bims-medebr 2024-05-19 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–05–19
seventeen papers selected by
Regina F. Fernández, Johns Hopkins University

Drosophila Models Uncover Substrate Channeling Effects on Phospholipids and Sphingolipids in Peroxisomal Biogenesis Disorders.
Metabolic regulation of single synaptic vesicle exo- and endocytosis in hippocampal synapses.
PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells.
Does glial lipid dysregulation alter sleep in Alzheimer's and Parkinson's disease?
Unraveling the Connection: Cholesterol, Calcium Signaling, and Neurodegeneration.
Lipid metabolism is dysregulated in endocrine glands upon autoimmune demyelination.
The protective role of endothelial GLUT1 in ischemic stroke.
1H-NMR metabolomics investigation of CSF from children with HIV reveals altered neuroenergetics due to persistent immune activation.
D-mannose as a new therapy for fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG).
The Role of Phospholipid Alterations in Mitochondrial and Brain Dysfunction after Cardiac Arrest.
Testosterone deficiency worsens mitochondrial dysfunction in APP/PS1 mice.
Ketogenic Diet in the Treatment of Epilepsy.
Retinal metabolism displays evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle.
Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.
The differential effects of palmitic acid and oleic acid on the metabolic response of hypothalamic astrocytes from male and female mice.
Short-chain fatty acids: Important components of the gut-brain axis against AD.
The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.

bioRxiv. 2024 Apr 29. pii: 2024.04.26.591192. [Epub ahead of print]

Drosophila Models Uncover Substrate Channeling Effects on Phospholipids and Sphingolipids in Peroxisomal Biogenesis Disorders.

Michael F Wangler, Yu-Hsin Chao, Mary Roth, Ruth Welti, James A McNew.

Peroxisomal Biogenesis Disorders Zellweger Spectrum (PBD-ZSD) disorders are a group of autosomal recessive defects in peroxisome formation that produce a multi-systemic disease presenting at birth or in childhood. Well documented clinical biomarkers such as elevated very long chain fatty acids (VLCFA) are key biochemical diagnostic findings in these conditions. Additional, secondary biochemical alterations such as elevated very long chain lysophosphatidylcholines are allowing newborn screening for peroxisomal disease. In addition, a more widespread impact on metabolism and lipids is increasingly being documented by metabolomic and lipidomic studies. Here we utilize Drosophila models of pex2 and pex16 as well as human plasma from individuals with PEX1 mutations. We identify phospholipid abnormalities in Drosophila larvae and brain characterized by differences in the quantities of phosphatidylcholine (PC) and phosphatidylethanolamines (PE) with long chain lengths and reduced levels of intermediate chain lengths. For diacylglycerol (DAG) the precursor of PE and PC through the Kennedy pathway, the intermediate chain lengths are increased suggesting an imbalance between DAGs and PE and PC that suggests the two acyl chain pools are not in equilibrium. Altered acyl chain lengths are also observed in PE ceramides in the fly models. Interestingly, plasma from human subjects exhibit phospholipid alterations similar to the fly model. Moreover, human plasma shows reduced levels of sphingomyelin with 18 and 22 carbon lengths but normal levels of C24. Our results suggest that peroxisomal biogenesis defects alter shuttling of the acyl chains of multiple phospholipid and ceramide lipid classes, whereas DAG species with intermediate fatty acids are more abundant. These data suggest an imbalance between de novo synthesis of PC and PE through the Kennedy pathway and remodeling of existing PC and PE through the Lands cycle. This imbalance is likely due to overabundance of very long and long acyl chains in PBD and a subsequent imbalance due to substrate channeling effects. Given the fundamental role of phospholipid and sphingolipids in nervous system functions, these observations suggest PBD-ZSD are diseases characterized by widespread cell membrane lipid abnormalities.

DOI: https://doi.org/10.1101/2024.04.26.591192
Cell Rep. 2024 May 16. pii: S2211-1247(24)00546-1. [Epub ahead of print]43(5): 114218

Metabolic regulation of single synaptic vesicle exo- and endocytosis in hippocampal synapses.

Jongyun Myeong, Marion I Stunault, Vitaly A Klyachko, Ghazaleh Ashrafi.

