gaining a comprehensive understanding of the functions of microglia and astrocytes in ASD is crucial for the development of effective therapeutic interventions. This review aims to provide a summary of the metabolism of astrocytes and microglia during post-natal development and the evidence of disrupted metabolic pathways in ASD, with particular emphasis on those potentially important for the regulation of neuronal post-natal maturation by astrocytes and microglia.

Keywords:  astrocyte; autism spectrum disorders; brain metabolism; fatty acid oxidation; lactate; lipids; microglia; mitochondria

DOI:  https://doi.org/10.3389/fncel.2024.1354259
Life Sci Alliance. 2024 May;pii: e202402622. [Epub ahead of print]7(5):

Lipotype acquisition during neural development is not recapitulated in stem cell-derived neurons.

Anusha B Gopalan, Lisa van Uden, Richard R Sprenger, Nadine Fernandez-Novel Marx, Helle Bogetofte, Pierre A Neveu, Morten Meyer, Kyung-Min Noh, Alba Diz-Muñoz, Christer S Ejsing.

During development, different tissues acquire distinct lipotypes that are coupled to tissue function and homeostasis. In the brain, where complex membrane trafficking systems are required for neural function, specific glycerophospholipids, sphingolipids, and cholesterol are highly abundant, and defective lipid metabolism is associated with abnormal neural development and neurodegenerative disease. Notably, the production of specific lipotypes requires appropriate programming of the underlying lipid metabolic machinery during development, but when and how this occurs is unclear. To address this, we used high-resolution MSALL lipidomics to generate an extensive time-resolved resource of mouse brain development covering early embryonic and postnatal stages. This revealed a distinct bifurcation in the establishment of the neural lipotype, whereby the canonical lipid biomarkers 22:6-glycerophospholipids and 18:0-sphingolipids begin to be produced in utero, whereas cholesterol attains its characteristic high levels after birth. Using the resource as a reference, we next examined to which extent this can be recapitulated by commonly used protocols for in vitro neuronal differentiation of stem cells. Here, we found that the programming of the lipid metabolic machinery is incomplete and that stem cell-derived cells can only partially acquire a neural lipotype when the cell culture media is supplemented with brain-specific lipid precursors. Altogether, our work provides an extensive lipidomic resource for early mouse brain development and highlights a potential caveat when using stem cell-derived neuronal progenitors for mechanistic studies of lipid biochemistry, membrane biology and biophysics, which nonetheless can be mitigated by further optimizing in vitro differentiation protocols.

DOI: https://doi.org/10.26508/lsa.202402622
J Neurotrauma. 2024 Feb 29.

Cerebral lactate uptake following half-molar sodium lactate therapy in traumatic brain injury : a brief report.

Guillaume Plourde, Carole Ichai, Hervé Quintard.

  Exogenous sodium lactate has many advantages following traumatic brain injury, including intracranial pressure control and alternative energetic supply. However, it remains unclear whether half-molar sodium lactate (HSL) is effectively incorporated in brain metabolism, which we can verify using the arteriovenous difference in lactate (AVDlac). Hence we compared the AVDlac in patients with severe traumatic brain injury receiving equiosmolar bolus of sodium lactate or mannitol for intracranial hypertension (IH) treatment. We included 23 patients : 14 received HSL for 25 IH episodes, and 9 received mannitol for 19 episodes (total of 44 IH episodes). We observed that the median variation in AVDlac was positive in the group that received HSL (∆ +0.1 [IQR -0.08-0.2] mmol/L), which suggests a net lactate uptake by the brain. On the other hand, it was negative in the group that received mannitol (∆ -0.0 [IQR -0.1 to 0.0] mmol/L), indicating a net lactate export. Finally, there were more positive AVDlac values in the group that received HSL, and more negative AVDlac values in the group that received mannitol (Fisher's exact p = 0.04). Our study reports the first evidence of a positive AVDlac, which corresponds to a net lactate uptake by the brain, in patients that received HSL for severe TBI. Our results constitute a bedside confirmation of the integration of lactate into the brain metabolism and pave the way for a wider dissemination of sodium lactate in the daily clinical care of patients with traumatic brain injury.

Keywords:  ADULT BRAIN INJURY; METABOLISM; TRAUMATIC BRAIN INJURY

DOI:  https://doi.org/10.1089/neu.2023.0508
Mol Neurobiol. 2024 Mar 01.

Lactate/Hydroxycarboxylic Acid Receptor 1 in Alzheimer's Disease: Mechanisms and Therapeutic Implications-Exercise Perspective.

Xiangyuan Meng, Weijia Wu, Yingzhe Tang, Mei Peng, Jialun Yang, Shunling Yuan, Zelin Hu, Wenfeng Liu.

