bims-medebr 2024-04-14 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–04–14
thirty papers selected by
Regina F. Fernández, Johns Hopkins University

Preface: Special issue: 14th International Conference on Brain Energy Metabolism: Energy substrates and microbiome govern brain bioenergetics and cognitive function with aging.
Neuroprotective effects of lactate and ketone bodies in acute brain injury.
Progress in The Research of Lactate Metabolism Disruption And Astrocyte-Neuron Lactate Shuttle Impairment in Schizophrenia: A Comprehensive Review.
Effects of APOE4 on omega-3 brain metabolism across the lifespan.
Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons.
S-Adenosyl-l-methionine restores brain mitochondrial membrane fluidity and GSH content improving Niemann-Pick type C disease.
Impact of cannabidiol on brain glucose metabolism of C57Bl/6 male mice previously exposed to cocaine.
Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination.
Daily fluctuations in blood glucose with normal aging are inversely related to hippocampal synaptic mitochondrial proteins.
Mitochondrial Permeability Transition, Cell Death and Neurodegeneration.
1H and 31P magnetic resonance spectroscopy reveals potential pathogenic and biomarker metabolite alterations in Lafora disease.
Nervonic Acid Synthesis Substrates as Essential Components in Profiled Lipid Supplementation for More Effective Central Nervous System Regeneration.
Cockayne Syndrome Patient iPSC-Derived Brain Organoids and Neurospheres Show Early Transcriptional Dysregulation of Biological Processes Associated with Brain Development and Metabolism.
Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease.
Fasting upregulates the monocarboxylate transporter MCT1 at the rat blood-brain barrier through PPAR δ activation.
Cytosolic RNA binding of the mitochondrial TCA cycle enzyme malate dehydrogenase (MDH2).
Editorial: Movement disorders in neurometabolic conditions.
Preconditioning-induced facilitation of lactate release from astrocytes is essential for brain ischemic tolerance.
Arachidonic acid and docosahexaenoic acid levels correlate with the inflammation proteome in extremely preterm infants.
Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
Energy metabolic pathways in neuronal development and function.
The lipid droplet lipidome.
Targeting VDAC: A potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.
Determination of fatty acid uptake and desaturase activity in mammalian cells by NMR-based stable isotope tracing.
Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α.
The following article for this Special Issue was previously published and can be found in its respective issue online: "How can I measure brain acetylcholine levels in vivo? Advantages and caveats of commonly used approaches".
An energy-conserving reaction in amino acid metabolism catalyzed by arginine synthetase.
Inhibition of Crif1 protects fatty acid-induced POMC neuron damage by increasing CPT-1 function.
Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.
Glutaminase deficiency in rod photoreceptors disrupts nonessential amino acid levels to activate the integrated stress response and induce rapid degeneration.

J Neurochem. 2024 Apr 12.

Preface: Special issue: 14th International Conference on Brain Energy Metabolism: Energy substrates and microbiome govern brain bioenergetics and cognitive function with aging.

Mary C McKenna, In-Young Choi, Arne Schousboe.

  This Preface introduces the Special Issue entitled, "Energy Substrates and Microbiome Govern Brain Bioenergetics and Cognitive Function with Aging", which is comprised of manuscripts contributed by invited speakers and program/organizing committee members who participated in the 14th International Conference on Brain Energy Metabolism (ICBEM) held on October 24-27, 2022 in Santa Fe, New Mexico, USA. The conference covered the latest developments in research related to neuronal energetics, emerging roles for glycogen in higher brain functions, the impact of dietary intervention on aging, memory, and Alzheimer's disease, roles of the microbiome in gut-brain signaling, astrocyte-neuron interactions related to cognition and memory, novel roles for mitochondria and their metabolites, and metabolic neuroimaging in aging and neurodegeneration. The special issue contains 25 manuscripts on these topics plus three tributes to outstanding scientists who have made important contributions to brain energy metabolism and participated in numerous ICBEM conferences. In addition, two of the manuscripts describe important directions and the rationale for future research in many thematic areas covered by the conference.

Keywords:  Alzheimer's; aging; astrocyte‐neuron interactions; bioenergetics; brain energy metabolism; cognitive function; glycogen; memory; metabolic neuroimaging; mitochondria; spreading depolarization

DOI:  https://doi.org/10.1111/jnc.16094
J Cereb Blood Flow Metab. 2024 Apr 11. 271678X241245486

Neuroprotective effects of lactate and ketone bodies in acute brain injury.

Guillaume Plourde, Hélène Roumes, Laurent Suissa, Lorenz Hirt, Émilie Doche, Luc Pellerin, Anne-Karine Bouzier-Sore, Hervé Quintard.

  The goal of neurocritical care is to prevent and reverse the pathologic cascades of secondary brain injury by optimizing cerebral blood flow, oxygen supply and substrate delivery. While glucose is an essential energetic substrate for the brain, we frequently observe a strong decrease in glucose delivery and/or a glucose metabolic dysregulation following acute brain injury. In parallel, during the last decades, lactate and ketone bodies have been identified as potential alternative fuels to provide energy to the brain, both under physiological conditions and in case of glucose shortage. They are now viewed as integral parts of brain metabolism. In addition to their energetic role, experimental evidence also supports their neuroprotective properties after acute brain injury, regulating in particular intracranial pressure control, decreasing ischemic volume, and leading to an improvement in cognitive functions as well as survival. In this review, we present preclinical and clinical evidence exploring the mechanisms underlying their neuroprotective effects and identify research priorities for promoting lactate and ketone bodies use in brain injury.

Keywords:  Alternative brain fuels; TBI; brain metabolism; hypoxia; ketone bodies; lactate; neuroprotection; stroke

DOI:  https://doi.org/10.1177/0271678X241245486
Adv Biol (Weinh). 2024 Apr 10. e2300409

Progress in The Research of Lactate Metabolism Disruption And Astrocyte-Neuron Lactate Shuttle Impairment in Schizophrenia: A Comprehensive Review.

Yingying Zhang, Liang Tong, Li Ma, Hong Ye, Shue Zeng, Shaochuan Zhang, Yu Ding, Weiwei Wang, Tianhao Bao.

  Schizophrenia (SCZ) is a complex neuropsychiatric disorder widely recognized for its impaired bioenergy utilization. The astrocyte-neuron lactate shuttle (ANLS) plays a critical role in brain energy supply. Recent studies have revealed abnormal lactate metabolism in SCZ, which is associated with mitochondrial dysfunction, tissue hypoxia, gastric acid retention, oxidative stress, neuroinflammation, abnormal brain iron metabolism, cerebral white matter hypermetabolic activity, and genetic susceptibility. Furthermore, astrocytes, neurons, and glutamate abnormalities are prevalent in SCZ with abnormal lactate metabolism, which are essential components for maintaining ANLS in the brain. Therefore, an in-depth study of the pathophysiological mechanisms of ANLS in SCZ with abnormal lactate metabolism will contribute to a better understanding of the pathogenesis of SCZ and provide new ideas and approaches for the diagnosis and treatment of SCZ.

