Variable bioenergetic sensitivity of neurons and astrocytes to insulin and extracellular glucose DOI Creative Commons
Stuart Sims, Hilaree N. Frazier, Sami L. Case

и другие.

npj Metabolic Health and Disease, Год журнала: 2024, Номер 2(1)

Опубликована: Ноя. 8, 2024

Energy flow within cellular elements of the brain is a well-orchestrated, tightly regulated process, however, details underlying these functions at single-cell level are still poorly understood. Studying hypometabolism in aging and neurodegenerative diseases may benefit from experimentation on unicellular bioenergetics. Here, we examined energy status neurons astrocytes using mixed hippocampal cultures PercevalHR, an ATP:ADP nanosensor. We assessed exposures several compounds including KCl, glutamate, FCCP, insulin, glucose. A mitochondrial stress test was performed, PercevalHR's fluorescence corrected for pH pHrodo. Results demonstrate that PercevalHR can reliably report energetic two cell types communicate mixed-culture setting. While FCCP showed clear changes fluorescence, insulin glucose responses were found to be more subtle sensitive extracellular These results highlight mechanisms mediate sensitivity brain.

Язык: Английский

Understanding glucose metabolism and insulin action at the blood–brain barrier: Implications for brain health and neurodegenerative diseases DOI Creative Commons

Yiyi Zhu,

Alexei Verkhratsky, Hui Chen

и другие.

Acta Physiologica, Год журнала: 2025, Номер 241(2)

Опубликована: Янв. 16, 2025

The blood-brain barrier (BBB) is a highly selective, semipermeable critical for maintaining brain homeostasis. BBB regulates the transport of essential nutrients, hormones, and signaling molecules between bloodstream central nervous system (CNS), while simultaneously protecting from potentially harmful substances pathogens. This selective permeability ensures that nourished shielded toxins. An exception to this are regions, such as hypothalamus circumventricular organs, which irrigated by fenestrated capillaries, allowing rapid direct response various blood components. We overview metabolic functions BBB, with an emphasis on impact altered glucose metabolism insulin in pathogenesis neurodegenerative diseases. Notably, endothelial cells constituting exhibit distinct characteristics, primarily generating ATP through aerobic glycolysis. occurs despite their exposure abundant oxygen bloodstream, typically supports oxidative phosphorylation. effects astrocytes, form glial limitans component show marked sexual dimorphism. nutrient sensing hypothalamus, along signaling, systemic metabolism. Insulin modifies regulating expression tight junction proteins, angiogenesis, vascular remodeling, well modulating flow brain. disruptions particularly evident diseases, Alzheimer's disease Parkinson's disease, where breakdown accelerates cognitive decline. review highlights role normal functionality investigates how these pathways contribute onset progression

Язык: Английский

Процитировано

5
Retinal metabolism displays evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle DOI Creative Commons
Yiyi Chen, Laimdota Zizmare, Victor Calbiague

и другие.

eLife, Год журнала: 2023, Номер 12

Опубликована: Сен. 28, 2023

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

Язык: Английский

Процитировано

11
Genetically Encoded Metabolic Sensors to Study Retina Metabolism DOI
Gabriele M Wögenstein, Christian Grimm

Advances in experimental medicine and biology, Год журнала: 2025, Номер unknown, С. 465 - 469

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Human In Vitro Models of Neuroenergetics and Neurometabolic Disturbances: Current Advances and Clinical Perspectives DOI Creative Commons
Julia Rogal, Laura N. Zamproni, Polyxeni Nikolakopoulou

и другие.

Stem Cells Translational Medicine, Год журнала: 2024, Номер 13(6), С. 505 - 514

Опубликована: Апрель 8, 2024

Neurological conditions conquer the world; they are leading cause of disability and second death worldwide, appear all around world in every age group, gender, nationality, socioeconomic class. Despite growing evidence an immense impact perturbations neuroenergetics on overall brain function, only little is known about underlying mechanisms. Especially human insights sparse, owing to a shortage physiologically relevant model systems. With this perspective, we aim explore key steps considerations involved developing advanced vitro for studying neuroenergetics. We discuss biological technological strategies meet requirements predictive model, aiming at providing guide inspiration future models

Язык: Английский

Процитировано

1
Retinal metabolism: Evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle DOI Open Access
Yiyi Chen, Laimdota Zizmare, Victor Calbiague

и другие.

Опубликована: Апрель 8, 2024

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 under entirely controlled conditions utilized 1 H-NMR spectroscopy-based metabolomics, in situenzyme detection, cell viability readouts uncover the pathways production. Our experimental manipulations resulted varying degrees photoreceptor degeneration, while inner pigment epithelium were essentially unaffected. This selective vulnerability photoreceptors suggested very specific adaptations their metabolism. Rod found rely strongly on oxidative phosphorylation, but only mildly glycolysis. Conversely, cone dependent glycolysis insensitive electron transport chain decoupling. Importantly, appeared uncouple glycolytic Krebs-cycle via three different pathways: 1) mini-Krebs-cycle, fueled by glutamine branched-chain amino acids, generating N-acetylaspartate; 2) alanine-generating Cahill-cycle; 3) lactate-releasing Cori-cycle. Moreover, metabolomic data indicated shuttling taurine hypotaurine between photoreceptors, likely resulting an additional net transfer reducing power photoreceptors. These findings expand our understanding physiology pathology shed new light neuronal homeostasis pathogenesis neurodegenerative diseases.

Язык: Английский

Процитировано

1
Dynamics in Redox-Active Molecules Following Ischemic Preconditioning in the Brain DOI Creative Commons

Terezia Lysikova,

Anna Tomašcová,

Mária Kovalská

и другие.