  Lactate has a novel function different from previously known functions despite its traditional association with hypoxia in skeletal muscle. It plays various direct and indirect physiological functions. It is a vital energy source within the central nervous system (CNS) and a signal transmitter regulating crucial processes, such as angiogenesis and inflammation. Activating lactate and its associated receptors elicits effects like synaptic plasticity and angiogenesis alterations. These effects can significantly influence the astrocyte-neuron lactate shuttle, potentially impacting cognitive performance. Decreased cognitive function relates to different neurodegenerative conditions, including Alzheimer's disease (AD), ischemic brain injury, and frontotemporal dementia. Therefore, lactic acid has significant potential for treating neurodegenerative disorders. Exercise is a method that induces the production of lactic acid, which is similar to the effect of lactate injections. It is a harmless and natural way to achieve comparable results. Animal experiments demonstrate that high-intensity intermittent exercise can increase vascular endothelial growth factor (VEGF) levels, thus promoting angiogenesis. In vivo, lactate receptor-hydroxycarboxylic acid receptor 1 (HCAR1) activation can occur by various stimuli, including variations in ion concentrations, cyclic adenosine monophosphate (cAMP) level elevations, and fluctuations in the availability of energy substrates. While several articles have been published on the benefits of physical activity on developing Alzheimer's disease in the CNS, could lactic acid act as a bridge? Understanding how HCAR1 responds to these signals and initiates associated pathways remains incomplete. This review comprehensively analyzes lactate-induced signaling pathways, investigating their influence on neuroinflammation, neurodegeneration, and cognitive decline. Consequently, this study describes the unique role of lactate in the progression of Alzheimer's disease.

Keywords:  Alzheimer’s disease; Cognitive function; Lactic acid; Neuroinflammation; Signal pathway

DOI:  https://doi.org/10.1007/s12035-024-04067-x
Mol Genet Metab Rep. 2024 Jun;39 101066

Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency.

Déborah Mathis, Jasmine Koch, Sophie Koller, Kay Sauter, Christa Flück, Anne-Christine Uldry, Patrick Forny, D Sean Froese, Alexander Laemmle.

  Mitochondrial malate dehydrogenase 2 (MDH2) is crucial to cellular energy generation through direct participation in the tricarboxylic acid (TCA) cycle and the malate aspartate shuttle (MAS). Inherited MDH2 deficiency is an ultra-rare metabolic disease caused by bi-allelic pathogenic variants in the MDH2 gene, resulting in early-onset encephalopathy, psychomotor delay, muscular hypotonia and frequent seizures. Currently, there is no cure for this devastating disease. We recently reported symptomatic improvement of a three-year-old girl with MDH2 deficiency following treatment with the triglyceride triheptanoin. Here, we aimed to better characterize this disease and improve our understanding of the potential utility of triheptanoin treatment. Using fibroblasts derived from this patient, we generated induced pluripotent stem cells (hiPSCs) and differentiated them into hepatocytes (hiPSC-Heps). Characterization of patient-derived hiPSCs and hiPSC-Heps revealed significantly reduced MDH2 protein expression. Untargeted proteotyping of hiPSC-Heps revealed global dysregulation of mitochondrial proteins, including upregulation of TCA cycle and fatty acid oxidation enzymes. Metabolomic profiling confirmed TCA cycle and MAS dysregulation, and demonstrated normalization of malate, fumarate and aspartate following treatment with the triheptanoin components glycerol and heptanoate. Taken together, our results provide the first patient-derived hiPSC-Hep-based model of MDH2 deficiency, confirm altered TCA cycle function, and provide further evidence for the implementation of triheptanoin therapy for this ultra-rare disease.
Synopsis: This study reveals altered expression of mitochondrial pathways including the tricarboxylic acid cycle and changes in metabolite profiles in malate dehydrogenase 2 deficiency and provides the molecular basis for triheptanoin treatment in this ultra-rare disease.

Keywords:  Human induced pluripotent stem cell technology; Malate aspartate shuttle; Malate dehydrogenase 2 deficiency; Metabolic profiling; Proteomics; Triheptanoin; hiPSC-derived hepatocytes

DOI:  https://doi.org/10.1016/j.ymgmr.2024.101066
Cell Rep. 2024 Feb 26. pii: S2211-1247(24)00193-1. [Epub ahead of print]43(3): 113865

Metabolic rescue of α-synuclein-induced neurodegeneration through propionate supplementation and intestine-neuron signaling in C. elegans.

Chenyin Wang, Meigui Yang, Dongyao Liu, Chaogu Zheng.

  Microbial metabolites that can modulate neurodegeneration are promising therapeutic targets. Here, we found that the short-chain fatty acid propionate protects against α-synuclein-induced neuronal death and locomotion defects in a Caenorhabditis elegans model of Parkinson's disease (PD) through bidirectional regulation between the intestine and neurons. Both depletion of dietary vitamin B12, which induces propionate breakdown, and propionate supplementation suppress neurodegeneration and reverse PD-associated transcriptomic aberrations. Neuronal α-synuclein aggregation induces intestinal mitochondrial unfolded protein response (mitoUPR), which leads to reduced propionate levels that trigger transcriptional reprogramming in the intestine and cause defects in energy production. Weakened intestinal metabolism exacerbates neurodegeneration through interorgan signaling. Genetically enhancing propionate production or overexpressing metabolic regulators downstream of propionate in the intestine rescues neurodegeneration, which then relieves mitoUPR. Importantly, propionate supplementation suppresses neurodegeneration without reducing α-synuclein aggregation, demonstrating metabolic rescue of neuronal proteotoxicity downstream of protein aggregates. Our study highlights the involvement of small metabolites in the gut-brain interaction in neurodegenerative diseases.