Keywords:  astrocyte‐neuron lactate shuttle (ANLS); glutamate; l‐lactate; schizophrenia (SCZ)

DOI:  https://doi.org/10.1002/adbi.202300409
Trends Endocrinol Metab. 2024 Apr 11. pii: S1043-2760(24)00065-1. [Epub ahead of print]

Effects of APOE4 on omega-3 brain metabolism across the lifespan.

Brandon Ebright, Marlon V Duro, Kai Chen, Stan Louie, Hussein N Yassine.

  Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), have important roles in human nutrition and brain health by promoting neuronal functions, maintaining inflammatory homeostasis, and providing structural integrity. As Alzheimer's disease (AD) pathology progresses, DHA metabolism in the brain becomes dysregulated, the timing and extent of which may be influenced by the apolipoprotein E ε4 (APOE4) allele. Here, we discuss how maintaining adequate DHA intake early in life may slow the progression to AD dementia in cognitively normal individuals with APOE4, how recent advances in DHA brain imaging could offer insights leading to more personalized preventive strategies, and how alternative strategies targeting PUFA metabolism pathways may be more effective in mitigating disease progression in patients with existing AD dementia.

Keywords:  APOE4; Alzheimer’s; DHA; fatty acids; imaging

DOI:  https://doi.org/10.1016/j.tem.2024.03.003
Glia. 2024 Apr 08.

Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons.

Erik Späte, Baoyu Zhou, Ting Sun, Kathrin Kusch, Ebrahim Asadollahi, Sophie B Siems, Constanze Depp, Hauke B Werner, Gesine Saher, Johannes Hirrlinger, Wiebke Möbius, Klaus-Armin Nave, Sandra Goebbels.

  Oligodendrocytes and astrocytes are metabolically coupled to neuronal compartments. Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters. However, lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions. Here we show that mice with a cell type-specific disruption of both Ldha and Ldhb genes in oligodendrocytes lack a pathological phenotype that would be indicative of oligodendroglial dysfunctions or lack of axonal metabolic support. Indeed, when combining immunohistochemical, electron microscopical, and in situ hybridization analyses in adult mice, we found that the vast majority of mature oligodendrocytes lack detectable expression of LDH. Even in neurodegenerative disease models and in mice under metabolic stress LDH was not increased. In contrast, at early development and in the remyelinating brain, LDHA was readily detectable in immature oligodendrocytes. Interestingly, by immunoelectron microscopy LDHA was particularly enriched at gap junctions formed between adjacent astrocytes and at junctions between astrocytes and oligodendrocytes. Our data suggest that oligodendrocytes metabolize lactate during development and remyelination. In contrast, for metabolic support of axons mature oligodendrocytes may export their own glycolysis products as pyruvate rather than lactate. Lacking LDH, these oligodendrocytes can also "funnel" lactate through their "myelinic" channels between gap junction-coupled astrocytes and axons without metabolizing it. We suggest a working model, in which the unequal cellular distribution of LDH in white matter tracts facilitates a rapid and efficient transport of glycolysis products among glial and axonal compartments.

Keywords:  2′,3′‐cyclic nucleotide phosphodiesterase (CNP); glycolysis; lactate, lactate dehydrogenase (LDH, LDHA, LDHB); metabolic support; myelin; oligodendrocyte; optic nerve; white matter

DOI:  https://doi.org/10.1002/glia.24533
Redox Biol. 2024 Apr 03. pii: S2213-2317(24)00126-5. [Epub ahead of print]72 103150

S-Adenosyl-l-methionine restores brain mitochondrial membrane fluidity and GSH content improving Niemann-Pick type C disease.

Leire Goicoechea, Sandra Torres, Laura Fàbrega, Mónica Barrios, Susana Núñez, Josefina Casas, Gemma Fabrias, Carmen García-Ruiz, José C Fernández-Checa.

  Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by impaired motor coordination due to neurological defects and cerebellar dysfunction caused by the accumulation of cholesterol in endolysosomes. Besides the increase in lysosomal cholesterol, mitochondria are also enriched in cholesterol, which leads to decreased membrane fluidity, impaired mitochondrial function and loss of GSH, and has been shown to contribute to the progression of NPC disease. S-Adenosyl-l-methionine (SAM) regulates membrane physical properties through the generation of phosphatidylcholine (PC) from phosphatidylethanolamine (PE) methylation and functions as a GSH precursor by providing cysteine in the transsulfuration pathway. However, the role of SAM in NPC disease has not been investigated. Here we report that Npc1-/- mice exhibit decreased brain SAM levels but unchanged S-adenosyl-l-homocysteine content and lower expression of Mat2a. Brain mitochondria from Npc1-/- mice display decreased mitochondrial GSH levels and liquid chromatography-high resolution mass spectrometry analysis reveal a lower PC/PE ratio in mitochondria, contributing to increased mitochondrial membrane order. In vivo treatment of Npc1-/- mice with SAM restores SAM levels in mitochondria, resulting in increased PC/PE ratio, mitochondrial membrane fluidity and subsequent replenishment of mitochondrial GSH levels. In vivo SAM treatment improves the decline of locomotor activity, increases Purkinje cell survival in the cerebellum and extends the average and maximal life spam of Npc1-/- mice. These findings identify SAM as a potential therapeutic approach for the treatment of NPC disease.

Keywords:  Antioxidants; Membrane fluidity; Mitochondrial GSH; Neurodegeneration

DOI:  https://doi.org/10.1016/j.redox.2024.103150
J Neurosci Res. 2024 Apr;102(4): e25327

Impact of cannabidiol on brain glucose metabolism of C57Bl/6 male mice previously exposed to cocaine.

Lidia Emmanuela Wiazowski Spelta, Caroline Cristiano Real, Vitor Bruno, Carlos Alberto Buchpiguel, Raphael Caio Tamborelli Garcia, Larissa Helena Torres, Daniele de Paula Faria, Tania Marcourakis.

