scholarly journals Molecular tuning of the axonal mitochondrial Ca2+ uniporter ensures metabolic flexibility of neurotransmission

2019 ◽  
Author(s):  
Ghazaleh Ashrafi ◽  
Jaime de Juan-Sanz ◽  
Ryan Farrell ◽  
Timothy A Ryan
Keyword(s):  
Oxidative Metabolism ◽  
Neuronal Cells ◽  
Atp Synthesis ◽  
Specific Protein ◽  
Metabolic Flexibility ◽  
Nerve Terminals ◽  
Atp Production ◽  
Presynaptic Function ◽  
The Brain ◽  
Do So

The brain is a vulnerable metabolic organ and must adapt to different fuel conditions to sustain function. Nerve terminals are a locus of this vulnerability but how they regulate ATP synthesis as fuel conditions vary is unknown. We show that synapses can switch from glycolytic to oxidative metabolism, but to do so, they rely on activity-driven presynaptic mitochondrial Ca2+ uptake to accelerate ATP production. We demonstrate that while in non-neuronal cells mitochondrial Ca2+ uptake requires elevated extramitochondrial Ca2+, axonal mitochondria readily take up Ca2+ in response to small changes in Ca2+. We identified the brain-specific protein MICU3 as a critical driver of this tuning of Ca2+ sensitivity. Ablation of MICU3 renders axonal mitochondria similar to non-neuronal mitochondria, prevents acceleration of local ATP synthesis, and impairs presynaptic function under oxidative conditions. Thus, presynaptic mitochondria rely on MICU3 to facilitate mitochondrial Ca2+ uptake during activity and achieve metabolic flexibility.

Assessing Bioenergetic Function in Response to Reactive Oxygen Species in Neural Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Mahyar Sameti ◽  
Pablo R. Castello ◽  
Matthew Lanoue ◽  
Tatiana Karpova ◽  
Carlos F. Martino
Keyword(s):  
Oxidative Stress ◽  
Cell Line ◽  
Cell Lines ◽  
Oxidative Metabolism ◽  
Neuronal Cells ◽  
Flux Analysis ◽  
Neural Cells ◽  
Atp Production ◽  
Extracellular Flux ◽  
Energy Demands

In this study, we characterized the bioenergetic response of the Lund human mesencephalic (LUHMES) cell line and a mouse astrocyte cell line to oxidative stress. Extracellular hydrogen peroxide  (H2O2) levels and bioenergetic response were investigated in these cell lines after exposure to paraquat (PQ), a redox cycling compound that causes oxidative stress in cells. We used extracellular flux analysis to measure mitochondrial function in adherent astrocytes and LUHMES cells. Extracellular H2O2 was measured fluorometrically. H2O2 levels increased in both cell lines after exposure to 5 µM PQ for 18 h; however, the extent of H2O2 increase with astrocytes was significantly lower than that with LUHMES cells (33% vs. 67%). Measurements of basal mitochondrial respiration showed that PQ almost completely eliminated oxygen consumption rate (OCR) in astrocytes and significantly reduced it in LUHMES cells. Notably, OCR in LUHMES cells was higher than that in astrocytes, indicating that neuronal cells maintain higher oxidative metabolism than glial cells, which is also consistent with higher energy demands of the neuronal cells. Moreover, LUHMES cells exhibited a higher amount of adenosine triphosphate (ATP) being produced by oxidative phosphorylation than by glycolysis. In contrast, astrocytes demonstrated a higher glycolytic capacity and glycolytic reserve than LUHMES cells and higher ATP production rate by glycolysis than its production by mitochondrial oxidative metabolism. Collectively, this study showed the differential bioenergetic responses between astrocytes and LUHMES cells in responding to oxidative stress and the findings may provide insights into the mitochondrial reserve capacity in neurons and astrocytes in responding to oxidative stress. (First online: Mar 30, 2021)

Neural and Environmental Modulation of Motivation

2018 ◽  
Author(s):  
Thomas Douglas
Keyword(s):  
Environmental Influence ◽  
Environmental Intervention ◽  
Argument Proceeds ◽  
The Brain ◽  
Moral Difference ◽  
Do So