  Glucose has long been considered a primary energy source for synaptic function. However, it remains unclear to what extent alternative fuels, such as lactate/pyruvate, contribute to powering synaptic transmission. By detecting individual release events in hippocampal synapses, we find that mitochondrial ATP production regulates basal vesicle release probability and release location within the active zone (AZ), evoked by single action potentials. Mitochondrial inhibition shifts vesicle release closer to the AZ center and alters the efficiency of vesicle retrieval by increasing the occurrence of ultrafast endocytosis. Furthermore, we uncover that terminals can use oxidative fuels to maintain the vesicle cycle during trains of activity. Mitochondria are sparsely distributed along hippocampal axons, and we find that terminals containing mitochondria display enhanced vesicle release and reuptake during high-frequency trains. Our findings suggest that mitochondria not only regulate several fundamental features of synaptic transmission but may also contribute to modulation of short-term synaptic plasticity.

Keywords:  ATP; CP: Metabolism; CP: Neuroscience; glycolysis; hippocampal neuron; mitochondria; nerve terminal; synapse; synaptic transmission

DOI:  https://doi.org/10.1016/j.celrep.2024.114218
Brain. 2024 May 14. pii: awae158. [Epub ahead of print]

PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells.

Robert Prior, Alessio Silva, Tim Vangansewinkel, Jakub Idkowiak, Arun Kumar Tharkeshwar, Tom P Hellings, Iliana Michailidou, Jeroen Vreijling, Maarten Loos, Bastijn Koopmans, Nina Vlek, Cedrick Agaser, Thomas B Kuipers, Christine Michiels, Elisabeth Rossaert, Stijn Verschoren, Wendy Vermeire, Vincent de Laat, Jonas Dehairs, Kristel Eggermont, Diede van den Biggelaar, Adekunle T Bademosi, Frederic A Meunier, Martin vandeVen, Philip Van Damme, Hailiang Mei, Johannes V Swinnen, Ivo Lambrichts, Frank Baas, Kees Fluiter, Esther Wolfs, Ludo Van Den Bosch.

  Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 megabase tandem duplication of chromosome 17 harboring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To get better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication on cellular homeostasis in CMT1A mouse models and in patient-derived induced pluripotent stem cells differentiated into Schwann cell precursors (iPSC-SCPs). We performed lipidomic profiling and bulk RNA sequencing on sciatic nerves of two developing CMT1A mouse models and on CMT1A patient derived iPSC-SCPs. For the sciatic nerves of the CMT1A mice, cholesterol and lipid metabolism was dose-dependently downregulated throughout development. For the CMT1A iPSC-SCPs, transcriptional analysis unveiled a strong suppression of genes related to autophagy and lipid metabolism. Gene ontology enrichment analysis identified disturbances in pathways related to plasma membrane components and cell receptor signaling. Lipidomic analysis confirmed the severe dysregulation in plasma membrane lipids, particularly sphingolipids, in CMT1A iPSC-SCPs. Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity, and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs. Importantly, this phenotype could be rescued by stimulating autophagy and lipolysis. We conclude that PMP22 duplication disturbs intracellular lipid storage and leads to a more disordered plasma membrane due to an alteration in the lipid composition, which ultimately may lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of CMT1A patients.

Keywords:  CMT1A; Schwann cells; autophagy; human iPSCs; lipid metabolism; lipid storage; plasma membrane

DOI:  https://doi.org/10.1093/brain/awae158
Trends Mol Med. 2024 May 15. pii: S1471-4914(24)00098-4. [Epub ahead of print]

Does glial lipid dysregulation alter sleep in Alzheimer's and Parkinson's disease?

Lindsey D Goodman, Matthew J Moulton, Guang Lin, Hugo J Bellen.

  In this opinion article, we discuss potential connections between sleep disturbances observed in Alzheimer's disease (AD) and Parkinson's disease (PD) and the dysregulation of lipids in the brain. Research using Drosophila has highlighted the role of glial-mediated lipid metabolism in sleep and diurnal rhythms. Relevant to AD, the formation of lipid droplets in glia, which occurs in response to elevated neuronal reactive oxygen species (ROS), is required for sleep. In disease models, this process is disrupted, arguing a connection to sleep dysregulation. Relevant to PD, the degradation of neuronally synthesized glucosylceramides by glia requires glucocerebrosidase (GBA, a PD-associated risk factor) and this regulates sleep. Loss of GBA in glia causes an accumulation of glucosylceramides and neurodegeneration. Overall, research primarily using Drosophila has highlighted how dysregulation of glial lipid metabolism may underlie sleep disturbances in neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Drosophila; Parkinson’s disease; glia; lipids; sleep

DOI:  https://doi.org/10.1016/j.molmed.2024.04.010
Neurosci Insights. 2024 ;19 26331055241252772

Unraveling the Connection: Cholesterol, Calcium Signaling, and Neurodegeneration.

