bims-medebr 2024-08-25 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–08–25
twelve papers selected by
Regina F. Fernández, Johns Hopkins University

Insulin and leptin acutely modulate the energy metabolism of primary hypothalamic and cortical astrocytes.
Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer's disease.
The Role of Mitochondrial Pyruvate Carrier in Neurological Disorders.
Acyl-CoA synthetase 6 controls rod photoreceptor function and survival by shaping the phospholipid composition of retinal membranes.
Excessive lipid production shapes glioma tumor microenvironment.
Phosphoglycerate kinase is a central leverage point in Parkinson's disease-driven neuronal metabolic deficits.
Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases.
Lactate administration causes long-term neuroprotective effects following neonatal hypoxia-ischemia.
Transcriptomics analysis reveals potential regulatory role of nSMase2 (Smpd3) in nervous system development and function of middle-aged mouse brains.
Acetate enables metabolic fitness and cognitive performance during sleep disruption.
Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.
Control of innate immunity and lipid biosynthesis in neurodegeneration.

J Neurochem. 2024 Aug 22.

Insulin and leptin acutely modulate the energy metabolism of primary hypothalamic and cortical astrocytes.

Christopher Wolff, Dorit John, Ulrike Winkler, Luise Hochmuth, Johannes Hirrlinger, Susanne Köhler.

  Astrocytes constitute a heterogeneous cell population within the brain, contributing crucially to brain homeostasis and playing an important role in overall brain function. Their function and metabolism are not only regulated by local signals, for example, from nearby neurons, but also by long-range signals such as hormones. Thus, two prominent hormones primarily known for regulating the energy balance of the whole organism, insulin, and leptin, have been reported to also impact astrocytes within the brain. In this study, we investigated the acute regulation of astrocytic metabolism by these hormones in cultured astrocytes prepared from the mouse cortex and hypothalamus, a pivotal region in the context of nutritional regulation. Utilizing genetically encoded, fluorescent nanosensors, the cytosolic concentrations of glucose, lactate, and ATP, along with glycolytic rate and the NADH/NAD+ redox state were measured. Under basal conditions, differences between the two populations of astrocytes were observed for glucose and lactate concentrations as well as the glycolytic rate. Additionally, astrocytic metabolism responded to insulin and leptin in both brain regions, with some unique characteristics for each cell population. Finally, both hormones influenced how cells responded to elevated extracellular levels of potassium ions, a common indicator of neuronal activity. In summary, our study provides evidence that insulin and leptin acutely regulate astrocytic metabolism within minutes. Additionally, while astrocytes from the hypothalamus and cortex share similarities in their metabolism, they also exhibit distinct properties, further underscoring the growing recognition of astrocyte heterogeneity.

Keywords:  astrocyte; energy metabolism; heterogeneity; insulin; leptin; metabolic nanosensors

DOI:  https://doi.org/10.1111/jnc.16211
Alzheimers Dement. 2024 Aug 22.

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer's disease.

Andrés Norambuena, Vijay Kumar Sagar, Zhuoying Wang, Prakash Raut, Ziang Feng, Horst Wallrabe, Evelyn Pardo, Taylor Kim, Shagufta Rehman Alam, Song Hu, Ammasi Periasamy, George S Bloom.

   INTRODUCTION: Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well-known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient-induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo.
METHODS: Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock-in (APPSAA) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy.
RESULTS: NiMA is inhibited in APPSAA mice before other defects are detected in these Aβ-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice.
DISCUSSION: NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APPSAA mice, and may represent an early stage in human AD.
HIGHLIGHTS: Amyloid beta blocks communication between lysosomes and mitochondria in vivo. Nutrient-induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer's disease (AD) histopathology in heterozygous amyloid precursor protein knock-in (APPSAA/+) mice. NiMA is disrupted long before learning and memory deficits in APPSAA/+ mice. Pharmacological interventions can rescue AD-related NiMA disruption in vivo.

Keywords:  amino acids; brain metabolism; insulin; mammalian target of rapamycin; tau

DOI:  https://doi.org/10.1002/alz.14144
Mol Neurobiol. 2024 Aug 23.

The Role of Mitochondrial Pyruvate Carrier in Neurological Disorders.