Keywords:  C. elegans; CP: Metabolism; CP: Neuroscience; Parkinson's disease; SCFAs; energy production; gut-brain axis; mitoUPR; mitochondrial unfolded protein response; neurodegeneration; propionate; short-chain fatty acids; vitamin B12; α-synuclein

DOI:  https://doi.org/10.1016/j.celrep.2024.113865
Brain Res. 2024 Feb 23. pii: S0006-8993(24)00080-5. [Epub ahead of print] 148826

Hypothermia promotes tunneling nanotube formation and the transfer of astrocytic mitochondria into oxygen-glucose deprivation/reoxygenation-injured neurons.

Xiao-Rui Xi, Zhi-Qiang Zhang, Yan-Li Li, Zheng Liu, Dong-Yang Ma, Zan Gao, Shan Zhang.

  Mitochondrial transfer occurs between cells, and it is important for damaged cells to receive healthy mitochondria to maintain their normal function and protect against cell death. Accumulating evidence suggests that the functional mitochondria of astrocytes are released and transferred to oxygen-glucose deprivation/reoxygenation (OGD/R)-injured neurons. Mild hypothermia (33 °C) is capable of promoting this process, which partially restores the function of damaged neurons. However, the pathways and mechanisms by which mild hypothermia facilitates mitochondrial transfer remain unclear. We are committed to studying the role of mild hypothermia in neuroprotection to provide reliable evidence and insights for the clinical application of mild hypothermia in brain protection. Tunneling nanotubes (TNTs) are considered to be one of the routes through which mitochondria are transferred between cells. In this study, an OGD/R-injured neuronal model was successfully established, and TNTs, mitochondria, neurons and astrocytes were double labeled using immunofluorescent probes. Our results showed that TNTs were present and involved in the transfer of mitochondria between cells in the mixed-culture system of neurons and astrocytes. When neurons were subjected to OGD/R exposure, TNT formation and mitochondrial transportation from astrocytes to injured neurons were facilitated. Further analysis revealed that mild hypothermia increased the quantity of astrocytic mitochondria transferred into damaged neurons through TNTs, raised the mitochondrial membrane potential (MMP), and decreased the neuronal damage and death during OGD/R. Altogether, our data indicate that TNTs play an important role in the endogenous neuroprotection of astrocytic mitochondrial transfer. Furthermore, mild hypothermia enhances astrocytic mitochondrial transfer into OGD/R-injured neurons via TNTs, thereby promoting neuroprotection and neuronal recovery.

Keywords:  Hypothermia; Mitochondrial transfer; Oxygen–glucose deprivation/reoxygenation (OGD/R); Tunneling nanotubes (TNTs)

DOI:  https://doi.org/10.1016/j.brainres.2024.148826
bioRxiv. 2024 Feb 13. pii: 2024.02.12.579972. [Epub ahead of print]

Most axonal mitochondria in cortical pyramidal neurons lack mitochondrial DNA and consume ATP.

Yusuke Hirabayashi, Tommy L Lewis, Yudan Du, Daniel M Virga, Aubrianna M Decker, Giovanna Coceano, Jonatan Alvelid, Maëla A Paul, Stevie Hamilton, Parker Kneis, Yasufumi Takahashi, Jellert T Gaublomme, Ilaria Testa, Franck Polleux.

In neurons of the mammalian central nervous system (CNS), axonal mitochondria are thought to be indispensable for supplying ATP during energy-consuming processes such as neurotransmitter release. Here, we demonstrate using multiple, independent, in vitro and in vivo approaches that the majority (~80-90%) of axonal mitochondria in cortical pyramidal neurons (CPNs), lack mitochondrial DNA (mtDNA). Using dynamic, optical imaging analysis of genetically encoded sensors for mitochondrial matrix ATP and pH, we demonstrate that in axons of CPNs, but not in their dendrites, mitochondrial complex V (ATP synthase) functions in a reverse way, consuming ATP and protruding H+ out of the matrix to maintain mitochondrial membrane potential. Our results demonstrate that in mammalian CPNs, axonal mitochondria do not play a major role in ATP supply, despite playing other functions critical to regulating neurotransmission such as Ca2+ buffering.

DOI: https://doi.org/10.1101/2024.02.12.579972
Methods Mol Biol. 2024 ;2785 221-260

High-Throughput Lipidomic and Metabolomic Profiling for Brain Tissue and Biofluid Samples in Neurodegenerative Disorders.

Bonne M Thompson, Giuseppe Astarita.

  Recent research has revealed the potential of lipidomics and metabolomics in identifying new biomarkers and mechanistic insights for neurodegenerative disorders. To contribute to this promising area, we present a detailed protocol for conducting an integrated lipidomic and metabolomic profiling of brain tissue and biofluid samples. In this method, a single-phase methanol extraction is employed for extracting both nonpolar and highly polar lipids and metabolites from each biological sample. The extracted samples are then subjected to liquid chromatography-mass spectrometry-based assays to provide relative or semiquantitative measurements for hundreds of selected lipids and metabolites per sample. This high-throughput approach enables the generation of new hypotheses regarding the mechanistic and functional significance of lipid and metabolite alterations in neurodegenerative disorders while also facilitating the discovery of new biomarkers to support drug development.