Maria Casas, Eamonn J Dickson.

  Cholesterol and calcium play crucial roles as integral structural components and functional signaling entities within the central nervous system. Disruption in cholesterol homeostasis has been linked to Alzheimer's, Parkinson's, and Huntington's Disease while alterations in calcium signaling is hypothesized to be a key substrate for neurodegeneration across many disorders. Despite the importance of regulated cholesterol and calcium homeostasis for brain health there has been an absence of research investigating the interdependence of these signaling molecules and how they can tune each other's abundance at membranes to influence membrane identity. Here, we discuss the role of cholesterol in shaping calcium dynamics in a neurodegenerative disorder that arises due to mutations in the lysosomal cholesterol transporter, Niemann Pick Type C1 (NPC1). We discuss the molecular mechanisms through which altered lysosomal cholesterol transport influences calcium signaling pathways through remodeling of ion channel distribution at organelle-organelle membrane contacts leading to neurodegeneration. This scientific inquiry not only sheds light on NPC disease but also holds implications for comprehending other cholesterol-associated neurodegenerative disorders.

Keywords:  Calcium (Ca2+); Niemann-Pick type C1 (NPC1); membrane contact sites; neurodegeneration; voltage-gated calcium channel (CaV); voltage-gated potassium channel

DOI:  https://doi.org/10.1177/26331055241252772
J Neuroimmunol. 2024 May 07. pii: S0165-5728(24)00084-5. [Epub ahead of print]391 578366

Lipid metabolism is dysregulated in endocrine glands upon autoimmune demyelination.

Jonathan J Carver, Bryce A Pugh, Kristy M Lau, Alessandro Didonna.

  Disturbance in neuroendocrine signaling has been consistently documented in multiple sclerosis (MS), a chronic autoimmune disorder of the central nervous system (CNS) representing the main cause of non-traumatic brain injury among young adults. In fact, MS patients display altered hormonal levels and psychiatric symptoms along with the pathologic hallmarks of the disease, which include demyelination, neuroinflammation and axonal injury. In addition, we have recently shown that extensive transcriptional changes take place in the hypothalamus of mice upon the MS model experimental autoimmune encephalomyelitis (EAE). We also detected structural and functional aberrancies in endocrine glands of EAE animals. Specifically, we described the hyperplasia of adrenal glands and the atrophy of ovaries at disease peak. To further expand the characterization of these phenotypes, here we profiled the transcriptomes of both glands by means of RNA-seq technology. Notably, we identified fatty acid and cholesterol biosynthetic pathways as the most dysregulated molecular processes in adrenals and ovaries, respectively. Furthermore, we demonstrated that key genes encoding neuropeptides and hormone receptors undergo distinct expression dynamics in the hypothalamus along disease progression. Altogether, our results corroborate the dysfunction of the neuroendocrine system as a major pathological event of autoimmune demyelination and highlight the crosstalk between the CNS and the periphery in mediating such disease phenotypes.

Keywords:  Autoimmunity; Endocrine system; Hypothalamus; Multiple sclerosis; Neuropeptides

DOI:  https://doi.org/10.1016/j.jneuroim.2024.578366
Brain Behav. 2024 May;14(5): e3536

The protective role of endothelial GLUT1 in ischemic stroke.

Qiwei Peng, Weiqi Zeng.

   OBJECTIVE: To provide thorough insight on the protective role of endothelial glucose transporter 1 (GLUT1) in ischemic stroke.
METHODS: We comprehensively review the role of endothelial GLUT1 in ischemic stroke by narrating the findings concerning biological characteristics of GLUT1 in brain in depth, summarizing the changes of endothelial GLUT1 expression and activity during ischemic stroke, discussing how GLUT1 achieves its neuroprotective effect via maintaining endothelial function, and identifying some outstanding blind spots in current studies.
RESULTS: Endothelial GLUT1 maintains persistent high glucose and energy requirements of the brain by transporting glucose through the blood-brain barrier, which preserves endothelial function and is beneficial to stroke prognosis.
CONCLUSION: This review underscores the potential involvement of GLUT1 trafficking, activity modulation, and degradation, and we look forward to more clinical and animal studies to illuminate these mechanisms.