Yue Liu, Xiying Yu, Wei Jiang.

  The mitochondrial pyruvate carrier (MPC) is a specific protein complex located in the inner mitochondrial membrane. Comprising a heterodimer of two homodimeric membrane proteins, mitochondrial pyruvate carrier 1 and mitochondrial pyruvate carrier 2, MPC connects cytoplasmic metabolism to mitochondrial metabolism by transferring pyruvate from the cytoplasm to the mitochondria. The nervous system requires substantial energy to maintain its function, and the mitochondrial energy supply is closely linked to neurological function. Mitochondrial dysfunction can induce or exacerbate intracerebral pathologies. MPC influences mitochondrial function due to its specific role as a pyruvate transporter. However, recent studies on MPC and mitochondrial dysfunction in neurological disorders have yielded controversial results, and the underlying mechanisms remain unclear. In this brief review, we provide an overview of the structure and function of MPC. We further discuss the potential mechanisms and feasibility of targeting MPC in treating Parkinson's disease, Alzheimer's disease, and cerebral ischemia/hypoxia injury. This review aims to offer insights into MPC as a target for clinical treatment.

Keywords:  Metabolism; Mitochondrial dysfunction; Mitochondrial pyruvate carrier; Neurological disorders

DOI:  https://doi.org/10.1007/s12035-024-04435-7
Commun Biol. 2024 Aug 21. 7(1): 1027

Acyl-CoA synthetase 6 controls rod photoreceptor function and survival by shaping the phospholipid composition of retinal membranes.

Yixiao Wang, Silke Becker, Stella Finkelstein, Frank M Dyka, Haitao Liu, Mark Eminhizer, Ying Hao, Richard S Brush, William J Spencer, Vadim Y Arshavsky, John D Ash, Jianhai Du, Martin-Paul Agbaga, Frans Vinberg, Jessica M Ellis, Ekaterina S Lobanova.

The retina is light-sensitive neuronal tissue in the back of the eye. The phospholipid composition of the retina is unique and highly enriched in polyunsaturated fatty acids, including docosahexaenoic fatty acid (DHA). While it is generally accepted that a high DHA content is important for vision, surprisingly little is known about the mechanisms of DHA enrichment in the retina. Furthermore, the biological processes controlled by DHA in the eye remain poorly defined as well. Here, we combined genetic manipulations with lipidomic analysis in mice to demonstrate that acyl-CoA synthetase 6 (Acsl6) serves as a regulator of the unique composition of retinal membranes. Inactivation of Acsl6 reduced the levels of DHA-containing phospholipids, led to progressive loss of light-sensitive rod photoreceptor neurons, attenuated the light responses of these cells, and evoked distinct transcriptional response in the retina involving the Srebf1/2 (sterol regulatory element binding transcription factors 1/2) pathway. This study identifies one of the major enzymes responsible for DHA enrichment in the retinal membranes and introduces a model allowing an evaluation of rod functioning and pathology caused by impaired DHA incorporation/retention in the retina.

DOI: https://doi.org/10.1038/s42003-024-06691-8
Ultrastruct Pathol. 2024 Aug 19. 1-11

Excessive lipid production shapes glioma tumor microenvironment.

Haitham H Maraqah, John Paul Aboubechara, Mones S Abu-Asab, Han Sung Lee, Orwa Aboud.

  Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n = 18) and IDH1 mutant (IDH1-mt) astrocytoma (n = 12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.

Keywords:  Astrocytoma; glioblastoma; glycolysis; immune evasion; lipid accumulation; mitochondrial dysfunction; oxidative phosphorylation; therapeutic strategies; tumor microenvironment; ultrastructural analysis

DOI:  https://doi.org/10.1080/01913123.2024.2392728
Sci Adv. 2024 Aug 23. 10(34): eadn6016

Phosphoglycerate kinase is a central leverage point in Parkinson's disease-driven neuronal metabolic deficits.

Alexandros C Kokotos, Aldana M Antoniazzi, Santiago R Unda, Myung Soo Ko, Daehun Park, David Eliezer, Michael G Kaplitt, Pietro De Camilli, Timothy A Ryan.