  Despite evidence of the beneficial effects of cannabidiol (CBD) in animal models of cocaine use disorder (CUD), CBD neuronal mechanisms remain poorly understood. This study investigated the effects of CBD treatment on brain glucose metabolism, in a CUD animal model, using [18F]FDG positron emission tomography (PET). Male C57Bl/6 mice were injected with cocaine (20 mg/kg, i.p.) every other day for 9 days, followed by 8 days of CBD administration (30 mg/kg, i.p.). After 48 h, animals were challenged with cocaine. Control animals received saline/vehicle. [18F]FDG PET was performed at four time points: baseline, last day of sensitization, last day of withdrawal/CBD treatment, and challenge. Subsequently, the animals were euthanized and immunohistochemistry was performed on the hippocampus and amygdala to assess the CB1 receptors, neuronal nuclear protein, microglia (Iba1), and astrocytes (GFAP). Results showed that cocaine administration increased [18F]FDG uptake following sensitization. CBD treatment also increased [18F]FDG uptake in both saline and cocaine groups. However, animals that were sensitized and challenged with cocaine, and those receiving only an acute cocaine injection during the challenge phase, did not exhibit increased [18F]FDG uptake when treated with CBD. Furthermore, CBD induced modifications in the integrated density of NeuN, Iba, GFAP, and CB1R in the hippocampus and amygdala. This is the first study addressing the impact of CBD on brain glucose metabolism in a preclinical model of CUD using PET. Our findings suggest that CBD disrupts cocaine-induced changes in brain energy consumption and activity, which might be correlated with alterations in neuronal and glial function.

Keywords:  18F‐FDG; PET; RRID:AB_2298772; RRID:AB_2336819; RRID:AB_2336990; RRID:AB_2337258; RRID:AB_2337959; RRID:AB_447623; RRID:AB_477010; RRID:AB_839504; RRID:SCR_016547; cannabidiol; cocaine; mouse model

DOI:  https://doi.org/10.1002/jnr.25327
J Biol Chem. 2024 Apr 04. pii: S0021-9258(24)01760-5. [Epub ahead of print] 107259

Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination.

Lance G A Nunes, Chi Ma, FuKun W Hoffmann, Ashley E Shay, Matthew W Pitts, Peter R Hoffmann.

  Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE) and plasmenyl-PE. Plasmenyl-PE is a key component of myelin and is characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant. In humans, multiple loss-of-function mutations in genes affecting plasmenyl-PE metabolism have been implicated in hereditary spastic paraplegia (HSP), including SELENOI. Herein, we developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of HSP. Resulting mice exhibited pronounced alterations in brain lipid composition, which coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly. Further studies revealed increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro. Altogether, these findings detail a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment.

Keywords:  Selenoprotein; corticospinal tract; ether lipid; hereditary spastic paraplegia; lipid peroxidation; myelin; oligodendrocyte

DOI:  https://doi.org/10.1016/j.jbc.2024.107259
Aging Brain. 2024 ;5 100116

Daily fluctuations in blood glucose with normal aging are inversely related to hippocampal synaptic mitochondrial proteins.

Paul W Braunstein, David J Horovitz, Andreina M Hampton, Fiona Hollis, Lori A Newman, Reilly T Enos, Joseph A McQuail.

  Defective brain glucose utilization is a hallmark of Alzheimer's disease (AD) while Type II diabetes and elevated blood glucose escalate the risk for AD in later life. Isolating contributions of normal aging from coincident metabolic or brain diseases could lead to refined approaches to manage specific health risks and optimize treatments targeted to susceptible older individuals. We evaluated metabolic, neuroendocrine, and neurobiological differences between young adult (6 months) and aged (24 months) male rats. Compared to young adults, blood glucose was significantly greater in aged rats at the start of the dark phase of the day but not during the light phase. When challenged with physical restraint, a potent stressor, aged rats effected no change in blood glucose whereas blood glucose increased in young adults. Tissues were evaluated for markers of oxidative phosphorylation (OXPHOS), neuronal glucose transport, and synapses. Outright differences in protein levels between age groups were not evident, but circadian blood glucose was inversely related to OXPHOS proteins in hippocampal synaptosomes, independent of age. The neuronal glucose transporter, GLUT3, was positively associated with circadian blood glucose in young adults whereas aged rats tended to show the opposite trend. Our data demonstrate aging increases daily fluctuations in blood glucose and, at the level of individual differences, negatively associates with proteins related to synaptic OXPHOS. Our findings imply that glucose dyshomeostasis may exacerbate metabolic aspects of synaptic dysfunction that contribute to risk for age-related brain disorders.

Keywords:  BDNF; Blood glucose; Glucose transport; Hippocampus; Normal aging; Oxidative phosphorylation; Synapse

DOI:  https://doi.org/10.1016/j.nbas.2024.100116
Cells. 2024 Apr 08. pii: 648. [Epub ahead of print]13(7):

Mitochondrial Permeability Transition, Cell Death and Neurodegeneration.

Artyom Y Baev, Andrey Y Vinokurov, Elena V Potapova, Andrey V Dunaev, Plamena R Angelova, Andrey Y Abramov.

  Neurodegenerative diseases are chronic conditions occurring when neurons die in specific brain regions that lead to loss of movement or cognitive functions. Despite the progress in understanding the mechanisms of this pathology, currently no cure exists to treat these types of diseases: for some of them the only help is alleviating the associated symptoms. Mitochondrial dysfunction has been shown to be involved in the pathogenesis of most the neurodegenerative disorders. The fast and transient permeability of mitochondria (the mitochondrial permeability transition, mPT) has been shown to be an initial step in the mechanism of apoptotic and necrotic cell death, which acts as a regulator of tissue regeneration for postmitotic neurons as it leads to the irreparable loss of cells and cell function. In this study, we review the role of the mitochondrial permeability transition in neuronal death in major neurodegenerative diseases, covering the inductors of mPTP opening in neurons, including the major ones-free radicals and calcium-and we discuss perspectives and difficulties in the development of a neuroprotective strategy based on the inhibition of mPTP in neurodegenerative disorders.

Keywords:  astrocyte; cell death; mitochondrial permeability transition; neurodegeneration; neuron

DOI:  https://doi.org/10.3390/cells13070648
Brain Commun. 2024 ;6(2): fcae104

1H and 31P magnetic resonance spectroscopy reveals potential pathogenic and biomarker metabolite alterations in Lafora disease.

Kimberly L Chan, Aparna Panatpur, Souad Messahel, Hamza Dahshi, Talon Johnson, Anke Henning, Jimin Ren, Berge A Minassian.