Keywords:  GLUT1; endothelial function; ischemic stroke; neuroprotection

DOI:  https://doi.org/10.1002/brb3.3536
Front Neurosci. 2024 ;18 1270041

1H-NMR metabolomics investigation of CSF from children with HIV reveals altered neuroenergetics due to persistent immune activation.

Anicia Thirion, Du Toit Loots, Monray E Williams, Regan Solomons, Shayne Mason.

   Background: HIV can invade the central nervous system (CNS) early during infection, invading perivascular macrophages and microglia, which, in turn, release viral particles and immune mediators that dysregulate all brain cell types. Consequently, children living with HIV often present with neurodevelopmental delays.
Methods: In this study, we used proton nuclear magnetic resonance (1H-NMR) spectroscopy to analyze the neurometabolic profile of HIV infection using cerebrospinal fluid samples obtained from 17 HIV+ and 50 HIV- South African children.
Results: Nine metabolites, including glucose, lactate, glutamine, 1,2-propanediol, acetone, 3-hydroxybutyrate, acetoacetate, 2-hydroxybutyrate, and myo-inositol, showed significant differences when comparing children infected with HIV and those uninfected. These metabolites may be associated with activation of the innate immune response and disruption of neuroenergetics pathways.
Conclusion: These results elucidate the neurometabolic state of children infected with HIV, including upregulation of glycolysis, dysregulation of ketone body metabolism, and elevated reactive oxygen species production. Furthermore, we hypothesize that neuroinflammation alters astrocyte-neuron communication, lowering neuronal activity in children infected with HIV, which may contribute to the neurodevelopmental delay often observed in this population.

Keywords:  HIV-associated neurocognitive disorder (HAND); cerebrospinal fluid (CSF); human immunodeficiency virus (HIV); metabolomics; neuroenergetics; pediatric; proton nuclear magnetic resonance (1H-NMR)

DOI:  https://doi.org/10.3389/fnins.2024.1270041
Mol Genet Metab. 2024 May 09. pii: S1096-7192(24)00372-X. [Epub ahead of print]142(2): 108488

D-mannose as a new therapy for fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG).

Rodrigo Tzovenos Starosta, Angela J Lee, Elizabeth R Toolan, Miao He, Parith Wongkittichote, Earnest James Paul Daniel, Silvia Radenkovic, Rohit Budhraja, Akhilesh Pandey, Jaiprakash Sharma, Eva Morava, Hoanh Nguyen, Patricia I Dickson.

   INTRODUCTION: Fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG) is a rare autosomal recessive inborn error of metabolism characterized by a decreased flux through the salvage pathway of GDP-fucose biosynthesis due to a block in the recycling of L-fucose that exits the lysosome. FCSK-CDG has been described in 5 individuals to date in the medical literature, with a phenotype comprising global developmental delays/intellectual disability, hypotonia, abnormal myelination, posterior ocular disease, growth and feeding failure, immune deficiency, and chronic diarrhea, without clear therapeutic recommendations.
PATIENT AND METHODS: In a so far unreported FCSK-CDG patient, we studied proteomics and glycoproteomics in vitro in patient-derived fibroblasts and also performed in vivo glycomics, before and after treatment with either D-Mannose or L-Fucose.
RESULTS: We observed a marked increase in fucosylation after D-mannose supplementation in fibroblasts compared to treatment with L-Fucose. The patient was then treated with D-mannose at 850 mg/kg/d, with resolution of the chronic diarrhea, resolution of oral aversion, improved weight gain, and observed developmental gains. Serum N-glycan profiles showed an improvement in the abundance of fucosylated glycans after treatment. No treatment-attributed adverse effects were observed.
CONCLUSION: D-mannose is a promising new treatment for FCSK-CDG.

Keywords:  Aleuria aurantia; CDG; Chronic diarrhea; Congenital disorders of glycosylation; Developmental delay; Exome sequencing; Fucose; Fucose kinase; Glycoproteomics; Mannose

DOI:  https://doi.org/10.1016/j.ymgme.2024.108488
Int J Mol Sci. 2024 Apr 24. pii: 4645. [Epub ahead of print]25(9):

The Role of Phospholipid Alterations in Mitochondrial and Brain Dysfunction after Cardiac Arrest.