Although certain drivers of familial Parkinson's disease (PD) compromise mitochondrial integrity, whether metabolic deficits underly other idiopathic or genetic origins of PD is unclear. Here, we demonstrate that phosphoglycerate kinase 1 (PGK1), a gene in the PARK12 susceptibility locus, is rate limiting in neuronal glycolysis and that modestly increasing PGK1 expression boosts neuronal adenosine 5'-triphosphate production kinetics that is sufficient to suppress PARK20-driven synaptic dysfunction. We found that this activity enhancement depends on the molecular chaperone PARK7/DJ-1, whose loss of function significantly disrupts axonal bioenergetics. In vivo, viral expression of PGK1 confers protection of striatal dopamine axons against metabolic lesions. These data support the notion that bioenergetic deficits may underpin PD-associated pathologies and point to improving neuronal adenosine 5'-triphosphate production kinetics as a promising path forward in PD therapeutics.

DOI: https://doi.org/10.1126/sciadv.adn6016
Rev Neurosci. 2024 Aug 20.

Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases.

Abdul Aziz Mohamed Yusoff, Siti Zulaikha Nashwa Mohd Khair.

  Neurodegenerative diseases represent a significant challenge to modern medicine, with their complex etiology and progressive nature posing hurdles to effective treatment strategies. Among the various contributing factors, mitochondrial dysfunction has emerged as a pivotal player in the pathogenesis of several neurodegenerative disorders. This review paper provides a comprehensive overview of how mitochondrial impairment contributes to the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, driven by bioenergetic defects, biogenesis impairment, alterations in mitochondrial dynamics (such as fusion or fission), disruptions in calcium buffering, lipid metabolism dysregulation and mitophagy dysfunction. It also covers current therapeutic interventions targeting mitochondrial dysfunction in these diseases.

Keywords:  mitochondrial bioenergetics and biogenesis; mitochondrial dynamics and mitophagy; mitochondrial dysfunctions; neurodegenerative diseases; therapy

DOI:  https://doi.org/10.1515/revneuro-2024-0080
Exp Neurol. 2024 Aug 19. pii: S0014-4886(24)00255-3. [Epub ahead of print] 114929

Lactate administration causes long-term neuroprotective effects following neonatal hypoxia-ischemia.

Isadora D'Ávila Tassinari, Janaína Zang, Nícolas Heller Ribeiro, Bianca Büchele Martins, João Vitor Miotto Tauffer, Ricardo Ribeiro Nunes, Eduardo Farias Sanches, Stéphane Sizonenko, Carlos Alexandre Netto, Ana Helena Paz, Luciano Stürmer de Fraga.

  Neonatal hypoxia-ischemia (HI) is one of the main causes of mortality and long-term disabilities in newborns, and the only clinical approach to treat this condition is therapeutic hypothermia, which shows some limitations. Thus, putative neuroprotective agents have been tested in animal models of HI. Lactate is a preferential metabolic substrate of the neonatal brain and has already been shown to produce beneficial neuroprotective outcomes in neonatal animals exposed to HI. Here, we administered lactate as a treatment in neonatal rats previously exposed to HI and evaluated the impact of this treatment in adulthood. Seven-day-old (P7) male and female Wistar rats underwent permanent common right carotid occlusion combined with an exposition to a hypoxic atmosphere (8% oxygen) for 60 min. Animals were assigned to one of four experimental groups: HI, HI + LAC, SHAM, SHAM+LAC. Lactate was administered intraperitoneally 30 min and 2 h after hypoxia in HI + LAC and SHAM+LAC groups, whereas HI and SHAM groups received vehicle. Animals were tested in the behavioral tasks of negative geotaxis and righting reflex (P8), cylinder test (P24), and the modified neurological severity score was calculated (P25). Open field (OF), and novel object recognition (NOR) were evaluated in adulthood. Animals were killed at P60, and the brains were harvested and processed to evaluate the volume of brain injury. Our results showed that lactate administration reduced the volume of brain lesion and improved sensorimotor and cognitive behavior both in neonatal, juvenile, and adult life in HI animals from both sexes. Thus, lactate administration might be considered as a potential neuroprotective strategy for the treatment of neonatal HI, which is a prevalent disorder affecting newborns.