Interventions that modify a person’s motivations through chemically or physically influencing the brain seem morally objectionable, at least when they are performed nonconsensually. This chapter raises a puzzle for attempts to explain their objectionability. It first seeks to show that the objectionability of such interventions must be explained at least in part by reference to the sort of mental interference that they involve. It then argues that it is difficult to furnish an explanation of this sort. The difficulty is that these interventions seem no more objectionable, in terms of the kind of mental interference that they involve, than certain forms of environmental influence that many would regard as morally innocuous. The argument proceeds by comparing a particular neurointervention with a comparable environmental intervention. The author argues, first, that the two dominant explanations for the objectionability of the neurointervention apply equally to the environmental intervention, and second, that the descriptive difference between the environmental intervention and the neurointervention that most plausibly grounds the putative moral difference in fact fails to do so. The author concludes by presenting a trilemma that falls out of the argument.

scholarly journals Human Trisomic iPSCs from Down Syndrome Fibroblasts Manifest Mitochondrial Alterations Early during Neuronal Differentiation

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 609
Author(s):  
Nunzia Mollo ◽  
Matteo Esposito ◽  
Miriam Aurilia ◽  
Roberta Scognamiglio ◽  
Rossella Accarino ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mitochondrial Dysfunction ◽  
Neuronal Differentiation ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Atp Synthesis ◽  
Differentiation Markers ◽  
Differentiation Potential ◽  
Atp Production ◽  
Mitochondrial Alterations

Background: The presence of mitochondrial alterations in Down syndrome suggests that it might affect neuronal differentiation. We established a model of trisomic iPSCs, differentiating into neural precursor cells (NPCs) to monitor the occurrence of differentiation defects and mitochondrial dysfunction. Methods: Isogenic trisomic and euploid iPSCs were differentiated into NPCs in monolayer cultures using the dual-SMAD inhibition protocol. Expression of pluripotency and neural differentiation genes was assessed by qRT-PCR and immunofluorescence. Meta-analysis of expression data was performed on iPSCs. Mitochondrial Ca2+, reactive oxygen species (ROS) and ATP production were investigated using fluorescent probes. Oxygen consumption rate (OCR) was determined by Seahorse Analyzer. Results: NPCs at day 7 of induction uniformly expressed the differentiation markers PAX6, SOX2 and NESTIN but not the stemness marker OCT4. At day 21, trisomic NPCs expressed higher levels of typical glial differentiation genes. Expression profiles indicated that mitochondrial genes were dysregulated in trisomic iPSCs. Trisomic NPCs showed altered mitochondrial Ca2+, reduced OCR and ATP synthesis, and elevated ROS production. Conclusions: Human trisomic iPSCs can be rapidly and efficiently differentiated into NPC monolayers. The trisomic NPCs obtained exhibit greater glial-like differentiation potential than their euploid counterparts and manifest mitochondrial dysfunction as early as day 7 of neuronal differentiation.

scholarly journals Intracellular pH in the Brain following Transient Ischemia

1983 ◽  
Vol 3 (1) ◽  
pp. 109-114 ◽  
Author(s):  
Hideo Mabe ◽  
Photjanee Blomqvist ◽  
Bo K. Siesjö
Keyword(s):  
Creatine Kinase ◽  
Lactic Acid ◽  
Intracellular Ph ◽  
Adenine Nucleotides ◽  
Recovery Period ◽  
Transient Ischemia ◽  
Vessel Occlusion ◽  
Atp Production ◽  
Creatine Kinase Reaction ◽  
The Brain

The objective of the present study was to discover whether or not intracellular alkalosis develops in the brain in the recovery period following transient ischemia. Forebrain ischemia of 15-min duration was induced by four-vessel occlusion in rats, with recovery periods of 15, 60, and 180 min. Intracellular pH was derived both by the HCO3−–H2CO3 method and from the creatine kinase equilibrium. The ischemia was associated with energy failure and marked accumulation of lactic acid in the cerebral cortex. Recirculation brought about rapid rephosphorylation of adenine nucleotides and gradual normalization of lactic acid levels. After 15 min of recovery, the HCO3−–H2CO3 method indicated persisting acidosis, but the creatine kinase reaction did not. After 60 min, a shift of pH in the alkaline direction was demonstrated in both methods. This alkalosis had disappeared after 3 h of recovery. It is concluded that resumption of ATP production after ischemia is followed by a rapid rise in intracellular pH, which transiently increases above normal.

