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Lactate fuels the neonatal brain.

Kasischke K - Front Neuroenergetics (2011)

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Center for Neural Development and Disease, University of Rochester Medical Center Rochester, NY, USA.

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The brain is a highly oxidative organ and the prevailing dogma is that under normal conditions glucose is its principal metabolic substrate... However, it is well established that the brain is capable of oxidizing alternative substrates such as acetate, glutamate, lactate, and ketone bodies... A related question is whether alternative oxidative substrates such as lactate or hydroxybutyrate per se can sustain synaptic function in this developmental period... When the experiments were repeated with the ketone body β-hydroxybutyrate (10 mM) as alternative oxidative substrate, similar effects on all measured parameters were observed... The results of the study by Ivanov et al. are clear-cut: (1) lactate, whether alone or in the presence of glucose, sustains and even augments synaptic activity and oxidative metabolism in excited neonatal brain tissue. (2) Metabolic recovery pathways are fundamentally altered when lactate or hydroxybutyrate replaces glucose as the primary oxidative substrate... While the observations that lactate can serve as a substrate for the neonatal brain confirms existing knowledge, the facts that it enhances synaptic transmission and oxygen utilization are new... Furthermore, their results imply that lactate may be preferentially utilized vs. glucose, when both substrates are present at equal concentrations... The study by Ivanov et al. also provides novel data on biphasic NAD(P)H fluorescence transients (Figure 1), an important physiological response to neural activation that has been reproduced in many studies and that is believed to originate predominately from activity-induced concentration changes to the cellular NADH pools... As stated by Galeffi et al., there seems to be general agreement that the initial NADH decrease is the consequence of mitochondrial oxidation and occurs predominantly in neurons (Shuttleworth et al., ; Kasischke et al., ; Foster et al., )... Some authors have suggested that the NADH overshoot may representing glycolysis (Lipton, ; Mofett and LaManna,, Kasischke et al., ), while others have implied a rise in mitochondrial NADH as a consequence of Ca-induced activation of the Krebs cycle dehydrogenases (Duchen, ; Kann et al., ; Shuttleworth et al., ; Brennan et al., )... Now, Ivanov et al. show that the biphasic NADH response is fundamentally altered when lactate or β-hydroxybutyrate replaces glucose as the principal oxidative substrate: in the early phase, NADH oxidation is augmented, while during the late phase the NADH overshoot is strongly reduced... Under two-photon excitation the blue intrinsic NADH fluorescence could be simultaneously excited together with fluorescence from YFP and sulforhodamine, which would serve as image processing masks for neuronal mitochondria and astrocytes... While technically challenging, such imaging studies or other approaches may resolve activity-dependent metabolism in glia and neurons and shed some light on the elusive origins and sinks of extracellular lactate.

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Focal neural activity induces a characteristic biphasic NADH transient in brain tissue. This distinct physiological response (Kasischke et al., 2004) has been reported in numerous studies using brain slice preparations from mice, rats, and toad. There is general agreement that the early phase, the NADH dip, is the consequence of mitochondrial NADH oxidation due to activation of the respiratory chain and may occur predominately in neurons. In contrast, the metabolic nature and cellular localization of the late phase, the NADH overshoot, remain ambiguous. Possibilities, which are not necessarily mutually exclusive, are (i) Ca2+-dependent activation of the Krebs cycle with mitochondrial NADH production, (ii) tissue hypoxia with increase of both cytoplasmic and mitochondrial NADH, and (iii) activation of glycolysis with increase in cytoplasmic NADH. Ivanov et al. (2011) show that the biphasic NADH response is fundamentally altered when lactate or β-hydroxybutyrate replace glucose as the principal oxidative substrate.
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Figure 1: Focal neural activity induces a characteristic biphasic NADH transient in brain tissue. This distinct physiological response (Kasischke et al., 2004) has been reported in numerous studies using brain slice preparations from mice, rats, and toad. There is general agreement that the early phase, the NADH dip, is the consequence of mitochondrial NADH oxidation due to activation of the respiratory chain and may occur predominately in neurons. In contrast, the metabolic nature and cellular localization of the late phase, the NADH overshoot, remain ambiguous. Possibilities, which are not necessarily mutually exclusive, are (i) Ca2+-dependent activation of the Krebs cycle with mitochondrial NADH production, (ii) tissue hypoxia with increase of both cytoplasmic and mitochondrial NADH, and (iii) activation of glycolysis with increase in cytoplasmic NADH. Ivanov et al. (2011) show that the biphasic NADH response is fundamentally altered when lactate or β-hydroxybutyrate replace glucose as the principal oxidative substrate.

Mentions: The study by Ivanov et al. (2011) also provides novel data on biphasic NAD(P)H fluorescence transients (Figure 1), an important physiological response to neural activation that has been reproduced in many studies and that is believed to originate predominately from activity-induced concentration changes to the cellular NADH pools. As stated by Galeffi et al. (2007), there seems to be general agreement that the initial NADH decrease is the consequence of mitochondrial oxidation and occurs predominantly in neurons (Shuttleworth et al., 2003; Kasischke et al., 2004; Foster et al., 2005). In contrast, conflicting interpretations on the metabolic nature of the second phase, the NADH overshoot, have been provided. Some authors have suggested that the NADH overshoot may representing glycolysis (Lipton, 1973; Mofett and LaManna, 1978, Kasischke et al., 2004), while others have implied a rise in mitochondrial NADH as a consequence of Ca2+-induced activation of the Krebs cycle dehydrogenases (Duchen, 1992; Kann et al., 2003; Shuttleworth et al., 2003; Brennan et al., 2006).


Lactate fuels the neonatal brain.