Keywords:  Lactate; Metabolism; Neonatal hypoxia-ischemia; Neurodevelopment; Neuroprotection

DOI:  https://doi.org/10.1016/j.expneurol.2024.114929
Genes Brain Behav. 2024 Aug;23(4): e12911

Transcriptomics analysis reveals potential regulatory role of nSMase2 (Smpd3) in nervous system development and function of middle-aged mouse brains.

Zhihui Zhu, Timothy S McClintock, Erhard Bieberich.

  Neutral sphingomyelinase-2 (nSMase2), gene name sphingomyelin phosphodiesterase-3 (Smpd3), is a key regulatory enzyme responsible for generating the sphingolipid ceramide. The function of nSMase2 in the brain is still controversial. To better understand the functional roles of nSMase2 in the aging mouse brain, we applied RNA-seq analysis, which identified a total of 1462 differentially abundant mRNAs between +/fro and fro/fro, of which 891 were increased and 571 were decreased in nSMase2-deficient mouse brains. The most strongly enriched GO and KEGG annotation terms among transcripts increased in fro/fro mice included synaptogenesis, synapse development, synaptic signaling, axon development, and axonogenesis. Among decreased transcripts, enriched annotations included ribosome assembly and mitochondrial protein complex functions. KEGG analysis of decreased transcripts also revealed overrepresentation of annotations for Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington disease (HD). Ingenuity Pathway Analysis (IPA) tools predicted lower susceptibility to these neurodegenerative disorders, as well as predictions agreeing with stronger synaptic function, learning, and memory in fro/fro mice. The IPA tools identified signaling proteins, epigenetic regulators, and microRNAs as likely upstream regulators of the broader set of genes encoding the affected transcripts. It also revealed 16 gene networks, each linked to biological processes identified as overrepresented annotations among the affected transcripts by multiple analysis methods. Therefore, the analysis of these RNA-seq data indicates that nSMase2 impacts synaptic function and neural development, and may contribute to the onset and development of neurodegenerative diseases in middle-aged mice.

Keywords:  RNA‐seq analysis; fro/fro; neurodegenerative diseases; neutral sphingomyelinase‐2

DOI:  https://doi.org/10.1111/gbb.12911
Cell Metab. 2024 Aug 12. pii: S1550-4131(24)00290-0. [Epub ahead of print]

Acetate enables metabolic fitness and cognitive performance during sleep disruption.

Qinqin He, Liwei Ji, Yanyan Wang, Yarong Zhang, Haiyan Wang, Junyan Wang, Qing Zhu, Maodi Xie, Wei Ou, Jun Liu, Kuo Tang, Kening Lu, Qingmei Liu, Jian Zhou, Rui Zhao, Xintian Cai, Nanfang Li, Yang Cao, Tao Li.

  Sleep is essential for overall health, and its disruption is linked to increased risks of metabolic, cognitive, and cardiovascular dysfunctions; however, the molecular mechanisms remain poorly understood. This study investigated how sleep disturbances contribute to metabolic imbalance and cognition impairment using a chronic sleep fragmentation (SF) mouse model. SF mice exhibited impaired cognition, glucose metabolism, and insulin sensitivity compared with controls. We identified increased acetate levels in hypothalamic astrocytes as a defensive response in SF mice. Through acetate infusion or astrocyte-specific Acss1 deletion to elevate acetate levels, we observed mitigated metabolic and cognitive impairments in SF mice. Mechanistically, acetate binds and activates pyruvate carboxylase, thereby restoring glycolysis and the tricarboxylic acid cycle. Among individuals most commonly affected by SF, patients with obstructive sleep apnea exhibited elevated acetate levels when coupled with type 2 diabetes. Our study uncovers the protective effect of acetate against sleep-induced metabolic and cognitive impairments.

Keywords:  acetate; astrocyte; cognitive performance; glucose homeostasis; hypothalamus; pyruvate carboxylase; sleep disruption

DOI:  https://doi.org/10.1016/j.cmet.2024.07.019
Brain Behav Immun. 2024 Aug 18. pii: S0889-1591(24)00548-8. [Epub ahead of print]122 279-286

Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.