Keywords:  Biomarker; Drug development; Drug discovery; Lipidomics; Lipids; Metabolomics; Neurodegeneration; Omics

DOI:  https://doi.org/10.1007/978-1-0716-3774-6_14
J Cell Physiol. 2024 Feb 25.

AMP-activated protein kinase as a mediator of mitochondrial dysfunction of multiple sclerosis in animal models: A systematic review.

Hamid Askari, Fatemeh Rabiei, Fatemeh Lohrasbi, Sara Ghadir, Ahmad Mehdipour Arbastan, Maryam Ghasemi-Kasman.

  Multiple sclerosis (MS) is a chronic central nervous system (CNS) disorder characterized by demyelination, neuronal damage, and oligodendrocyte depletion. Reliable biomarkers are essential for early diagnosis and disease management. Emerging research highlights the role of mitochondrial dysfunction and oxidative stress in CNS disorders, including MS, in which mitochondria are central to the degenerative process. Adenosine monophosphate-activated protein kinase (AMPK) regulates the mitochondrial energy balance and initiates responses in neurodegenerative conditions. This systematic review, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, aimed to comprehensively assess the literature on AMPK pathways, mitochondrial dysfunction, and in vivo studies using MS animal models. The search strategy involved the use of AMPK syntaxes, MS syntaxes, and animal model syntaxes. The PubMed, Scopus, Web of Science, and Google Scholar databases were systematically searched on August 26, 2023 without publication year restrictions. The review identified and analyzed relevant papers to provide a comprehensive overview of the current state of related research. Eight studies utilizing various interventions and methodological approaches were included. Risk of bias assessment revealed some areas of low risk but lacked explicit reporting in others. These studies collectively revealed a complex relationship between AMPK, mitochondrial dysfunction, and MS pathogenesis, with both cuprizone and experimental autoimmune encephalomyelitis models demonstrating associations between AMPK and mitochondrial disorders, including oxidative stress and impaired expression of mitochondrial genes. These studies illuminate the multifaceted role of AMPK in MS animal models, involving energy metabolism, inflammatory processes, oxidative stress, and gene regulation leading to mitochondrial dysfunction. However, unanswered questions about its mechanisms and clinical applications underscore the need for further research to fully harness its potential in addressing MS-related mitochondrial dysfunction.

Keywords:  AMP-activated protein kinase; biomarkers; mitochondrial dysfunction; multiple sclerosis; neurodegenerative conditions; oxidative Stress

DOI:  https://doi.org/10.1002/jcp.31230
J Cell Biol. 2024 Apr 01. pii: e202211062. [Epub ahead of print]223(4):

Fatty acid-binding proteins 3, 7, and 8 bind cholesterol and facilitate its egress from lysosomes.

Xian-Xiu Fang, Pengcheng Wei, Kai Zhao, Zhao-Chen Sheng, Bao-Liang Song, Lei Yin, Jie Luo.

Cholesterol from low-density lipoprotein (LDL) can be transported to many organelle membranes by non-vesicular mechanisms involving sterol transfer proteins (STPs). Fatty acid-binding protein (FABP) 7 was identified in our previous study searching for new regulators of intracellular cholesterol trafficking. Whether FABP7 is a bona fide STP remains unknown. Here, we found that FABP7 deficiency resulted in the accumulation of LDL-derived cholesterol in lysosomes and reduced cholesterol levels on the plasma membrane. A crystal structure of human FABP7 protein in complex with cholesterol was resolved at 2.7 Å resolution. In vitro, FABP7 efficiently transported the cholesterol analog dehydroergosterol between the liposomes. Further, the silencing of FABP3 and 8, which belong to the same family as FABP7, caused robust cholesterol accumulation in lysosomes. These two FABP proteins could transport dehydroergosterol in vitro as well. Collectively, our results suggest that FABP3, 7, and 8 are a new class of STPs mediating cholesterol egress from lysosomes.

DOI: https://doi.org/10.1083/jcb.202211062
Methods Mol Biol. 2024 ;2772 137-148

ER Membrane Lipid Composition and Metabolism: Lipidomic Analysis.

Laetitia Fouillen, Lilly Maneta-Peyret, Patrick Moreau.

  Plant ER membranes are the major site of biosynthesis of several lipid families (phospholipids, sphingolipids, neutral lipids such as sterols and triacylglycerols). The structural diversity of lipids presents considerable challenges to comprehensive lipid analysis. This chapter will briefly review the various biosynthetic pathways and will detail several aspects of the lipid analysis: lipid extraction, handling, separation, detection, identification, and data presentation. The different tools/approaches used for lipid analysis will also be discussed in relation to the studies to be carried out on lipid metabolism and function.

Keywords:  Ceramides; GC-FID; GC-MS; Glucosylceramides; HPTLC; LC-MS; Long-chain bases (LCB); Phospholipids; Phytosterols; Triacylglycerols

DOI:  https://doi.org/10.1007/978-1-0716-3710-4_10
Sci Transl Med. 2024 Feb 28. 16(736): eadg5116

APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model.

Shihe Jiang, Xindi Li, Yan Li, Zhilin Chang, Meng Yuan, Ying Zhang, Huimin Zhu, Yuwen Xiu, Hengri Cong, Linlin Yin, Zhen-Wei Yu, Junwan Fan, Wenyan He, Kaibin Shi, De-Cai Tian, Jing Zhang, Alexei Verkhratsky, Wei-Na Jin, Fu-Dong Shi.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE-/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

DOI: https://doi.org/10.1126/scitranslmed.adg5116
Orphanet J Rare Dis. 2024 Feb 28. 19(1): 92

Lack of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile-onset brainstem neurodegenerative disease with early lethality.