The brain-specific protein MLC1 implicated in megalencephalic leukoencephalopathy with subcortical cysts is expressed in glial cells in the murine brain

Glia ◽  
2003 ◽  
Vol 44 (3) ◽  
pp. 283-295 ◽  
Author(s):  
Angelika Schmitt ◽  
Viktor Gofferje ◽  
Melanie Weber ◽  
Jobst Meyer ◽  
Rainald Mössner ◽  
...  
Keyword(s):  
Glial Cells ◽  
Specific Protein ◽  
Murine Brain ◽  
The Brain ◽  
Subcortical Cysts

T3 increases mitochondrial ATP production in oxidative muscle despite increased expression of UCP2 and -3

2001 ◽  
Vol 280 (5) ◽  
pp. E761-E769 ◽  
Author(s):  
Kevin R. Short ◽  
Jonas Nygren ◽  
Rocco Barazzoni ◽  
James Levine ◽  
K. Sreekumaran Nair
Keyword(s):  
Skeletal Muscle ◽  
Citrate Synthase ◽  
Atp Synthesis ◽  
Nutrient Flux ◽  
Oxidative Enzymes ◽  
Mrna Levels ◽  
Plantaris Muscle ◽  
Atp Production ◽  
Protein Levels ◽  
Different Types

Triiodothyronine (T3) increases O2 and nutrient flux through mitochondria (Mito) of many tissues, but it is unclear whether ATP synthesis is increased, particularly in different types of skeletal muscle, because variable changes in uncoupling proteins (UCP) and enzymes have been reported. Thus Mito ATP production was measured in oxidative and glycolytic muscles, as well as in liver and heart, in rats administered T3 for 14 days. Relative to saline-treated controls, T3 rats had 80, 168, and 62% higher ATP production in soleus muscle, liver, and heart, respectively, as well as higher activities of citrate synthase (CS; 63, 90, 25%) and cytochrome c oxidase (COX; 119, 225, 52%) in the same tissues (all P < 0.01). In plantaris muscle of T3 rats, CS was only slightly higher (17%, P < 0.05) than in controls, and ATP production and COX were unaffected. mRNA levels of COX I and III were 33 and 47% higher in soleus of T3 rats ( P < 0.01), but there were no differences in plantaris. In contrast, UCP2 and -3 mRNAs were 2.5- to 14-fold higher, and protein levels were 3- to 10-fold higher in both plantaris and soleus of the T3 group. We conclude that T3 increases oxidative enzymes and Mito ATP production and Mito-encoded transcripts in oxidative but not glycolytic rodent tissues. Despite large increases in UCP expression, ATP production was enhanced in oxidative tissues and maintained in glycolytic muscle of hyperthyroid rats.

Ammonia toxicity and cerebral oxidative metabolism

1961 ◽  
Vol 200 (3) ◽  
pp. 420-424 ◽  
Author(s):  
Guy M. McKhann ◽  
Donald B. Tower
Keyword(s):  
Oxidative Metabolism ◽  
Incubation Medium ◽  
Lactic Acid Production ◽  
Ammonia Toxicity ◽  
Thiamine Pyrophosphate ◽  
Oxidative Decarboxylation ◽  
Cortex Slices ◽  
The Brain ◽  
Cat Cerebral Cortex