Rishabh C Choudhary, Cyrus E Kuschner, Jacob Kazmi, Liam Mcdevitt, Blanca B Espin, Mohammed Essaihi, Mitsuaki Nishikimi, Lance B Becker, Junhwan Kim.

  The human brain possesses three predominate phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS), which account for approximately 35-40%, 35-40%, and 20% of the brain's phospholipids, respectively. Mitochondrial membranes are relatively diverse, containing the aforementioned PC, PE, and PS, as well as phosphatidylinositol (PI) and phosphatidic acid (PA); however, cardiolipin (CL) and phosphatidylglycerol (PG) are exclusively present in mitochondrial membranes. These phospholipid interactions play an essential role in mitochondrial fusion and fission dynamics, leading to the maintenance of mitochondrial structural and signaling pathways. The essential nature of these phospholipids is demonstrated through the inability of mitochondria to tolerate alteration in these specific phospholipids, with changes leading to mitochondrial damage resulting in neural degeneration. This review will emphasize how the structure of phospholipids relates to their physiologic function, how their metabolism facilitates signaling, and the role of organ- and mitochondria-specific phospholipid compositions. Finally, we will discuss the effects of global ischemia and reperfusion on organ- and mitochondria-specific phospholipids alongside the novel therapeutics that may protect against injury.

Keywords:  cardiac arrest; fatty acids; ischemia; lysophospholipids; phospholipids

DOI:  https://doi.org/10.3390/ijms25094645
Front Aging Neurosci. 2024 ;16 1390915

Testosterone deficiency worsens mitochondrial dysfunction in APP/PS1 mice.

Tianyun Zhang, Yun Chu, Yue Wang, Yu Wang, Jinyang Wang, Xiaoming Ji, Guoliang Zhang, Geming Shi, Rui Cui, Yunxiao Kang.

   Background: Recent studies show testosterone (T) deficiency worsens cognitive impairment in Alzheimer's disease (AD) patients. Mitochondrial dysfunction, as an early event of AD, is becoming critical hallmark of AD pathogenesis. However, currently, whether T deficiency exacerbates mitochondrial dysfunction of men with AD remains unclear.
Objective: The purpose of this study is to explore the effects of T deficiency on mitochondrial dysfunction of male AD mouse models and its potential mechanisms.
Methods: Alzheimer's disease animal model with T deficiency was performed by castration to 3-month-old male APP/PS1 mice. Hippocampal mitochondrial function of mice was analyzed by spectrophotometry and flow cytometry. The gene expression levels related to mitochondrial biogenesis and mitochondrial dynamics were determined through quantitative real-time PCR (qPCR) and western blot analysis. SH-SY5Y cells treated with flutamide, T and/or H2O2 were processed for analyzing the potential mechanisms of T on mitochondrial dysfunction.
Results: Testosterone deficiency significantly aggravated the cognitive deficits and hippocampal pathologic damage of male APP/PS1 mice. These effects were consistent with exacerbated mitochondrial dysfunction by gonadectomy to male APP/PS1 mice, reflected by further increase in oxidative damage and decrease in mitochondrial membrane potential, complex IV activity and ATP levels. More importantly, T deficiency induced the exacerbation of compromised mitochondrial homeostasis in male APP/PS1 mice by exerting detrimental effects on mitochondrial biogenesis and mitochondrial dynamics at mRNA and protein level, leading to more defective mitochondria accumulated in the hippocampus. In vitro studies using SH-SY5Y cells validated T's protective effects on the H2O2-induced mitochondrial dysfunction, mitochondrial biogenesis impairment, and mitochondrial dynamics imbalance. Administering androgen receptor (AR) antagonist flutamide weakened the beneficial effects of T pretreatment on H2O2-treated SH-SY5Y cells, demonstrating a critical role of classical AR pathway in maintaining mitochondrial function.
Conclusion: Testosterone deficiency exacerbates hippocampal mitochondrial dysfunction of male APP/PS1 mice by accumulating more defective mitochondria. Thus, appropriate T levels in the early stage of AD might be beneficial in delaying AD pathology by improving mitochondrial biogenesis and mitochondrial dynamics.

Keywords:  Alzheimer’s disease; hippocampus; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; testosterone deficiency

DOI:  https://doi.org/10.3389/fnagi.2024.1390915
Nutrients. 2024 Apr 24. pii: 1258. [Epub ahead of print]16(9):

Ketogenic Diet in the Treatment of Epilepsy.