Firas Abu Hanna, Yoav Zehavi, Eran Cohen-Barak, Morad Khayat, Nasim Warwar, Roni Shreter, Richard J Rodenburg, Ronen Spiegel.

   BACKGROUND: Congenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among them, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Biallelic pathogenic variants in NDUFAF2, encoding the nuclear assembly CI factor NDUFAF2, were initially reported to cause progressive encephalopathy beginning in infancy. Since the initial report in 2005, less than a dozen patients with NDUFAF2-related disease have been reported.
METHODS: Clinical, biochemical, and neuroradiological features of four new patients residing in Northern Israel were collected during 2016-2022 at Emek Medical Center. Enzymatic activities of the five respiratory-chain complexes were determined in isolated fibroblast mitochondria by spectrophotometric methods. Western blot analyses were conducted with anti-human NDUFAF2 antibody; antibody against the mitochondrial marker VDAC1 was used as a loading control. Genetic studies were performed by chromosome microarray analysis using Affymetrix CytoScan 750 K arrays.
RESULTS: All four patients presented with infantile-onset growth retardation, ophthalmological impairments with nystagmus, strabismus (starting between 5 and 9 months), and further progressed to life-threatening episodes of apnea usually triggered by trivial febrile illnesses (between 10 and 18 months) with gradual loss of acquired developmental milestones (3 of 4 patients). Serial magnetic-resonance imaging studies in two of the four patients showed a progressive pattern of abnormal T2-weighted hyperintense signals involving primarily the brainstem, the upper cervical cord, and later, the basal ganglia and thalami. Magnetic-resonance spectroscopy in one patient showed an increased lactate peak. Disease progression was marked by ventilatory dependency and early lethality. 3 of the 4 patients tested, harbored a homozygous 142-kb partial interstitial deletion that omits exons 2-4 of NDUFAF2. Mitochondrial CI activity was significantly decreased in the only patient tested. Western blot analysis disclosed the absence of NDUFAF2 protein compared to normal controls. In addition, we reviewed all 10 previously reported NDUFAF2-deficient cases to better characterize the disease.
CONCLUSIONS: Biallelic loss-of-function mutations in NDUFAF2 result in a distinctive phenotype in the spectrum of Leigh syndrome with clinical and neuroradiological features that are primarily attributed to progressive brainstem damage.

Keywords:   NDUFAF2 gene; Leigh syndrome; Mitochondrial disease; Optic neuropathy; Oxidative phosphorylation

DOI:  https://doi.org/10.1186/s13023-024-03094-0
Biol Psychiatry. 2024 Feb 22. pii: S0006-3223(24)01106-5. [Epub ahead of print]

A metabolome-wide Mendelian randomization study identifies dysregulated arachidonic acid synthesis as a potential causal risk factor for bipolar disorder.

David Stacey, Beben Benyamin, S Hong Lee, Elina Hyppönen.

   BACKGROUND: Bipolar disorder (BPD) is a debilitating mood disorder with an unclear aetiology. A better understanding of the underlying pathophysiological mechanisms will help to identify novel targets for improved treatment options and prevention strategies. In this metabolome-wide Mendelian randomization study, we screened for metabolites that may have a causal role in BPD.
METHODS: We tested a total of 913 circulating metabolite exposures assessed in 14,296 Europeans using a mass spectrometry-based platform. For the BPD outcome, we used summary data from the largest and most recent genome-wide association study (GWAS) to date, including 41,917 BPD cases.
RESULTS: We identified 33 metabolites associated with BPD (padj<5.48x10-5). Most of them were lipids, including arachidonic acid (β=-0.154, se=0.023, p=3.30x10-11), a polyunsaturated omega-6 fatty acid, along with several complex lipids containing either an arachidonic or a linoleic fatty acid side chain. These associations did not extend to other closely related psychiatric disorders like schizophrenia or depression, though they may be involved in the regulation of lithium response. These lipid associations were driven by genetic variants within the FADS1/2/3 gene cluster, which is a robust BPD risk locus encoding a family of fatty acid desaturase enzymes responsible for catalysing the conversion of linoleic into arachidonic acid. Statistical colocalization analyses indicated that 27 of the 33 metabolites share the same genetic aetiology with BPD at the FADS1/2/3 cluster, demonstrating that our findings are not confounded by linkage disequilibrium.
CONCLUSIONS: Overall, our findings support the notion that ARA and other polyunsaturated fatty acids may represent potential targets for BPD.

Keywords:  Bipolar disorder; FADS1/2/3 gene cluster; Genetics; Mendelian randomization; arachidonic acid; metabolomics

DOI:  https://doi.org/10.1016/j.biopsych.2024.02.1005
Life Sci. 2024 Feb 28. pii: S0024-3205(24)00126-7. [Epub ahead of print] 122537

Sirtuin dysregulation in Parkinson's disease: Implications of acetylation and deacetylation processes.

