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The distinct roles of calcium in rapid control of neuronal glycolysis and the tricarboxylic acid cycle.

ABSTRACT: When neurons engage in intense periods of activity, the consequent increase in energy demand can be met by the coordinated activation of glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. However, the trigger for glycolytic activation is unknown and the role for Ca²⁺ in the mitochondrial responses has been debated. Using genetically encoded fluorescent biosensors and NAD(P)H autofluorescence imaging in acute hippocampal slices, here we find that Ca²⁺ uptake into the mitochondria is responsible for the buildup of mitochondrial NADH, probably through Ca²⁺ activation of dehydrogenases in the TCA cycle. In the cytosol, we do not observe a role for the Ca²⁺/calmodulin signaling pathway, or AMPK, in mediating the rise in glycolytic NADH in response to acute stimulation. Aerobic glycolysis in neurons is triggered mainly by the energy demand resulting from either Na⁺ or Ca²⁺ extrusion, and in mouse dentate granule cells, Ca²⁺ creates the majority of this demand.

SUBMITTER: Diaz-Garcia CM

PROVIDER: S-EPMC7870136 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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The distinct roles of calcium in rapid control of neuronal glycolysis and the tricarboxylic acid cycle.

Díaz-García Carlos Manlio CM Meyer Dylan J DJ Nathwani Nidhi N Rahman Mahia M Martínez-François Juan Ramón JR Yellen Gary G

eLife 20210208

When neurons engage in intense periods of activity, the consequent increase in energy demand can be met by the coordinated activation of glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. However, the trigger for glycolytic activation is unknown and the role for Ca<sup>2+</sup> in the mitochondrial responses has been debated. Using genetically encoded fluorescent biosensors and NAD(P)H autofluorescence imaging in acute hippocampal slices, here we find that Ca<sup>2+</ ...[more]

PMID: 33555254

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Project description:BackgroundGlycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle metabolites have been associated with type 2 diabetes (T2D). However, the associations of these metabolites with T2D incidence and the potential effect of dietary interventions remain unclear.ObjectivesWe aimed to evaluate the association of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with insulin resistance and T2D incidence, and the potential modifying effect of Mediterranean diet (MedDiet) interventions.MethodsWe included 251 incident T2D cases and 638 noncases in a nested case-cohort study within the PREDIMED Study during median follow-up of 3.8 y. Participants were allocated to MedDiet + extra-virgin olive oil, MedDiet + nuts, or control diet. Plasma metabolites were measured using a targeted approach by LC-tandem MS. We tested the associations of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with subsequent T2D risk using weighted Cox regression models and adjusting for potential confounders. We designed a weighted score combining all these metabolites and applying the leave-one-out cross-validation approach.ResultsBaseline circulating concentrations of hexose monophosphate, pyruvate, lactate, alanine, glycerol-3 phosphate, and isocitrate were significantly associated with higher T2D risk (17-44% higher risk for each 1-SD increment). The weighted score including all metabolites was associated with a 30% (95% CI: 1.12, 1.51) higher relative risk of T2D for each 1-SD increment. Baseline lactate and alanine were associated with baseline and 1-y changes of homeostasis model assessment of insulin resistance. One-year increases in most metabolites and in the weighted score were associated with higher relative risk of T2D after 1 y of follow-up. Lower risks were observed in the MedDiet groups than in the control group although no significant interactions were found after adjusting for multiple comparisons.ConclusionsWe identified a panel of glycolysis/gluconeogenesis-related metabolites that was significantly associated with T2D risk in a Mediterranean population at high cardiovascular disease risk. A MedDiet could counteract the detrimental effects of these metabolites.This trial was registered at controlled-trials.com as ISRCTN35739639.

Project description:1. The equations derived by Heath (1968) were applied to data from experiments on rats in four metabolic states: fed, post-absorptive, starved and 2hr. after an eventually lethal injury. The data used were: (a) The fractions of label injected as C1-, C2- and C3-pyruvate (where the prefix indicates the position of labelling) that are incorporated into carbon dioxide and glucose in post-absorptive and injured rats (yields). Yields could be corrected to yields on label taken up by the liver. (b) The (C5-label in glutamate)/(total label in glutamate) ratio in the liver after C2-pyruvate in rats in all four states. (c) The distribution of label within glutamate after C2-pyruvate or C2-alanine in the livers of fed, post-absorptive and starved rats. (d) The distribution of label within glucose after C2-lactate or C2-pyruvate in starved rats. (e) The relative specific radioactivities of pyruvate, aspartate, glutamate and (in two states only) of glucose 6-phosphate after injection of [U-(14)C]glucose into rats in all four states. These data were previously published, except those after (e) and some after (b) above, which are given in this paper. 2. In addition the concentrations of pyruvate, citrate, glutamate and aspartate in the livers of post-absorptive and injured rats were found. Injury decreased glutamate and citrate concentrations and to a smaller extent aspartate and pyruvate concentrations. 3. Non-steady-state theory showed that most of the data could be used without serious error in steady-state theory. Steady-state theory correlated all but one observation (the relative yields of (14)CO(2) from C2- and C3-pyruvate) listed after (a)-(e) above within the experimental errors, and gave rough estimates of the rates of pyruvate carboxylation, conversion of pyruvate and fat into acetyl-CoA and utilization of glutamate. The main conclusions were: (a) symmetrization of label in oxaloacetate both in the mitochondrion and in the cytoplasm was far from complete, because oxaloacetate did not equilibrate with fumarate in either. From this and other findings it was deduced: (b) that malate or fumarate or both left the mitochondrion, and not oxaloacetate; (c) that there was a loss from the mitochondrion of a fraction of the malate or fumarate or both formed from succinate, and (d) the resulting deficiency of oxaloacetate for the perpetuation of the tricarboxylic acid cycle was made up from pyruvate in fed and post-absorptive rats, but (e) in the starved rat could only be made up by utilization of glutamate. (f) In the fed rat the tricarboxylic acid cycle ran mostly on pyruvate, but in the post-absorptive and starved rat mostly on fat. (g) In the injured rat the tricarboxylic acid cycle was slowed, label in oxaloacetate was completely symmetrized (cf. conclusion a), and the tricarboxylic acid cycle utilized glutamate. (h) The conclusions were not invalidated by isotopic exchange, i.e. flux of label without net flux of compound, nor by interaction with lipogenic processes. (i) In the kidneys interaction between the tricarboxylic acid cycle and gluconeogenesis was different from in the liver, and was much less. The effects on the theory were roughly assessed, and were small. 4. The experiments and optimum experimental conditions required to check the theory are listed, and several predictions, open to experimental confirmation, are made.

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The distinct roles of calcium in rapid control of neuronal glycolysis and the tricarboxylic acid cycle.

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The distinct roles of calcium in rapid control of neuronal glycolysis and the tricarboxylic acid cycle.

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