  Lafora disease is a fatal teenage-onset progressive myoclonus epilepsy and neurodegenerative disease associated with polyglucosan bodies. Polyglucosans are long-branched and as a result precipitation- and aggregation-prone glycogen. In mouse models, downregulation of glycogen synthase, the enzyme that elongates glycogen branches, prevents polyglucosan formation and rescues Lafora disease. Mouse work, however, has not yet revealed the mechanisms of polyglucosan generation, and few in vivo human studies have been performed. Here, non-invasive in vivo magnetic resonance spectroscopy (1H and 31P) was applied to test scan feasibility and assess neurotransmitter balance and energy metabolism in Lafora disease towards a better understanding of pathogenesis. Macromolecule-suppressed gamma-aminobutyric acid (GABA)-edited 1H magnetic resonance spectroscopy and 31P magnetic resonance spectroscopy at 3 and 7 tesla, respectively, were performed in 4 Lafora disease patients and a total of 21 healthy controls (12 for the 1H magnetic resonance spectroscopy and 9 for the 31PMRS). Spectra were processed using in-house software and fit to extract metabolite concentrations. From the 1H spectra, we found 33% lower GABA concentrations (P = 0.013), 34% higher glutamate + glutamine concentrations (P = 0.011) and 24% lower N-acetylaspartate concentrations (P = 0.0043) in Lafora disease patients compared with controls. From the 31P spectra, we found 34% higher phosphoethanolamine concentrations (P = 0.016), 23% lower nicotinamide adenine dinucleotide concentrations (P = 0.003), 50% higher uridine diphosphate glucose concentrations (P = 0.004) and 225% higher glucose 6-phosphate concentrations in Lafora disease patients versus controls (P = 0.004). Uridine diphosphate glucose is the substrate of glycogen synthase, and glucose 6-phosphate is its extremely potent allosteric activator. The observed elevated uridine diphosphate glucose and glucose 6-phosphate levels are expected to hyperactivate glycogen synthase and may underlie the generation of polyglucosans in Lafora disease. The increased glutamate + glutamine and reduced GABA indicate altered neurotransmission and energy metabolism, which may contribute to the disease's intractable epilepsy. These results suggest a possible basis of polyglucosan formation and potential contributions to the epilepsy of Lafora disease. If confirmed in larger human and animal model studies, measurements of the dysregulated metabolites by magnetic resonance spectroscopy could be developed into non-invasive biomarkers for clinical trials.

Keywords:  1H MRS; 31P MRS; EPM2A; EPM2B; Lafora disease

DOI:  https://doi.org/10.1093/braincomms/fcae104
Int J Mol Sci. 2024 Mar 28. pii: 3792. [Epub ahead of print]25(7):

Nervonic Acid Synthesis Substrates as Essential Components in Profiled Lipid Supplementation for More Effective Central Nervous System Regeneration.

Magdalena Namiecinska, Paweł Piatek, Przemysław Lewkowicz.

  Central nervous system (CNS) damage leads to severe neurological dysfunction as a result of neuronal cell death and axonal degeneration. As, in the mature CNS, neurons have little ability to regenerate their axons and reconstruct neural loss, demyelination is one of the hallmarks of neurological disorders such as multiple sclerosis (MS). Unfortunately, remyelination, as a regenerative process, is often insufficient to prevent axonal loss and improve neurological deficits after demyelination. Currently, there are still no effective therapeutic tools to restore neurological function, but interestingly, emerging studies prove the beneficial effects of lipid supplementation in a wide variety of pathological processes in the human body. In the future, available lipids with a proven beneficial effect on CNS regeneration could be included in supportive therapy, but this topic still requires further studies. Based on our and others' research, we review the role of exogenous lipids, pointing to substrates that are crucial in the remyelination process but are omitted in available studies, justifying the properly profiled supply of lipids in the human diet as a supportive therapy during CNS regeneration.

Keywords:  CNS regeneration; PUFAs; natural fish oil; nervonic acid; neurodegenerative diseases; remyelination

DOI:  https://doi.org/10.3390/ijms25073792
Cells. 2024 Mar 28. pii: 591. [Epub ahead of print]13(7):

Cockayne Syndrome Patient iPSC-Derived Brain Organoids and Neurospheres Show Early Transcriptional Dysregulation of Biological Processes Associated with Brain Development and Metabolism.

Leon-Phillip Szepanowski, Wasco Wruck, Julia Kapr, Andrea Rossi, Ellen Fritsche, Jean Krutmann, James Adjaye.

  Cockayne syndrome (CS) is a rare hereditary autosomal recessive disorder primarily caused by mutations in Cockayne syndrome protein A (CSA) or B (CSB). While many of the functions of CSB have been at least partially elucidated, little is known about the actual developmental dysregulation in this devasting disorder. Of particular interest is the regulation of cerebral development as the most debilitating symptoms are of neurological nature. We generated neurospheres and cerebral organoids utilizing Cockayne syndrome B protein (CSB)-deficient induced pluripotent stem cells derived from two patients with distinct severity levels of CS and healthy controls. The transcriptome of both developmental timepoints was explored using RNA-Seq and bioinformatic analysis to identify dysregulated biological processes common to both patients with CS in comparison to the control. CSB-deficient neurospheres displayed upregulation of the VEGFA-VEGFR2 signalling pathway, vesicle-mediated transport and head development. CSB-deficient cerebral organoids exhibited downregulation of brain development, neuron projection development and synaptic signalling. We further identified the upregulation of steroid biosynthesis as common to both timepoints, in particular the upregulation of the cholesterol biosynthesis branch. Our results provide insights into the neurodevelopmental dysregulation in patients with CS and strengthen the theory that CS is not only a neurodegenerative but also a neurodevelopmental disorder.

Keywords:  Cockayne syndrome; RNA-Seq; brain development; brain organoids; steroid biosynthesis

DOI:  https://doi.org/10.3390/cells13070591
Cell Biosci. 2024 Apr 06. 14(1): 45

Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease.

Martin Grønbæk-Thygesen, Rasmus Hartmann-Petersen.

  Canavan disease is an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of the white matter in the brain. The disease is caused by a deficiency of the cytosolic aspartoacylase (ASPA) enzyme, which catalyzes the hydrolysis of N-acetyl-aspartate (NAA), an abundant brain metabolite, into aspartate and acetate. On the physiological level, the mechanism of pathogenicity remains somewhat obscure, with multiple, not mutually exclusive, suggested hypotheses. At the molecular level, recent studies have shown that most disease linked ASPA gene variants lead to a structural destabilization and subsequent proteasomal degradation of the ASPA protein variants, and accordingly Canavan disease should in general be considered a protein misfolding disorder. Here, we comprehensively summarize the molecular and cell biology of ASPA, with a particular focus on disease-linked gene variants and the pathophysiology of Canavan disease. We highlight the importance of high-throughput technologies and computational prediction tools for making genotype-phenotype predictions as we await the results of ongoing trials with gene therapy for Canavan disease.

Keywords:  NAA; NAAG; Neurodegeneration; Proteasome; Protein degradation; Protein folding; Protein misfolding; Protein quality control; Protein stability; VUS

DOI:  https://doi.org/10.1186/s13578-024-01224-6
Fluids Barriers CNS. 2024 Apr 08. 21(1): 33

Fasting upregulates the monocarboxylate transporter MCT1 at the rat blood-brain barrier through PPAR δ activation.