Sonia Dhiman, Ashi Mannan, Ayushi Taneja, Maneesh Mohan, Thakur Gurjeet Singh.

  Parkinson's disease (PD) is a progressive neurodegenerative condition that primarily affects motor function and is caused by a gradual decline of dopaminergic neurons in the brain's substantia pars compacta (Snpc) region. Multiple molecular pathways are involved in the pathogenesis, which results in impaired cellular functions and neuronal degeneration. However, the role of sirtuins, a type of NAD+-dependent deacetylase, in the pathogenesis of Parkinson's disease has recently been investigated. Sirtuins are essential for preserving cellular homeostasis because they control a number of biological processes, such as metabolism, apoptosis, and DNA repair. This review shed lights on the dysregulation of sirtuin activity in PD, highlighting the role that acetylation and deacetylation processes play in the development of the disease. Key regulators of protein acetylation, sirtuins have been found to be involved in the aberrant acetylation of vital substrates linked to PD pathology when their balance is out of balance. The hallmark characteristics of PD such as neuroinflammation, oxidative stress, and mitochondrial dysfunction have all been linked to the dysregulation of sirtuin expression and activity. Furthermore, we have also explored how the modulators of sirtuins can be a promising therapeutic intervention in the treatment of PD.

Keywords:  Acetylation; Deacetylation; Mitochondrial dysfunction; Neuroinflammation; Oxidative stress; Parkinson's disease; Protein aggregation; Sirtuins

DOI:  https://doi.org/10.1016/j.lfs.2024.122537
Front Genet. 2024 ;15 1355962

Brain function in classic galactosemia, a galactosemia network (GalNet) members review.

Bianca Panis, E Naomi Vos, Ivo Barić, Annet M Bosch, Martijn C G J Brouwers, Alberto Burlina, David Cassiman, David J Coman, María L Couce, Anibh M Das, Didem Demirbas, Aurélie Empain, Matthias Gautschi, Olga Grafakou, Stephanie Grunewald, Sandra D K Kingma, Ina Knerr, Elisa Leão-Teles, Dorothea Möslinger, Elaine Murphy, Katrin Õunap, Adriana Pané, Sabrina Paci, Rossella Parini, Isabel A Rivera, Sabine Scholl-Bürgi, Ida V D Schwartz, Triantafyllia Sdogou, Loai A Shakerdi, Anastasia Skouma, Karolina M Stepien, Eileen P Treacy, Susan Waisbren, Gerard T Berry, M Estela Rubio-Gozalbo.

  Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.

Keywords:  brain; classic galactosemia; cognitive problems; galactose; movement disorders; neurodevelopment; neuropsychiatry

DOI:  https://doi.org/10.3389/fgene.2024.1355962
Methods Mol Biol. 2024 ;2761 457-475

Promises of Lipid-Based Nanocarriers for Delivery of Dimethyl Fumarate to Multiple Sclerosis Brain.

Sreya Subhash, Nishtha Chaurawal, Kaisar Raza.

  Multiple sclerosis (MS) is a neurodegenerative autoimmune disorder of the central nervous system (CNS) infecting 2.5 million people worldwide. It is the most common nontraumatic neurological impairment in young adults. The blood-brain barrier rupture for multiple sclerosis pathogenesis has two effects: first, during the onset of the immunological attack, and second, for the CNS self-sustained "inside-out" demyelination and neurodegeneration processes. In addition to genetic variations, environmental and lifestyle variables can also significantly increase the risk of developing MS. Dimethyl fumarate (DMF) and sphingosine-1-phosphate (S1P) receptor modulators that may pass the blood-brain barrier and have positive direct effects in the CNS with quite diverse mechanisms of action raise the possibility that a combination therapy could be successful in treating MS. Lipid nanocarriers are recognized as one of the best drug delivery techniques to the brain for effective brain delivery. Numerous scientific studies have shown that lipid nanoparticles can enhance the lipid solubility, oral bioavailability, and brain availability of the drugs. Nanolipidic carriers for DMF delivery could be derived through vitamin D, tocopherol acetate, stearic acid, quercetin, cell-mimicking platelet-based, and chitosan-alginate core-shell-corona-shaped nanoparticles. Clinical and laboratory diagnosis of MS can be performed mainly through magnetic resonance imaging. The advancements in nanotechnology have enabled the clinicians to cross the blood-brain barrier and to target the brain and central nervous system of the patient with multiple sclerosis.

Keywords:  Blood–brain barrier (BBB); Dimethyl fumarate (DMF); Lipid nanocarriers; Multiple sclerosis (MS); Pharmacokinetics; Targeted brain delivery

DOI:  https://doi.org/10.1007/978-1-0716-3662-6_31
Trends Endocrinol Metab. 2024 Feb 27. pii: S1043-2760(24)00038-9. [Epub ahead of print]

Mitochondrial dysfunction in lipid processing and gastrointestinal disorders.

Yan Hu, Hao Huang, Rong Xiang.

  Mitochondrial dysfunctions predominantly cause encephalomyopathies with muscle atrophy and neurodegeneration. However, their impact on other tissues, particularly the gastrointestinal tract, requires further investigation. In a recent report in Nature, Moschandrea et al. used mice deficient in the mitochondrial aminoacyl-tRNA synthetase DARS2 to investigate the role of enterocytic mitochondria in dietary lipid processing and transport. Their work sheds light on the development of gastrointestinal disorders as a result of mitochondrial dysfunction.