Kasischke K - Front Neuroenergetics (2011)

Focal neural activity induces a characteristic biphasic NADH transient in brain tissue. This distinct physiological response (Kasischke et al., 2004) has been reported in numerous studies using brain slice preparations from mice, rats, and toad. There is general agreement that the early phase, the NADH dip, is the consequence of mitochondrial NADH oxidation due to activation of the respiratory chain and may occur predominately in neurons. In contrast, the metabolic nature and cellular localization of the late phase, the NADH overshoot, remain ambiguous. Possibilities, which are not necessarily mutually exclusive, are (i) Ca2+-dependent activation of the Krebs cycle with mitochondrial NADH production, (ii) tissue hypoxia with increase of both cytoplasmic and mitochondrial NADH, and (iii) activation of glycolysis with increase in cytoplasmic NADH. Ivanov et al. (2011) show that the biphasic NADH response is fundamentally altered when lactate or β-hydroxybutyrate replace glucose as the principal oxidative substrate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108381&req=5

Figure 1: Focal neural activity induces a characteristic biphasic NADH transient in brain tissue. This distinct physiological response (Kasischke et al., 2004) has been reported in numerous studies using brain slice preparations from mice, rats, and toad. There is general agreement that the early phase, the NADH dip, is the consequence of mitochondrial NADH oxidation due to activation of the respiratory chain and may occur predominately in neurons. In contrast, the metabolic nature and cellular localization of the late phase, the NADH overshoot, remain ambiguous. Possibilities, which are not necessarily mutually exclusive, are (i) Ca2+-dependent activation of the Krebs cycle with mitochondrial NADH production, (ii) tissue hypoxia with increase of both cytoplasmic and mitochondrial NADH, and (iii) activation of glycolysis with increase in cytoplasmic NADH. Ivanov et al. (2011) show that the biphasic NADH response is fundamentally altered when lactate or β-hydroxybutyrate replace glucose as the principal oxidative substrate.
Mentions: The study by Ivanov et al. (2011) also provides novel data on biphasic NAD(P)H fluorescence transients (Figure 1), an important physiological response to neural activation that has been reproduced in many studies and that is believed to originate predominately from activity-induced concentration changes to the cellular NADH pools. As stated by Galeffi et al. (2007), there seems to be general agreement that the initial NADH decrease is the consequence of mitochondrial oxidation and occurs predominantly in neurons (Shuttleworth et al., 2003; Kasischke et al., 2004; Foster et al., 2005). In contrast, conflicting interpretations on the metabolic nature of the second phase, the NADH overshoot, have been provided. Some authors have suggested that the NADH overshoot may representing glycolysis (Lipton, 1973; Mofett and LaManna, 1978, Kasischke et al., 2004), while others have implied a rise in mitochondrial NADH as a consequence of Ca2+-induced activation of the Krebs cycle dehydrogenases (Duchen, 1992; Kann et al., 2003; Shuttleworth et al., 2003; Brennan et al., 2006).

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Center for Neural Development and Disease, University of Rochester Medical Center Rochester, NY, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The brain is a highly oxidative organ and the prevailing dogma is that under normal conditions glucose is its principal metabolic substrate... However, it is well established that the brain is capable of oxidizing alternative substrates such as acetate, glutamate, lactate, and ketone bodies... A related question is whether alternative oxidative substrates such as lactate or hydroxybutyrate per se can sustain synaptic function in this developmental period... When the experiments were repeated with the ketone body β-hydroxybutyrate (10 mM) as alternative oxidative substrate, similar effects on all measured parameters were observed... The results of the study by Ivanov et al. are clear-cut: (1) lactate, whether alone or in the presence of glucose, sustains and even augments synaptic activity and oxidative metabolism in excited neonatal brain tissue. (2) Metabolic recovery pathways are fundamentally altered when lactate or hydroxybutyrate replaces glucose as the primary oxidative substrate... While the observations that lactate can serve as a substrate for the neonatal brain confirms existing knowledge, the facts that it enhances synaptic transmission and oxygen utilization are new... Furthermore, their results imply that lactate may be preferentially utilized vs. glucose, when both substrates are present at equal concentrations... The study by Ivanov et al. also provides novel data on biphasic NAD(P)H fluorescence transients (Figure 1), an important physiological response to neural activation that has been reproduced in many studies and that is believed to originate predominately from activity-induced concentration changes to the cellular NADH pools... As stated by Galeffi et al., there seems to be general agreement that the initial NADH decrease is the consequence of mitochondrial oxidation and occurs predominantly in neurons (Shuttleworth et al., ; Kasischke et al., ; Foster et al., )... Some authors have suggested that the NADH overshoot may representing glycolysis (Lipton, ; Mofett and LaManna,, Kasischke et al., ), while others have implied a rise in mitochondrial NADH as a consequence of Ca-induced activation of the Krebs cycle dehydrogenases (Duchen, ; Kann et al., ; Shuttleworth et al., ; Brennan et al., )... Now, Ivanov et al. show that the biphasic NADH response is fundamentally altered when lactate or β-hydroxybutyrate replaces glucose as the principal oxidative substrate: in the early phase, NADH oxidation is augmented, while during the late phase the NADH overshoot is strongly reduced... Under two-photon excitation the blue intrinsic NADH fluorescence could be simultaneously excited together with fluorescence from YFP and sulforhodamine, which would serve as image processing masks for neuronal mitochondria and astrocytes... While technically challenging, such imaging studies or other approaches may resolve activity-dependent metabolism in glia and neurons and shed some light on the elusive origins and sinks of extracellular lactate.

No MeSH data available.


Related in: MedlinePlus