Stéphanie Chasseigneaux, Véronique Cochois-Guégan, Lucas Lecorgne, Murielle Lochus, Sophie Nicolic, Corinne Blugeon, Laurent Jourdren, David Gomez-Zepeda, Stefan Tenzer, Sylvia Sanquer, Valérie Nivet-Antoine, Marie-Claude Menet, Jean-Louis Laplanche, Xavier Declèves, Salvatore Cisternino, Bruno Saubaméa.

   BACKGROUND: The blood-brain barrier (BBB) is pivotal for the maintenance of brain homeostasis and it strictly regulates the cerebral transport of a wide range of endogenous compounds and drugs. While fasting is increasingly recognized as a potential therapeutic intervention in neurology and psychiatry, its impact upon the BBB has not been studied. This study was designed to assess the global impact of fasting upon the repertoire of BBB transporters.
METHODS: We used a combination of in vivo and in vitro experiments to assess the response of the brain endothelium in male rats that were fed ad libitum or fasted for one to three days. Brain endothelial cells were acutely purified and transcriptionaly profiled using RNA-Seq. Isolated brain microvessels were used to assess the protein expression of selected BBB transporters through western blot. The molecular mechanisms involved in the adaptation to fasting were investigated in primary cultured rat brain endothelial cells. MCT1 activity was probed by in situ brain perfusion.
RESULTS: Fasting did not change the expression of the main drug efflux ATP-binding cassette transporters or P-glycoprotein activity at the BBB but modulated a restrictive set of solute carrier transporters. These included the ketone bodies transporter MCT1, which is pivotal for the brain adaptation to fasting. Our findings in vivo suggested that PPAR δ, a major lipid sensor, was selectively activated in brain endothelial cells in response to fasting. This was confirmed in vitro where pharmacological agonists and free fatty acids selectively activated PPAR δ, resulting in the upregulation of MCT1 expression. Moreover, dosing rats with a specific PPAR δ antagonist blocked the upregulation of MCT1 expression and activity induced by fasting.
CONCLUSIONS: Altogether, our study shows that fasting affects a selected set of BBB transporters which does not include the main drug efflux transporters. Moreover, we describe a previously unknown selective adaptive response of the brain vasculature to fasting which involves PPAR δ and is responsible for the up-regulation of MCT1 expression and activity. Our study opens new perspectives for the metabolic manipulation of the BBB in the healthy or diseased brain.

Keywords:  Blood-brain barrier; Endothelial cells; Fasting; MCT1; PPAR δ

DOI:  https://doi.org/10.1186/s12987-024-00526-8
RNA. 2024 Apr 12. pii: rna.079925.123. [Epub ahead of print]

Cytosolic RNA binding of the mitochondrial TCA cycle enzyme malate dehydrogenase (MDH2).

Michelle Noble, Aindrila Chatterjee, Thileepan Sekaran, Thomas Schwarzl, Matthias W Hentze.

  Several enzymes of intermediary metabolism have been identified to bind RNA in 2 cells, with potential consequences for the bound RNAs and/or the enzyme. In this 3 study, we investigate the RNA-binding activity of the mitochondrial enzyme malate 4 dehydrogenase 2 (MDH2), which functions in the tricarboxylic acid (TCA) cycle and 5 the malate-aspartate shuttle. We confirmed in cellulo RNA-binding of MDH2 using 6 orthogonal biochemical assays and performed enhanced crosslinking and 7 immunoprecipitation (eCLIP) to identify the cellular RNAs associated with endogenous 8 MDH2. Surprisingly, MDH2 preferentially binds cytosolic over mitochondrial RNAs, 9 although the latter are abundant in the milieu of the mature protein. Subcellular 10 fractionation followed by RNA-binding assays revealed that MDH2-RNA interactions 11 occur predominantly outside of mitochondria. We also found that a cytosolically-12 retained N-terminal deletion mutant of MDH2 is competent to bind RNA, indicating that 13 mitochondrial targeting is dispensable for MDH2-RNA interactions. MDH2 RNA 14 binding increased when cellular NAD+ levels (MDH2's co-factor) was 15 pharmacologically diminished, suggesting that the metabolic state of cells affects RNA 16 binding. Taken together, our data implicate an as yet unidentified function of MDH2 17 binding RNA in the cytosol.

Keywords:  MDH2; RNA-binding proteins; metabolic enzymes

DOI:  https://doi.org/10.1261/rna.079925.123
Front Neurol. 2024 ;15 1397998

Editorial: Movement disorders in neurometabolic conditions.

Divyani Garg, Suvasini Sharma, Shekeeb S Mohammad, Asuri Narayan Prasad.



Keywords:  DBS (deep brain stimulation); metabolic disease; mitochondrial; movement disorders; neurodegeneration with brain iron accumulation (NBIA)

DOI:  https://doi.org/10.3389/fneur.2024.1397998
eNeuro. 2024 Apr 11. pii: ENEURO.0494-23.2024. [Epub ahead of print]

Preconditioning-induced facilitation of lactate release from astrocytes is essential for brain ischemic tolerance.

Yuri Hirayama, Ha Pham Ngoc Le, Hirofumi Hashimoto, Itsuko Ishii, Schuichi Koizumi, Naohiko Anzai.

A sub-lethal ischemic episode (termed preconditioning [PC]) protects neurons in the brain against a subsequent severe ischemic injury. This phenomenon is known as brain ischemic tolerance, and has received much attention from researchers because of its robust neuroprotective effects. We have previously reported that PC activates astrocytes and subsequently upregulates P2X7 receptors, thereby leading to ischemic tolerance. However, the downstream signals of P2X7 receptors that are responsible for PC-induced ischemic tolerance remain unknown. Here, we show that PC-induced P2X7 receptor-mediated lactate release from astrocytes has an indispensable role in this event. Using a transient focal cerebral ischemia model caused by middle cerebral artery occlusion, extracellular lactate levels during severe ischemia were significantly increased in mice who experienced PC; this increase was dependent on P2X7 receptors. In addition, the intracerebroventricular injection of lactate protected against cerebral ischemic injury. In in vitro experiments, although stimulation of astrocytes with the P2X7 receptor agonist BzATP had no effect on the protein levels of monocarboxylate transporter (MCT) 1 and MCT4 (which are responsible for lactate release from astrocytes), BzATP induced the plasma membrane translocation of these MCTs via their chaperone CD147. Importantly, CD147 was increased in activated astrocytes after PC, and CD147-blocking antibody abolished the PC-induced facilitation of astrocytic lactate release and ischemic tolerance. Taken together, our findings suggest that astrocytes induce ischemic tolerance via P2X7 receptor-mediated lactate release.Significance Statement Brain ischemic tolerance refers to an endogenous neuroprotective phenomenon whereby a non-lethal ischemic episode, termed preconditioning (PC), induces resistance to a subsequent severe ischemic injury. This phenomenon has received much attention because of its robust neuroprotective effects. We have previously reported that the PC-evoked activation of astrocytes leads to ischemic tolerance; however, the underlying molecular mechanisms remain unknown. Here, we have demonstrated that PC induces the membrane translocation of lactate transporters in activated astrocytes, thereby promoting lactate release from astrocytes during severe ischemia; this effect likely plays a role in ischemic tolerance. These findings may facilitate the development of new therapeutic strategies for cerebral ischemia.