Keywords:  DARS2; gastrointestinal disorders; lipid processing; mitochondria; mitochondrial aminoacyl-tRNA synthetases (mt-AaRSs)

DOI:  https://doi.org/10.1016/j.tem.2024.02.009
Ageing Res Rev. 2024 Feb 24. pii: S1568-1637(24)00066-7. [Epub ahead of print] 102248

The effect of Ferroptosis -related Mitochondrial Dysfunction in the Development of Temporal Lobe Epilepsy.

Yang Su, Ningrui Cao, Dingkun Zhang, Minjin Wang.

  Temporal lobe epilepsy (TLE) is the most common form of epileptic syndrome. It has been established that due to its complex pathogenesis, a considerable proportion of TLE patients often progress to drug-resistant epilepsy. Ferroptosis has emerged as an important neuronal death mechanism in TLE, which is primarily influenced by lipid accumulation and oxidative stress. In previous studies of ferroptosis, more attention has been focused on the impact of changes in the levels of proteins related to the redox equilibrium and signaling pathways on epileptic seizures. However, it is worth noting that the oxidative-reduction changes in different organelles may have different pathophysiological significance in the process of ferroptosis-related diseases. Mitochondria, as a key organelle involved in ferroptosis, its structural damage and functional impairment can lead to energy metabolism disorders and disruption of the excitatory inhibitory balance, significantly increasing the susceptibility to epileptic seizures. Therefore, secondary mitochondrial dysfunction in the process of ferroptosis could play a crucial role in TLE pathogenesis. This review focuses on ferroptosis and mitochondria, discussing the pathogenic role of ferroptosis-related mitochondrial dysfunction in TLE, thus aiming to provide novel insights and potential implications of ferroptosis-related secondary mitochondrial dysfunction in epileptic seizures and to offer new insights for the precise exploration of ferroptosis-related therapeutic targets for TLE patients.

Keywords:  Ferroptosis; Iron Overload; Mitochondrial Dysfunction; Oxidative Stress; Temporal Lobe Epilepsy

DOI:  https://doi.org/10.1016/j.arr.2024.102248
iScience. 2024 Mar 15. 27(3): 109189

Chemical inhibition of phosphatidylcholine biogenesis reveals its role in mitochondrial division.

Hiroya Shiino, Shinya Tashiro, Michiko Hashimoto, Yuki Sakata, Takamitsu Hosoya, Toshiya Endo, Hirotatsu Kojima, Yasushi Tamura.

  Phospholipids are major components of biological membranes and play structural and regulatory roles in various biological processes. To determine the biological significance of phospholipids, the use of chemical inhibitors of phospholipid metabolism offers an effective approach; however, the availability of such compounds is limited. In this study, we performed a chemical-genetic screening using yeast and identified small molecules capable of inhibiting phosphatidylcholine (PC) biogenesis, which we designated PC inhibitors 1, 2, 3, and 4 (PCiB-1, 2, 3, and 4). Biochemical analyses indicated that PCiB-2, 3, and 4 inhibited the phosphatidylethanolamine (PE) methyltransferase activity of Cho2, whereas PCiB-1 may inhibit PE transport from mitochondria to the endoplasmic reticulum (ER). Interestingly, we found that PCiB treatment resulted in mitochondrial fragmentation, which was suppressed by expression of a dominant-negative mutant of the mitochondrial division factor Dnm1. These results provide evidence that normal PC biogenesis is important for the regulation of mitochondrial division.

Keywords:  Biochemistry; Biological sciences; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.109189
J Integr Neurosci. 2024 Feb 19. 23(2): 39

No Effects of Decanoic Acid on Locomotor Activity and Antioxidant Defences in an Experimental Animal Model of Attention-Deficit/Hyperactivity Disorder.

Sonia Carreón-Trujillo, Juan Carlos Corona.

   BACKGROUND: Medium-chain triglycerides such as decanoic acid (C10), which is one of the fatty acids that constitute dietary fats, are of substantial interest for their potential therapeutic effects on neuropsychiatric disorders. However, the effects of C10 on attention-deficit/hyperactivity disorder (ADHD) remain to be studied. We explored the effects of C10 on behavioural activity and antioxidant defences in an experimental animal model of ADHD.
METHODS: To establish an experimental animal model of ADHD, neonatal rats were subjected to unilateral striatal lesions using 6-hydroxydopamine (6-OHDA). The rats sequentially underwent open-field and Y-maze tests before treatment [postnatal day 25 (PN25)]. After the subcutaneous administration of either vehicle or C10 solution (250 mg/kg) for 14 days, the behavioural tests were repeated on PN39. Next, we examined the effects of C10 on the expression of the constitutive antioxidant enzymes catalase and glutathione peroxidase-1/2 and the phase II transcription factor nuclear factor erythroid 2-related factor 2 in four different regions of the rat brain.
RESULTS: Injection of 6-OHDA unilaterally into the striatum resulted in elevated locomotor activity on PN39. The administration of C10 for a period of 14 days did not alter the locomotor hyperactivity. Moreover, the administration of C10 had no significant effects on the expression of proteins related to antioxidant defences in the hippocampus, prefrontal cortex, striatum or cerebellum of both control and lesioned rats.
CONCLUSIONS: The lack of significant effects of C10 in our study may depend on the dose and duration of C10 administration. Further exhaustive studies are needed to verify the efficacy and effects of different doses and treatment durations of C10 and to explore the underlying mechanisms.