Marisa N Spann, Ravi Bansal, Ezra Aydin, Angeliki Pollatou, Kiarra Alleyne, Margaret Bennett, Siddhant Sawardekar, Kayla Delapenha, Bin Cheng, Seonjoo Lee, Catherine Monk, Bradley S Peterson.

  Few human studies have assessed the association of prenatal maternal immune activation (MIA) with measures of brain development and psychiatric risk in newborn offspring. Our goal was to identify the effects of MIA during the 2nd and 3rd trimesters of pregnancy on newborn measures of brain metabolite concentrations, tissue microstructure, and motor development. This was a prospective longitudinal cohort study conducted with nulliparous pregnant women who were aged 14 to 19 years and recruited in their 2nd trimester, as well as their children who were followed through 14 months of age. MIA was indexed by maternal interleukin-6 (IL-6) and C-reactive protein (CRP) in both trimesters of pregnancy. Primary outcomes included: (1) newborn brain metabolite concentrations as ratios to creatine (N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr) measured using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity, measured using Diffusion Tensor Imaging; and (3) indices of motor development, assessed prenatally and postnatally at ages 4- and 14-months. Maternal IL-6 and CRP levels associated significantly with both metabolites in the putamen, thalamus, insula, and the internal capsule. Maternal IL-6 associated significantly with fractional anisotropy in the putamen, caudate, thalamus, insula, and precuneus, and with mean diffusivity in the inferior parietal and middle temporal gyrus. CRP associated significantly with fractional anisotropy in the thalamus, insula, and putamen. Significant associations were found in common regions across imaging modalities, though the direction of associations differed by immune marker. In addition, both maternal IL-6 and CRP (in both trimesters) prenatally associated significantly with offspring motor development at 4- and 14-months of age. The left thalamus mediated effects of IL-6 on postnatal motor development. These findings demonstrate that levels of MIA in mid- to late pregnancy in a generally healthy sample associate with tissue characteristics in newborn brain regions that primarily support motor integration and coordination, as well as behavioral regulation. Those brain effects may contribute to differences in motor development.

Keywords:  Diffusion tensor imaging; Early brain development; Maternal immune activation, magnetic resonance spectroscopy

DOI:  https://doi.org/10.1016/j.bbi.2024.08.025
Front Mol Neurosci. 2024 ;17 1402055

Control of innate immunity and lipid biosynthesis in neurodegeneration.

Daniel R Scoles, Stefan M Pulst.

  The cGAS-STING innate immunity pathway and the SREBP-activated cholesterol and fatty acid synthesis pathway are abnormally co-regulated in neurodegenerative disease. Activation of STING signaling occurs at the endoplasmic reticulum (ER) membrane with STING anchored by INSIG1 along with SREBP and the sterol-bound SREBP cleavage activating protein (SCAP) when sterols are in abundance. When sterols are low, the INSIG-dependent STING pathway is inactivated and the SREBP-SCAP complex is translocated to the Golgi where SREBP is cleaved and translocated to the nucleus to transactivate genes for cholesterol and fatty acid synthesis. Thus, there is inverse activation of STING vs. SREBP: when innate immunity is active, pathways for cholesterol and fatty acid synthesis are suppressed, and vice versa. The STING pathway is stimulated by foreign viral cytoplasmic nucleic acids interacting with the cyclic GMP-AMP synthase (cGAS) DNA sensor or RIG-I and MDA5 dsRNA sensors, but with neurodegeneration innate immunity is also activated by self-DNAs and double-stranded RNAs that accumulate with neuronal death. Downstream, activated STING recruits TBK1 and stimulates the transactivation of interferon stimulated genes and the autophagy pathway, which are both protective. However, chronic activation of innate immunity contributes to microglia activation, neuroinflammation and autophagy failure leading to neurodegeneration. STING is also a proton channel that when activated stimulates proton exit from STING vesicles leading to cell death. Here we review the salient features of the innate immunity and cholesterol and fatty acid synthesis pathways, observations of abnormal STING and SREBP signaling in neurodegenerative disease, and relevant therapeutic approaches.

Keywords:  INSIG1; SREBP; STING; TBK1; cholesterol biosynthesis; fatty acid biosynthesis; innate immunity; neurodegenerative disease

DOI:  https://doi.org/10.3389/fnmol.2024.1402055