Effects of NH4Cl on oxidative metabolism of cat cerebral cortex slices and mitochondria incubated in vitro were studied. In slices, addition of 10 mm NH4Cl to the incubation medium resulted in significant (16%) reduction of O2 uptake, doubling of lactic acid production and marked increase of glucose utilization compared to control slices. Mitochondria showed a 30–40% decrease of O2 consumption in the presence of 15 mm NH4Cl when pyruvate or α-ketoglutarate were substrates, but little if any difference from controls with succinate, glutamic acid or γ-aminobutyric acid as substrates. Pyruvate utilization by ammonia-treated mitochondria was inhibited to the same degree as O2 consumption and was not increased by supplementing the incubation medium with excess succinate. Additions of α-lipoic acid, thiamine pyrophosphate or DPN to such preparations failed to reverse the NH4Cl effect. Satisfactory P/O ratios were obtained for all mitochondrial preparations. It is concluded that a primary toxic effect of ammonia on the brain may be direct interference with oxidative decarboxylation of pyruvic and α-ketoglutaric acids.

scholarly journals ULTRASTRUCTURAL IDENTIFICATION OF CATECHOLAMINE-CONTAINING CENTRAL SYNAPTIC TERMINALS

1973 ◽  
Vol 21 (4) ◽  
pp. 333-348 ◽  
Author(s):  
FLOYD E. BLOOM
Keyword(s):  
Nervous System ◽  
Nerve Terminals ◽  
Synaptic Terminals ◽  
Direct Localization ◽  
Sympathetic Nervous ◽  
Neurotransmitter Substances ◽  
6 Hydroxydopamine ◽  
The Brain ◽  
Selective Accumulation ◽  
Peripheral Sympathetic Nervous System

Cytochemical methods for the localization of central catecholamine-containing synaptic terminals have been developed from an extensive foundation of biochemical work and from extrapolation of results on the peripheral sympathetic nervous system. Direct localization of catecholamines in central nerve terminals in some parts of the brain can now be obtained by fixation with permanganates. More broadly applicable, but less direct localizing methods depend upon selective accumulation of tritiated catecholamines for autoradiography or the accumulation of reactive catecholamine congeners which act as markers with conventional fixation. The pattern of acute degenerative changes which result after treatment with 6-hydroxydopamine can also be used to provide an indirect localization of the terminals which had stored catecholamines. When the results of each of the methods are combined, the present techniques indicate that catecholamine-containing terminals in the brain can be identified more confidently than any other system of neurotransmitter substances. Nevertheless, there is considerable need for future cytochemical innovation.

Anoxia and adenosine induce increased cerebral blood flow rate in crucian carp

1994 ◽  
Vol 267 (2) ◽  
pp. R590-R595 ◽  
Author(s):  
G. E. Nilsson ◽  
P. Hylland ◽  
C. O. Lofman
Keyword(s):  
Blood Flow ◽  
Flow Rate ◽  
Crucian Carp ◽  
Blood Flow Rate ◽  
Fold Increase ◽  
Liver Glycogen ◽  
Glycolytic Flux ◽  
Brain Blood Flow ◽  
Atp Production ◽  
The Brain

The crucian carp (Carassius carassius) has the rare ability to survive prolonged anoxia, indicating an extraordinary capacity for glycolytic ATP production, especially in a highly energy-consuming organ like the brain. For the brain to be able to increase its glycolytic flux during anoxia and profit from the large liver glycogen store, an increased glucose delivery from the blood would be expected. Nevertheless, the effect of anoxia on brain blood flow in crucian carp has never been studied previously. We have used epireflection microscopy to directly observe and measure blood flow rate on the brain surface (optic lobes) during normoxia and anoxia in crucian carp. We have also examined the possibility that adenosine participates in the regulation of brain blood flow rate in crucian carp. The results showed a 2.16-fold increase in brain blood flow rate during anoxia. A similar increase was seen after topical application of adenosine during normoxia, while adenosine was without effect during anoxia. Moreover, superfusing the brain with the adenosine receptor blocker aminophylline inhibited the effect of anoxia on brain blood flow rate, clearly suggesting a mediatory role of adenosine in the anoxia-induced increase in brain blood flow rate.

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