DOI: https://doi.org/10.1523/ENEURO.0494-23.2024
Clin Nutr. 2024 Apr 03. pii: S0261-5614(24)00105-5. [Epub ahead of print]43(5): 1162-1170

Arachidonic acid and docosahexaenoic acid levels correlate with the inflammation proteome in extremely preterm infants.

Susanna Klevebro, Simon Kebede Merid, Ulrika Sjöbom, Wen Zhong, Hanna Danielsson, Dirk Wackernagel, Ingrid Hansen-Pupp, David Ley, Karin Sävman, Mathias Uhlén, Lois E H Smith, Ann Hellström, Anders K Nilsson.

   BACKGROUND & AIM: Clinical trials supplementing the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) to preterm infants have shown positive effects on inflammation-related morbidities, but the molecular mechanisms underlying these effects are not fully elucidated. This study aimed to determine associations between DHA, AA, and inflammation-related proteins during the neonatal period in extremely preterm infants.
METHODS: A retrospective exploratory study of infants (n = 183) born below 28 weeks gestation from the Mega Donna Mega trial, a randomized multicenter trial designed to study the effect of DHA and AA on retinopathy of prematurity. Serial serum samples were collected after birth until postnatal day 100 (median 7 samples per infant) and analyzed for phospholipid fatty acids and proteins using targeted proteomics covering 538 proteins. Associations over time between LCPUFAs and proteins were explored using mixed effect modeling with splines, including an interaction term for time, and adjusted for gestational age, sex, and center.
RESULTS: On postnatal day one, 55 proteins correlated with DHA levels and 10 proteins with AA levels. Five proteins were related to both fatty acids, all with a positive correlation. Over the first 100 days after birth, we identified 57 proteins to be associated with DHA and/or AA. Of these proteins, 41 (72%) related to inflammation. Thirty-eight proteins were associated with both fatty acids and the overall direction of association did not differ between DHA and AA, indicating that both LCPUFAs similarly contribute to up- and down-regulation of the preterm neonate inflammatory proteome. Primary examples of this were the inflammation-modulating cytokines IL-6 and CCL7, both being negatively related to levels of DHA and AA in the postnatal period.
CONCLUSIONS: This study supports postnatal non-antagonistic and potentially synergistic effects of DHA and AA on the inflammation proteome in preterm infants, indicating that supplementation with both fatty acids may contribute to limiting the disease burden in this vulnerable population.
CLINICAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03201588).

Keywords:  Arachidonic acid; Docosahexaenoic acid; Immune response; Preterm birth; Proteomics

DOI:  https://doi.org/10.1016/j.clnu.2024.03.031
Nat Cell Biol. 2024 Apr 09.

Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.

Ao Liu, Frieda Kage, Asan F Abdulkareem, Mac Pholo Aguirre-Huamani, Gracie Sapp, Halil Aydin, Henry N Higgs.

Mitochondrial fission occurs in many cellular processes, but the regulation of fission is poorly understood. We show that long-chain acyl-coenzyme A (LCACA) activates two related mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization, which activates their ability to stimulate the DRP1 GTPase. The 1:1 stoichiometry of LCACA:MiD in the oligomer suggests interaction in the previously identified nucleotide-binding pocket, and a point mutation in this pocket reduces LCACA binding and LCACA-induced oligomerization for MiD51. In cells, this LCACA binding mutant does not assemble into puncta on mitochondria or rescue MiD49/51 knockdown effects on mitochondrial length and DRP1 recruitment. Furthermore, cellular treatment with BSA-bound oleic acid, which causes increased LCACA, promotes mitochondrial fission in an MiD49/51-dependent manner. These results suggest that LCACA is an endogenous ligand for MiDs, inducing mitochondrial fission and providing a potential mechanism for fatty-acid-induced mitochondrial division. Finally, MiD49 or MiD51 oligomers synergize with Mff, but not with actin filaments, in DRP1 activation, suggesting distinct pathways for DRP1 activation.

DOI: https://doi.org/10.1038/s41556-024-01400-3
Oxf Open Neurosci. 2023 ;2 kvad004

Energy metabolic pathways in neuronal development and function.

Sebastian Rumpf, Neeraja Sanal, Marco Marzano.

  Neuronal development and function are known to be among the most energy-demanding functions of the body. Constant energetic support is therefore crucial at all stages of a neuron's life. The two main adenosine triphosphate (ATP)-producing pathways in cells are glycolysis and oxidative phosphorylation. Glycolysis has a relatively low yield but provides fast ATP and enables the metabolic versatility needed in dividing neuronal stem cells. Oxidative phosphorylation, on the other hand, is highly efficient and therefore thought to provide most or all ATP in differentiated neurons. However, it has recently become clear that due to their distinct properties, both pathways are required to fully satisfy neuronal energy demands during development and function. Here, we provide an overview of how glycolysis and oxidative phosphorylation are used in neurons during development and function.

Keywords:  axon; dendrite; glycolysis; neuron; oxidative phosphorylation; synapse

DOI:  https://doi.org/10.1093/oons/kvad004
FEBS Lett. 2024 Apr 11.

The lipid droplet lipidome.

Michele Wölk, Maria Fedorova.

  Lipid droplets (LDs) are intracellular organelles with a hydrophobic core formed by neutral lipids surrounded by a phospholipid monolayer harboring a variety of regulatory and enzymatically active proteins. Over the last few decades, our understanding of LD biology has evolved significantly. Nowadays, LDs are appreciated not just as passive energy storage units, but rather as active players in the regulation of lipid metabolism and quality control machineries. To fulfill their functions in controlling cellular metabolic states, LDs need to be highly dynamic and responsive organelles. A large body of evidence supports a dynamic nature of the LD proteome and its contact sites with other organelles. However, much less is known about the lipidome of LDs. Numerous examples clearly indicate the intrinsic link between LD lipids and proteins, calling for a deeper characterization of the LD lipidome in various physiological and pathological settings. Here, we reviewed the current state of knowledge in the field of the LD lipidome, providing a brief overview of the lipid classes and their molecular species present within the neutral core and phospholipid monolayer.