Kinga Borowicz-Reutt, Marlena Krawczyk, Julia Czernia.

  Epilepsy is one of the most disabling neurological diseases. Despite proper pharmacotherapy and the availability of 2nd and 3rd generation antiepileptic drugs, deep brain stimulation, and surgery, up to 30-40% of epilepsy patients remain drug-resistant. Consequences of this phenomenon include not only decreased a quality of life, and cognitive, behavioral, and personal disorders, but also an increased risk of death, i.e., in the mechanism of sudden unexpected death in epilepsy patients (SUDEP). The main goals of epilepsy treatment include three basic issues: achieving the best possible seizure control, avoiding the undesired effects of treatment, and maintaining/improving the quality of patients' lives. Therefore, numerous attempts are made to offer alternative treatments for drug-resistant seizures, an example of which is the ketogenic diet. It is a long-known but rarely used dietary therapy for intractable seizures. One of the reasons for this is the unpalatability of the classic ketogenic diet, which reduces patient compliance and adherence rates. However, its antiseizure effects are often considered to be worth the effort. Until recently, the diet was considered the last-resort treatment. Currently, it is believed that a ketogenic diet should be used much earlier in patients with well-defined indications. In correctly qualified patients, seizure activity may be reduced by over 90% or even abolished for long periods after the diet is stopped. A ketogenic diet can be used in all age groups, although most of the available literature addresses pediatric epilepsy. In this article, we focus on the mechanisms of action, effectiveness, and adverse effects of different variants of the ketogenic diet, including its classic version, a medium-chain triglyceride diet, a modified Atkins diet, and a low glycemic index treatment.

Keywords:  KD; efficacy; epilepsy; ketogenic diet; safety; seizure

DOI:  https://doi.org/10.3390/nu16091258
Elife. 2024 May 13. pii: RP91141. [Epub ahead of print]12

Retinal metabolism displays evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle.

Yiyi Chen, Laimdota Zizmare, Victor Calbiague, Lan Wang, Shirley Yu, Fritz W Herberg, Oliver Schmachtenberg, Francois Paquet-Durand, Christoph Trautwein.

  The retina consumes massive amounts of energy, yet its metabolism and substrate exploitation remain poorly understood. Here, we used a murine explant model to manipulate retinal energy metabolism under entirely controlled conditions and utilised 1H-NMR spectroscopy-based metabolomics, in situ enzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experimental manipulations resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. This selective vulnerability of photoreceptors suggested very specific adaptations in their energy metabolism. Rod photoreceptors were found to rely strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were dependent on glycolysis but insensitive to electron transport chain decoupling. Importantly, photoreceptors appeared to uncouple glycolytic and Krebs-cycle metabolism via three different pathways: (1) the mini-Krebs-cycle, fuelled by glutamine and branched chain amino acids, generating N-acetylaspartate; (2) the alanine-generating Cahill-cycle; (3) the lactate-releasing Cori-cycle. Moreover, the metabolomics data indicated a shuttling of taurine and hypotaurine between the retinal pigment epithelium and photoreceptors, likely resulting in an additional net transfer of reducing power to photoreceptors. These findings expand our understanding of retinal physiology and pathology and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases.

Keywords:  aerobic glycolysis; glucose transport; glucose-alanine cycle; mouse; neuroscience; photoreceptor metabolism; retinal metabolism; retinitis pigmentosa

DOI:  https://doi.org/10.7554/eLife.91141
Acta Neuropathol. 2024 May 15. 147(1): 84

Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.

Nicolas Leventoux, Satoru Morimoto, Mitsuru Ishikawa, Shiho Nakamura, Fumiko Ozawa, Reona Kobayashi, Hirotaka Watanabe, Sopak Supakul, Satoshi Okamoto, Zhi Zhou, Hiroya Kobayashi, Chris Kato, Yoshifumi Hirokawa, Ikuko Aiba, Shinichi Takahashi, Shinsuke Shibata, Masaki Takao, Mari Yoshida, Fumito Endo, Koji Yamanaka, Yasumasa Kokubo, Hideyuki Okano.

  Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

Keywords:  Amyotrophic lateral sclerosis (ALS); Astrocyte; CHCHD2; Kii ALS/PDC; Mitochondria; Parkinsonism-dementia complex (PDC)

DOI:  https://doi.org/10.1007/s00401-024-02734-w
J Neurosci Res. 2024 May;102(5): e25339

The differential effects of palmitic acid and oleic acid on the metabolic response of hypothalamic astrocytes from male and female mice.

Roberto Collado-Perez, David Chamoso-Sánchez, Antonia García, María S Fernández-Alfonso, Maria Jiménez-Hernáiz, Sandra Canelles, Jesús Argente, Laura M Frago, Julie A Chowen.

  Diets rich in saturated fats are more detrimental to health than those containing mono- or unsaturated fats. Fatty acids are an important source of energy, but they also relay information regarding nutritional status to hypothalamic metabolic circuits and when in excess can be detrimental to these circuits. Astrocytes are the main site of central fatty acid β-oxidation, and hypothalamic astrocytes participate in energy homeostasis, in part by modulating hormonal and nutritional signals reaching metabolic neurons, as well as in the inflammatory response to high-fat diets. Thus, we hypothesized that how hypothalamic astrocytes process-specific fatty acids participates in determining the differential metabolic response and that this is sex dependent as males and females respond differently to high-fat diets. Male and female primary hypothalamic astrocyte cultures were treated with oleic acid (OA) or palmitic acid (PA) for 24 h, and an untargeted metabolomics study was performed. A clear predictive model for PA exposure was obtained, while the metabolome after OA exposure was not different from controls. The observed modifications in metabolites, as well as the expression levels of key metabolic enzymes, indicate a reduction in the activity of the Krebs and glutamate/glutamine cycles in response to PA. In addition, there were specific differences between the response of astrocytes from male and female mice, as well as between hypothalamic and cerebral cortical astrocytes. Thus, the response of hypothalamic astrocytes to specific fatty acids could result in differential impacts on surrounding metabolic neurons and resulting in varied systemic metabolic outcomes.

Keywords:  Krebs cycle; glia; glutamine cycle; high‐fat diet; metabolomics; oleic acid; palmitic acid; sex differences

DOI:  https://doi.org/10.1002/jnr.25339
Biomed Pharmacother. 2024 May 14. pii: S0753-3322(24)00485-2. [Epub ahead of print]175 116601

Short-chain fatty acids: Important components of the gut-brain axis against AD.

Yan Huang, Yi Feng Wang, Jing Miao, Rui Fang Zheng, Jin Yao Li.

  Alzheimer's disease (AD) comprises a group of neurodegenerative disorders with some changes in the brain, which could lead to the deposition of certain proteins and result in the degeneration and death of brain cells. Patients with AD manifest primarily as cognitive decline, psychiatric symptoms, and behavioural disorders. Short-chain fatty acids (SCFAs) are a class of saturated fatty acids (SFAs) produced by gut microorganisms through the fermentation of dietary fibre ingested. SCFAs, as a significant mediator of signalling, can have diverse physiological and pathological roles in the brain through the gut-brain axis, and play a positive effect on AD via multiple pathways. Firstly, differences in SCFAs and microbial changes have been stated in AD cases of humans and mice in this paper. And then, mechanisms of three main SCFAs in treating with AD have been summarized, as well as differences of gut bacteria. Finally, functions of SCFAs played in regulating intestinal flora homeostasis, modulating the immune system, and the metabolic system, which were considered to be beneficial for the treatment of AD, have been elucidated, and the key roles of gut bacteria and SCFAs were pointed out. All in all, this paper provides an overview of SCFAs and gut bacteria in AD, and can help people to understand the importance of gut-brain axis in AD.

Keywords:  Alzheimer's disease; Gut-brain axis; Intestinal flora; Short-chain fatty acid

DOI:  https://doi.org/10.1016/j.biopha.2024.116601
Aging Cell. 2024 May 16. e14165

The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.

Mohamed Ariff Iqbal, Maria Bilen, Yubing Liu, Vanessa Jabre, Bensun C Fong, Imane Chakroun, Smitha Paul, Jingwei Chen, Steven Wade, Michel Kanaan, Mary-Ellen Harper, Mireille Khacho, Ruth S Slack.

  Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1-inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc-RNA-seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1-deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4-mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration.

Keywords:  Hypoxia; Opa1; adult neurogenesis; intergrated stress response; metabolic adaptation; mitochondrial dynamics; neurodegeneration

DOI:  https://doi.org/10.1111/acel.14165