Neurology International, Год журнала: 2024, Номер 16(3), С. 533 - 550

Опубликована: Май 9, 2024

It is well known that the brain quite vulnerable to oxidative stress, initiating neuronal loss after ischemia-reperfusion (IR) injury. A potent protective mechanism ischemic preconditioning (IPC), where proteins are among primary targets. This study explores redox-active proteins' role in preserving energy supply. Adult rats were divided into control, IR, and IPC groups. Protein profiling was conducted identify modified then verified through activity assays, immunoblot, immunohistochemical analyses. protected cortex mitochondria, as evidenced by a 2.26-fold increase superoxide dismutase (SOD) activity. Additionally, stable core subunits of respiratory chain complexes ensured sufficient production, supported 16.6% ATP synthase In hippocampal cells, led downregulation energy-related dehydrogenases, while significantly higher level peroxiredoxin 6 (PRX6) observed. Notably, enhanced glutathione reductase provide maintain PRX6 function. Astrocytes may mobilize protect neurons during initial events, decreased positivity astrocytes, accompanied an following both IR injury IPC. Maintained redox signaling via astrocyte-neuron communication triggers IPC's state. The partnership PRX6, SOD, appears essential safeguarding stabilizing hippocampus.

Язык: Английский

Процитировано

1
Multi-modal, Label-free, Optical Mapping of Cellular Metabolic Function and Oxidative Stress in 3D Engineered Brain Tissue Models DOI Open Access
Yang Zhang, Maria G. Savvidou, Volha Liaudanskaya

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 9, 2024

Brain metabolism is essential for the function of organisms. While established imaging methods provide valuable insights into brain metabolic function, they lack resolution to capture important interactions and heterogeneity at cellular level. Label-free, two-photon excited fluorescence addresses this issue by enabling dynamic assessments single-cell level without manipulations. In study, we demonstrate impact spectral on development rigorous intensity lifetime label-free protocols assess dynamically over time in 3D engineered tissue models comprising human induced neural stem cells, astrocytes, microglia. Specifically, rely multi-wavelength identify excitation/emission profiles key fluorophores within including NAD(P)H, LipDH, FAD, lipofuscin. These enable mitigate lipofuscin's overlap with NAD(P)H flavin autofluorescence extract reliable optical metrics from images acquired two excitation wavelengths emission bands. We present reporting redox state, mitochondrial fragmentation, binding status neuronal monoculture triculture systems, highlight functional between different cell types. Our findings reveal significant differences neurons glial shedding light pathway utilization, glutathione pathway, OXPHOS, glycolysis, fatty acid oxidation. Collectively, our studies establish a label-free, non-destructive approach among types relying endogenous illustrate complementary nature information that gained combining lifetime-based images. Such can improve understanding physiological dysfunction occurs onset cancers, traumatic injuries neurodegenerative diseases.

Язык: Английский

Процитировано

1
Insulin and leptin acutely modulate the energy metabolism of primary hypothalamic and cortical astrocytes DOI Creative Commons
C Wolff, Dorit John,

Ulrike Winkler

и другие.

Journal of Neurochemistry, Год журнала: 2024, Номер 169(1)

Опубликована: Авг. 22, 2024

Astrocytes constitute a heterogeneous cell population within the brain, contributing crucially to brain homeostasis and playing an important role in overall function. Their function metabolism are not only regulated by local signals, for example, from nearby neurons, but also long-range signals such as hormones. Thus, two prominent hormones primarily known regulating energy balance of whole organism, insulin, leptin, have been reported impact astrocytes brain. In this study, we investigated acute regulation astrocytic these cultured prepared mouse cortex hypothalamus, pivotal region context nutritional regulation. Utilizing genetically encoded, fluorescent nanosensors, cytosolic concentrations glucose, lactate, ATP, along with glycolytic rate NADH/NAD

Язык: Английский

Процитировано

1
Retinal metabolism: Evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle DOI Open Access
Yiyi Chen, Laimdota Zizmare, Victor Calbiague

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Июнь 21, 2022

Abstract 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 under entirely controlled conditions utilized 1 H-NMR spectroscopy-based metabolomics, in situenzyme detection, cell viability readouts uncover the pathways production. Our experimental manipulations resulted varying degrees photoreceptor degeneration, while inner pigment epithelium were essentially unaffected. This selective vulnerability photoreceptors suggested very specific adaptations their metabolism. Rod found rely strongly on oxidative phosphorylation, but only mildly glycolysis. Conversely, cone dependent glycolysis insensitive electron transport chain decoupling. Importantly, appeared uncouple glycolytic Krebs-cycle via three different pathways: 1) mini-Krebs-cycle, fueled by glutamine branched-chain amino acids, generating N-acetylaspartate; 2) alanine-generating Cahill-cycle; 3) lactate-releasing Cori-cycle. Moreover, metabolomic data indicated shuttling taurine hypotaurine between photoreceptors, likely resulting an additional net transfer reducing power photoreceptors. These findings expand our understanding physiology pathology shed new light neuronal homeostasis pathogenesis neurodegenerative diseases. Graphical abstract Retinal employ both glucose glutamate as fuels. While rod phosphorylation N-acetylaspartate producing lactate-producing Cori cycle oxidative, alanine Cahill cycle. Highlights utilizes complex switchboard consisting Krebs cycle, mini-Krebs Mini-Krebs runs more efficiently than ‘full’ Alanine transaminase decouples from Lactate, alanine, are distinctive energetic pathway signatures.

Язык: Английский

Процитировано

3
Retinal metabolism displays evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle DOI Creative Commons
Yiyi Chen, Laimdota Zizmare, Victor Calbiague

и другие.

eLife, Год журнала: 2024, Номер 12

Опубликована: Май 13, 2024

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

Язык: Английский

Процитировано

0