Keywords:  lipid droplets; lipid molecular species; lipidome; neutral core; phospholipid monolayer

DOI:  https://doi.org/10.1002/1873-3468.14874
Brain Res. 2024 Apr 08. pii: S0006-8993(24)00174-4. [Epub ahead of print]1835 148920

Targeting VDAC: A potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.

Yaqian Yang, Xiaotao Jia, Xinmao Yang, Jie Wang, Yan Fang, Xiaoping Ying, Meiqian Zhang, Jing Wei, Yanfang Pan.

  Mitochondrial dysfunction has been implicated in the pathogenesis of Alzheimer's disease, a neurodegenerative disorder characterized by progressive cognitive decline. Voltage-dependent anion channel (VDAC), a protein located in the outer mitochondrial membrane, plays a critical role in regulating mitochondrial function and cellular energy metabolism. Recent studies have identified VDAC as a potential therapeutic target for Alzheimer's disease. This article aims to provide an overview of the role of VDAC in mitochondrial dysfunction, its association with Alzheimer's disease, and the potential of targeting VDAC for developing novel therapeutic interventions. Understanding the involvement of VDAC in Alzheimer's disease may pave the way for the development of effective treatments that can restore mitochondrial function and halt disease progression.

Keywords:  Alzheimer’s disease; Mitochondrial dynamics; Voltage-Dependent Anion Channel

DOI:  https://doi.org/10.1016/j.brainres.2024.148920
Anal Chim Acta. 2024 May 15. pii: S0003-2670(24)00312-X. [Epub ahead of print]1303 342511

Determination of fatty acid uptake and desaturase activity in mammalian cells by NMR-based stable isotope tracing.

Penghui Lin, James Sledziona, Kubra B Akkaya-Colak, Maria M Mihaylova, Andrew N Lane.

   BACKGROUND: Mammalian cells both import exogenous fatty acids and synthesize them de novo. Palmitate, the end product of fatty acid synthase (FASN) is a substrate for stearoyl-CoA desaturases (Δ-9 desaturases) that introduce a single double bond into fatty acyl-CoA substrates such as palmitoyl-CoA and stearoyl-CoA. This process is particularly upregulated in lipogenic tissues and cancer cells. Tracer methodology is needed to determine uptake versus de novo synthesis of lipids and subsequent chain elongation and desaturation. Here we describe an NMR method to determine the uptake of 13C-palmitate from the medium into HCT116 human colorectal cancer cells, and the subsequent desaturation and incorporation into complex lipids.
RESULTS: Exogenous 13C16-palmitate was absorbed from the medium by HCT116 cells and incorporated primarily into complex glycerol lipids. Desaturase activity was determined from the quantification of double bonds in acyl chains, which was greatly reduced by ablation of the major desaturase SCD1.
SIGNIFICANCE: The NMR approach requires minimal sample preparation, is non-destructive, and provides direct information about the level of saturation and incorporation of fatty acids into complex lipids.

Keywords:  Desaturase activity; Fatty acid uptake; NMR

DOI:  https://doi.org/10.1016/j.aca.2024.342511
Cell Rep. 2024 Apr 05. pii: S2211-1247(24)00384-X. [Epub ahead of print]43(4): 114056

Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α.

Gemma Molinaro, Jacob E Bowles, Katilynne Croom, Darya Gonzalez, Saba Mirjafary, Shari G Birnbaum, Khaleel A Razak, Jay R Gibson, Kimberly M Huber.

  Little is known of the brain mechanisms that mediate sex-specific autism symptoms. Here, we demonstrate that deletion of the autism spectrum disorder (ASD)-risk gene, Pten, in neocortical pyramidal neurons (NSEPten knockout [KO]) results in robust cortical circuit hyperexcitability selectively in female mice observed as prolonged spontaneous persistent activity states. Circuit hyperexcitability in females is mediated by metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) signaling to mitogen-activated protein kinases (Erk1/2) and de novo protein synthesis. Pten KO layer 5 neurons have a female-specific increase in mGluR5 and mGluR5-dependent protein synthesis. Furthermore, mGluR5-ERα complexes are generally elevated in female cortices, and genetic reduction of ERα rescues enhanced circuit excitability, protein synthesis, and neuron size selectively in NSEPten KO females. Female NSEPten KO mice display deficits in sensory processing and social behaviors as well as mGluR5-dependent seizures. These results reveal mechanisms by which sex and a high-confidence ASD-risk gene interact to affect brain function and behavior.

Keywords:  CP: Cell biology; CP: Neuroscience; ERα; PTEN; UP state; autism; cell size; circuit excitability; mGluR5; protein synthesis; signal transduction; somatosensory cortex

DOI:  https://doi.org/10.1016/j.celrep.2024.114056
J Neurochem. 2024 Apr;168(4): e1

The following article for this Special Issue was previously published and can be found in its respective issue online: "How can I measure brain acetylcholine levels in vivo? Advantages and caveats of commonly used approaches".

How can I measure brain acetylcholine levels in vivo? Advantages and caveats of commonly used approaches (Published in JNC 167.1 issue) https://onlinelibrary.wiley.com/doi/10.1111/jnc.15943.

DOI: https://doi.org/10.1111/jnc.16109
Proc Natl Acad Sci U S A. 2024 Apr 16. 121(16): e2401313121

An energy-conserving reaction in amino acid metabolism catalyzed by arginine synthetase.

Yuta Michimori, Yuusuke Yokooji, Haruyuki Atomi.

  All forms of life are presumed to synthesize arginine from citrulline via a two-step pathway consisting of argininosuccinate synthetase and argininosuccinate lyase using citrulline, adenosine 5'-triphosphate (ATP), and aspartate as substrates. Conversion of arginine to citrulline predominantly proceeds via hydrolysis. Here, from the hyperthermophilic archaeon Thermococcus kodakarensis, we identified an enzyme which we designate "arginine synthetase". In arginine synthesis, the enzyme converts citrulline, ATP, and free ammonia to arginine, adenosine 5'-diphosphate (ADP), and phosphate. In the reverse direction, arginine synthetase conserves the energy of arginine deimination and generates ATP from ADP and phosphate while releasing ammonia. The equilibrium constant of this reaction at pH 7.0 is [Cit][ATP][NH3]/[Arg][ADP][Pi] = 10.1 ± 0.7 at 80 °C, corresponding to a ΔG°' of -6.8 ± 0.2 kJ mol-1. Growth of the gene disruption strain was compared to the host strain in medium composed of amino acids. The results suggested that arginine synthetase is necessary in providing ornithine, the precursor for proline biosynthesis, as well as in generating ATP. Growth in medium supplemented with citrulline indicated that arginine synthetase can function in the direction of arginine synthesis. The enzyme is widespread in nature, including bacteria and eukaryotes, and catalyzes a long-overlooked energy-conserving reaction in microbial amino acid metabolism. Along with ornithine transcarbamoylase and carbamate kinase, the pathway identified here is designated the arginine synthetase pathway.

