Aminooxyacetic acid inhibits the malate-aspartate shuttle in isolated nerve terminals and prevents the mitochondria from utilizing glycolytic substrates

Kauppinen, Risto A.; Sihra, Talvinder S.; Nicholls, David G.

doi:10.1016/0167-4889(87)90029-2

Cited by 106 publications

(86 citation statements)

References 30 publications

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“…These shuttles not only allow reoxidation of cytosolic NAD ϩ but also provide more ATP (1.5 mol by means of the glycerolphosphate shuttle or 2.5 mol by means of the malate-aspartate shuttle) by oxidative phosphorylation (10). Blockade of the malate-aspartate shuttle by specific inhibitors is associated with an increase in the cytosolic NADH͞NAD ratio (19,20). Reduction of pyruvate to lactate is another important way to regenerate NAD ϩ , because it is extremely rapid and coupled to an equimolar reoxidation of NADH generated by glyceraldehyde 3-phosphate to NAD ϩ generated by lactate dehydrogenase.…”

Section: Discussionmentioning

confidence: 99%

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Mintun

Vlassenko

Rundle

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

130

104

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The factors regulating cerebral blood flow (CBF) changes in physiological activation remain the subject of great interest and debate. Recent experimental studies suggest that an increase in cytosolic NADH mediates increased blood flow in the working brain. Lactate injection should elevate NADH levels by increasing the lactate͞ pyruvate ratio, which is in near equilibrium with the NADH͞NAD ؉ ratio. We studied CBF responses to bolus lactate injection at rest and in visual stimulation by using positron-emission tomography in seven healthy volunteers. Bolus lactate injection augmented the CBF response to visual stimulation by 38 -53% in regions of the visual cortex but had no effect on the resting CBF or the wholebrain CBF. These lactate-induced CBF increases correlated with elevations in plasma lactate͞pyruvate ratios and in plasma lactate levels but not with plasma pyruvate levels. Our observations support the hypothesis that an increase in the NADH͞NAD ؉ ratio activates signaling pathways to selectively increase CBF in the physiologically stimulated brain regions.T he nature of the link between cerebral blood flow (CBF) and energy metabolism is of great interest and importance but remains controversial despite decades of research and debate. Although CBF augmentation is still considered to be a hallmark of intensified neural activity, previous assumptions that behaviorally induced increases in local blood flow reflect similar local increases in oxidative metabolism (1) have been contradicted by brain imaging studies with positron-emission tomography (PET) (2, 3) and functional MRI (4). Fox and his colleagues (2, 3) demonstrated that in normal, awake adult humans, stimulation of the visual or somatosensory cortex results in dramatic increases in CBF but minimal increases in oxygen consumption. Increases in glucose utilization are similar to changes in CBF (3, 5). Although it is often assumed that the increase in CBF in neural activation is driven by a need for increased delivery of oxygen or glucose, it has been demonstrated in human subjects that the CBF response to physiological activation is not altered by either stepped hypoglycemia (6) or hypoxia (7). These results suggest that increased CBF during physiological brain activation does not occur to prevent a shortage of these metabolic substrates. Ido et al. (8) recently reported that CBF in activated rat brain is modified by changes in the plasma lactate͞pyruvate ratio: CBF was augmented when lactate͞pyruvate ratios were raised and attenuated when the ratios were lowered. Specifically, immediately after lactate bolus injection, the magnitude of the CBF increase associated with sensory stimulation approximately doubled. Based on the near equilibrium between the ratios of lactate͞pyruvate and cytosolic free NADH͞NAD ϩ (which reflects the local environment redox state) (9), they suggested that cytosolic free NADH is an important trigger or sensor of blood flow. The reoxidation of NADH to NAD ϩ is a step of vital importance for brain cells, especially in the acti...

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Section: Discussionmentioning

confidence: 99%

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Mintun

Vlassenko

Rundle

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

130

104

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“…3). The affinity of mitochondria to pyruvate is extremely high (pyruvate K m ¼ 20-30 lM) compared to other substrates (36,45). In vitro measurements of mitochondrial oxygen consumption at such low pyruvate concentrations are difficult since the decreasing pyruvate concentrations immediately diminish the rate of respiration due to mitochondria de-energization.…”

Section: Kinetic and Thermodynamic Preferences Of The Pyruvate Supplymentioning

confidence: 99%

“…Owing to its low K m and high V max , pyruvate is the preferred substrate of BM (36). Because of the electrogenic nature of the glutamate transport via aralar (45) and the coupling of the pyruvate carrier (PC) to the electrochemical proton gradient (45,46), the complete MAS can actively increase intramitochondrial NADH and pyruvate in a manner of ''gas pedal'' (36). The biological importance of this mechanism targets particularly brain mitochondria, since they cannot use fatty acids as alternative oxidation substrates (48 acids due to the low activity of 3-ketoacyl-coenzyme A thiolase (48), we assume that the gas pedal mechanism is a special feature of neurons.…”

Section: Kinetic and Thermodynamic Preferences Of The Pyruvate Supplymentioning

confidence: 99%

“…3). The MAS oxidizes the NADH formed by the pyruvate regenerating reactions and transports the reducing hydrogen into the mitochondria against the concentration gradient of NADH (45). To overcome these generated concentration gradients, evolution created the glutamate-aspartate carrier to be electrogenic.…”

Section: Kinetic and Thermodynamic Preferences Of The Pyruvate Supplymentioning

confidence: 99%

“…In contrast, the pyruvate uptake by the pyruvate transporter is electroneutral. However, since pyruvate is cotransferred with protons, it is considered that the transport of pyruvate is driven also by the proton gradient (45,46) (Fig. 3).…”

Section: Kinetic and Thermodynamic Preferences Of The Pyruvate Supplymentioning

confidence: 99%

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The control of brain mitochondrial energization by cytosolic calcium: The mitochondrial gas pedal

et al. 2013

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This review focuses on problems of the intracellular regulation of mitochondrial function in the brain via the (i) supply of mitochondria with ADP by means of ADP shuttles and channels and (ii) the Ca 21 control of mitochondrial substrate supply. The permeability of the mitochondrial outer membrane for adenine nucleotides is low. Therefore rate dependent concentration gradients exist between the mitochondrial intermembrane space and the cytosol. The existence of dynamic ADP gradients is an important precondition for the functioning of ADP shuttles, for example CrP-shuttle. Cr at mM concentrations instead of ADP diffuses from the cytosol through the porin pores into the intermembrane space.

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Evaluation of the importance of transamination versus deamination in astrocytic metabolism of [U-13C] glutamate

Westergaard¹,

Drejer²,

Schousboe³

et al. 1996

Glia

103

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Aminooxyacetic acid inhibits the malate-aspartate shuttle in isolated nerve terminals and prevents the mitochondria from utilizing glycolytic substrates

Cited by 106 publications

References 30 publications

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

The control of brain mitochondrial energization by cytosolic calcium: The mitochondrial gas pedal

Evaluation of the importance of transamination versus deamination in astrocytic metabolism of [U-13C] glutamate

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