Keywords:  6-OHDA; ADHD; antioxidant defences; behavioural activity; decanoic acid

DOI:  https://doi.org/10.31083/j.jin2302039
Biochem Biophys Res Commun. 2024 Feb 02. pii: S0006-291X(24)00123-2. [Epub ahead of print]704 149588

The 3-hydroxyacyl-CoA dehydratase 1/2 form complex with trans-2-enoyl-CoA reductase involved in substrates transfer in very long chain fatty acid elongation.

Youli Zhou, Rui Lv, Richard D Ye, Ruobing Ren, Leiye Yu.

  Very long-chain fatty acids (VLCFAs) are fatty acids with a carbon chain length greater than 18 carbons (>C18) and exhibit various functions, such as in skin barrier formation, liver homeostasis, myelin maintenance, spermatogenesis, retinal function, and anti-inflammation. VLCFAs are absorbed by dietary or elongated from endogenous hexadecanoyl acids (C16). Similar to long-chain fatty acid synthesis, VLCFAs elongation begins with acyl-CoA and malonyl-CoA as sources, and the length of the acyl chain is extended by two carbon units in each cycle. However, the VLCFAs elongation machinery is located in ER membrane and consists of four components, FA elongase (ELOVL), 3-ketoacyl-CoA reductase (KAR), 3-hydroxyacyl-CoA dehydratase (HACD), and trans-2-enoyl-CoA reductase (TECR), which is different with the long-chain fatty acid machinery fatty acid synthase (FAS) complex. Although the critical components in the elongation cycle are identified, the detailed catalytic and regulation mechanisms are still poorly understood. Here, we focused on the structural and biochemical analysis of TECR-associated VLCFA elongation reactions. Firstly, we identified a stable complex of human HACD2-TECR based on extensive in vitro characterizations. Combining computational modeling and biochemical analysis, we confirmed the critical interactions between TECR and HACD1/2. Then, we proposed the putative substrate binding sites and catalytic residues for TECR and HACD2. Besides, we revealed the structural similarities of HACD with ELOVLs and proposed the possible competition mechanism of TECR-associated complex formation.

Keywords:  ELOVL; Fatty acid elongation; HACD; TECR; Very long-chain fatty acid

DOI:  https://doi.org/10.1016/j.bbrc.2024.149588
Methods Mol Biol. 2024 ;2761 49-55

High-Resolution Respirometry for Mitochondrial Function in Rodent Brain.

Aishika Datta, Deepaneeta Sarmah, Bijoyani Ghosh, Nikita Rana, Anupom Borah, Pallab Bhattacharya.

  High-resolution mitochondrial respirometry is a modern technique that enables to measure mitochondrial respiration in various cell types. It contains chambers with oxygen sensors that measure oxygen concentration via polarography and calculate its consumption. The chamber contains plastic stoppers with injection ports that allow the injection of samples and different substrates, inhibitors, and uncoupler substances to measure mitochondrial respiration with high efficiency. These substances act on the mitochondrial electron transport chain (ETC) and help to assess the mitochondrial ATP production capacity and oxidative phosphorylation. The respirograph obtained with the help of software represents the oxygen consumption in each stage after adding different reagents.

Keywords:  ATP; High-resolution respirometry; Mitochondria; OXPHOS; Respiratory control ratio; SUIT protocol

DOI:  https://doi.org/10.1007/978-1-0716-3662-6_4
Front Chem. 2024 ;12 1334209

Optimized combination of MALDI MSI and immunofluorescence for neuroimaging of lipids within cellular microenvironments.

Catelynn C Shafer, Elizabeth K Neumann.

  Proper neurological function relies on the cellular and molecular microenvironment of the brain, with perturbations of this environment leading to neurological disorders. However, studying the microenvironments of neurological tissue has proven difficult because of its inherent complexity. Both the cell type and metabolomic underpinnings of the cell have crucial functional roles, thus making multimodal characterization methods key to acquiring a holistic view of the brain's microenvironment. This study investigates methods for combining matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) and immunofluorescence (IF) microscopy to enable the concurrent investigation of cell types and lipid profiles on the same sample. In brief, 1,5-diaminonaphthalene (DAN), α-cyano-4-hydroxy-cinnamic acid (CHCA), and 2,5-dihydroxybenzoic acid (DHB) were tested in addition to instrument-specific parameters for compatibility with IF. Alternatively, the effects of IF protocols on MALDI MSI were also tested, showing significant signal loss with all tested permutations. Ultimately, the use of CHCA for MALDI MSI resulted in the best IF images, while the use of DAN gave the lowest quality IF images. Overall, increasing the laser power and number of shots per laser burst resulted in the most tissue ablation. However, optimized parameter settings allowed for minimal tissue ablation while maintaining sufficient MALDI MSI signal.

Keywords:  astrocyte; immunofluorecence; mass spec imaging; mass spectrometry; multimodal; neuroscience

DOI:  https://doi.org/10.3389/fchem.2024.1334209