Keywords:  Archaea; arginine; bioinformatics; catabolism; metabolism

DOI:  https://doi.org/10.1073/pnas.2401313121
Am J Physiol Endocrinol Metab. 2024 Apr 10.

Inhibition of Crif1 protects fatty acid-induced POMC neuron damage by increasing CPT-1 function.

Lara Regina-Ferreira, Fernando Valdivieso-Rivera, Monara K S C Angelim, Larissa Menezes Dos Reis, Vanessa O de Oliveira Furino, Joseane Morari, Lizandra Maia de Souza, Silvio R Consoni, Carlos H Sponton, Pedro M Moraes Vieira, Licio A Velloso.

  Hypothalamic proopiomelanocortin neurons are sensors of signals that reflect the energy stores in the body. Inducing mild stress in proopiomelanocortin neurons protect them from the damage promoted by the consumption of a high-fat diet, mitigating the development of obesity; however, the cellular mechanisms behind these effects are unknown. Here, we induced mild stress in a proopiomelanocortin neuron cell line by inhibiting Crif1. In proopiomelanocortin neurons exposed to high levels of palmitate, the partial inhibition of Crif1 reverted the defects in mitochondrial respiration and ATP production; this was accompanied by improved mitochondrial fusion/fission cycling. Furthermore, the partial inhibition of Crif1 resulted in increased reactive oxygen species production, increased fatty acid oxidation, and reduced dependency on glucose for mitochondrial respiration. These changes were dependent on the activity of CPT-1. Thus, we identified a CPT-1-dependent metabolic shift towards greater utilization of fatty acids as substrates for respiration as the mechanism behind the protective effect of mild stress against palmitate-induced damage of proopiomelanocortin neurons.

Keywords:  Energy balance; Energy substrate; Hypothlamus; Obesity; Respiration

DOI:  https://doi.org/10.1152/ajpendo.00420.2023
Neuron. 2024 Mar 26. pii: S0896-6273(24)00167-3. [Epub ahead of print]

Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.

Sandra M V Kochan, Meret Cepero Malo, Milica Jevtic, Hannah M Jahn-Kelleter, Gulzar A Wani, Kristiano Ndoci, Laura Pérez-Revuelta, Felix Gaedke, Iris Schäffner, Dieter Chichung Lie, Astrid Schauss, Matteo Bergami.

  Integration of new neurons into adult hippocampal circuits is a process coordinated by local and long-range synaptic inputs. To achieve stable integration and uniquely contribute to hippocampal function, immature neurons are endowed with a critical period of heightened synaptic plasticity, yet it remains unclear which mechanisms sustain this form of plasticity during neuronal maturation. We found that as new neurons enter their critical period, a transient surge in fusion dynamics stabilizes elongated mitochondrial morphologies in dendrites to fuel synaptic plasticity. Conditional ablation of fusion dynamics to prevent mitochondrial elongation selectively impaired spine plasticity and synaptic potentiation, disrupting neuronal competition for stable circuit integration, ultimately leading to decreased survival. Despite profuse mitochondrial fragmentation, manipulation of competition dynamics was sufficient to restore neuronal survival but left neurons poorly responsive to experience at the circuit level. Thus, by enabling synaptic plasticity during the critical period, mitochondrial fusion facilitates circuit remodeling by adult-born neurons.

Keywords:  LTP; Mfn2; adult neurogenesis; competition; experience; hippocampus; mitochondria; mitochondrial fusion; neural stem cell; synaptic plasticity

DOI:  https://doi.org/10.1016/j.neuron.2024.03.013
bioRxiv. 2024 Mar 27. pii: 2024.03.26.582525. [Epub ahead of print]

Glutaminase deficiency in rod photoreceptors disrupts nonessential amino acid levels to activate the integrated stress response and induce rapid degeneration.

Moloy T Goswami, Eric Weh, Shubha Subramanya, Katherine M Weh, Hima Bindu Durumutla, Heather Hager, Nicholas Miller, Sraboni Chaudhury, Anthony Andren, Peter Sajjakulnukit, Cagri G Besirli, Costas A Lyssiotis, Thomas J Wubben.

The bioenergetic demand of photoreceptors rivals that of cancer cells, and numerous metabolic similarities exist between these cells. Glutamine (Gln) anaplerosis via the tricarboxylic acid (TCA) cycle provides biosynthetic intermediates and is a hallmark of cancer metabolism. In this process, Gln is first converted to glutamate via glutaminase (GLS), which is a crucial pathway in many cancer cells. To date, no study has been undertaken to examine the role of Gln metabolism in vivo in photoreceptors. Here, mice lacking GLS in rod photoreceptors were generated. Animals lacking GLS experienced rapid photoreceptor degeneration with concomitant functional loss. Gln has multiple roles in metabolism including redox balance, biosynthesis of nucleotides and amino acids, and supplementing the TCA cycle. Few alterations were noted in redox balance. Unlabeled targeted metabolomics demonstrated few changes in glycolytic and TCA cycle intermediates, which corresponded with a lack of significant changes in mitochondrial function. GLS deficiency in rod photoreceptors did decrease the fractional labelling of TCA cycle intermediates when provided uniformly labeled 13 C-Gln in vivo . However, supplementation with alpha-ketoglutarate provided only marginal rescue of photoreceptor degeneration. Nonessential amino acids, glutamate and aspartate, were decreased in the retina of mice lacking GLS in rod photoreceptors. In accordance with this amino acid deprivation, the integrated stress response (ISR) was found to be activated with decreased global protein synthesis. Importantly, supplementation with asparagine delayed photoreceptor degeneration to a greater degree than alpha-ketoglutarate. These data show that GLS-mediated Gln catabolism is essential for rod photoreceptor amino acid biosynthesis, function, and survival.
Significance Statement: Glucose has been central in the study of photoreceptor cell metabolism. Recently, it was shown that fuel sources besides glucose can meet the metabolic needs of photoreceptors. Glutamine (Gln) is the most abundant circulating amino acid and has many biosynthetic and bioenergetic roles in cells. Glutaminolysis is the process by which Gln is metabolized into tricarboxylic acid cycle intermediates to provide biosynthetic precursors. Here, Gln is first converted to glutamate via the enzyme glutaminase (GLS). This research demonstrates that deletion of GLS in rod photoreceptors alters retinal metabolism, activates the integrated stress response (ISR), and results in rapid photoreceptor degeneration. As such, Gln is a critical fuel source that supports photoreceptor cell biomass, redox balance, and survival.

DOI: https://doi.org/10.1101/2024.03.26.582525