Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(8), P. 1290 - 1302

Published: July 17, 2023

Having direct access to brain vasculature, astrocytes can take up available blood nutrients and metabolize them fulfil their own energy needs deliver metabolic intermediates local synapses

Language: Английский

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Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: July 20, 2023

Abstract Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of (NDAs), such as Alzheimer’s disease, Parkinson’s Huntington’s Amyotrophic lateral sclerosis. Glucose is the major brain fuel glucose hypometabolism has been observed regions vulnerable to NDAs. Many susceptible are topological central hub connectome, linked by densely interconnected long-range axons. Axons, key components have high metabolic needs support neurotransmission other essential activities. Long-range axons particularly injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy often an early sign neurodegeneration. Recent ascribe axonal maintenance failures local dysregulation. With this review, we aim stimulate research exploring metabolically oriented neuroprotection strategies enhance or normalize bioenergetics NDA models. Here start summarizing evidence from human patients animal models reveal correlation between connectomic disintegration aging/NDAs. To encourage mechanistic investigations on how dysregulation occurs during aging/NDAs, first review current literature distinct subdomains: axon initial segments, myelinated arbors harboring pre-synaptic boutons. In each subdomain, focus organization, activity-dependent regulation system, external glial support. Second, mechanisms regulating nicotinamide adenine dinucleotide (NAD + ) homeostasis, molecule for energy metabolism processes, including NAD biosynthetic, recycling, consuming pathways. Third, highlight innate vulnerability connectome discuss its perturbation As deficits developing into NDAs, especially asymptomatic phase, they likely exaggerated further impaired energetic cost neural network hyperactivity, pathology. Future interrogating causal relationship vulnerability, axonopathy, amyloid/tau pathology, cognitive decline will provide fundamental knowledge therapeutic interventions.

Language: Английский

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Futile cycles: Emerging utility from apparent futility

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(6), P. 1184 - 1203

Published: April 1, 2024

Futile cycles are biological phenomena where two opposing biochemical reactions run simultaneously, resulting in a net energy loss without appreciable productivity. Such state was presumed to be aberration and thus deemed an energy-wasting "futile" cycle. However, multiple pieces of evidence suggest that utilities emerge from futile cycles. A few established functions control metabolic sensitivity, modulate homeostasis, drive adaptive thermogenesis. Yet, the physiological regulation, implication, pathological relevance most remain poorly studied. In this review, we highlight abundance versatility propose classification scheme. We further discuss energetic implications various their impact on basal rate, bona fide tentative pathophysiological implications, putative drug interactions.

Language: Английский

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Transcellular Barriers to Glucose Delivery in the Body

Annual Review of Physiology, Journal Year: 2024, Volume and Issue: 86(1), P. 149 - 173

Published: Feb. 12, 2024

Glucose is the universal fuel of most mammalian cells, and it largely replenished through dietary intake. availability to tissues paramount for maintenance homeostatic energetics and, hence, supply should match demand by consuming organs. In its journey body, glucose encounters cellular barriers transit at levels absorbing intestinal epithelial wall, renal epithelium mediating reabsorption, tight capillary endothelia (especially in brain). transiting these must escape degradation ensure optimal delivery bloodstream or tissues. The liver, which stores glycogen generates de novo, similarly be able release intact circulation. We present up-to-date knowledge on handling gut, brain endothelium, kidney, discuss underlying molecular mechanisms open questions. Diseases associated with defects homeostasis are also briefly addressed. propose that problem sparing from catabolism favor translocation across posed epithelia resolved common involving transfer endoplasmic reticulum, where exits cells via unconventional mechanisms.

Language: Английский

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pH regulating mechanisms of astrocytes: A critical component in physiology and disease of the brain

Cell Calcium, Journal Year: 2024, Volume and Issue: 120, P. 102882 - 102882

Published: April 8, 2024

Strict homeostatic control of pH in both intra- and extracellular compartments the brain is fundamentally important, primarily due to profound impact free protons ([H

Language: Английский

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A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 9, 2024

Astrocytes control brain activity via both metabolic processes and gliotransmission, but the physiological links between these functions are scantly known. Here we show that endogenous activation of astrocyte type-1 cannabinoid (CB1) receptors determines a shift glycolysis towards lactate-dependent production D-serine, thereby gating synaptic cognitive in male mice. Mutant mice lacking CB1 receptor gene astrocytes (GFAP-CB1-KO) impaired novel object recognition (NOR) memory. This phenotype is rescued by gliotransmitter its precursor L-serine, also lactate 3,5-DHBA, an agonist HCAR1. Such effect abolished when astrocyte-specific phosphorylated-pathway (PP), which diverts L-serine synthesis, blocked. Consistently, 3,5-DHBA promoted co-agonist binding site occupancy CA1 post-synaptic NMDA hippocampal slices PP-dependent manner. Thus, tight cross-talk astrocytic energy metabolism gliotransmission processes.

Language: Английский

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Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1282 - 1282

Published: Feb. 1, 2025

Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that provocation causes disabling limitation cognitive and functional effort (“fatigue”) does not respond to rest. Cerebrospinal fluid was examined as proxy for brain metabolite lipid flux provide objective evidence pathophysiological dysfunction. Two cohorts ME/CFS sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). metabolites lipids were quantified by targeted Biocrates mass spectrometry methods. Significant differences between control, non-exercise vs. post-exercise, gender multivariate general linear regression Bayesian Differences found groups indicating disease-related pathologies, post-exercise implicating PEM-related pathologies. A new, novel finding elevated serine its derivatives sarcosine phospholipids with decrease in 5-methyltetrahydrofolate (5MTHF), which suggests dysfunction folate one-carbon metabolism ME/CFS. Exercise led consumption controls while consumed but generated controls. In general, the frequentist analyses complementary identical sets analytes matched metabolic modules pathway analysis. unique because it samples choroid plexus, interstitial fluid, cells parenchyma. quantitative outcomes placed into context cell danger response hypothesis explain shifts phospholipid synthesis; affect sarcosine, creatine, purines, thymidylate; aromatic anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, coenzyme energy metabolism; vitamin activities may be altered exertion. profiles suggest additional white matter contribute

Language: Английский

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Sodium homeostasis and signalling: The core and the hub of astrocyte function

Cell Calcium, Journal Year: 2023, Volume and Issue: 117, P. 102817 - 102817

Published: Nov. 4, 2023

Language: Английский

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The Astrocyte: Metabolic Hub of the Brain

Cold Spring Harbor Perspectives in Biology, Journal Year: 2024, Volume and Issue: 16(9), P. a041355 - a041355

Published: March 4, 2024

Astrocytic metabolism has taken center stage. Interposed between the neuron and vasculature, astrocytes exert control over fluxes of energy building blocks required for neuronal activity plasticity. They are also key to local detoxification waste recycling. Whereas neurons metabolically rigid, can switch different metabolic profiles according demand nutritional state organism. Their even seems be instructive peripheral nutrient mobilization been implicated in information processing behavior. Here, we summarize recent progress our understanding astrocytic its effects on homeostasis cognition.

Language: Английский

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Astrocytic Na+, K+ ATPases in physiology and pathophysiology

Cell Calcium, Journal Year: 2024, Volume and Issue: 118, P. 102851 - 102851

Published: Jan. 28, 2024

The Na

Language: Английский

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