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

Gellerich, Frank N.; Gizatullina, Zemfira; Gainutdinov, T. M.; Muth, Katharina; Seppet, Enn; Orynbayeva, Zulfiya; Vielhaber, Stefan

doi:10.1002/iub.1131

Cited by 57 publications

(45 citation statements)

References 104 publications

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“…It has been shown that, together with LDH, the MAS regulated NAD+/NADH ratio determines the amount of pyruvate available for oxidation in mitochondria (Gellerich et al, 2012(Gellerich et al, , 2013. Since neuronal mitochondria are unable to oxidize fatty acids (Yang et al, 1987), pyruvate oxidation is critical (Gellerich et al, 2013). Increased quinone modification of MDH1 and LDH in aged SN reduces their enzyme activities, which disrupts the MAS transport and the availability of pyruvate to neuronal mitochondria.…”

Section: Discussionmentioning

confidence: 98%

“…This cytoplasmically localized MDH is part of the malate-aspartate shuttle (MAS) that transports the reducing equivalents of NADH into the mitochondria and regulates the cytoplasmic NAD+/NADH ratio. It has been shown that, together with LDH, the MAS regulated NAD+/NADH ratio determines the amount of pyruvate available for oxidation in mitochondria (Gellerich et al, 2012(Gellerich et al, , 2013. Since neuronal mitochondria are unable to oxidize fatty acids (Yang et al, 1987), pyruvate oxidation is critical (Gellerich et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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In vivo protein targets for increased quinoprotein adduct formation in aged substantia nigra

Liu

Zhou

et al. 2015

Experimental Neurology

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

In vivo protein targets for increased quinoprotein adduct formation in aged substantia nigra

Liu

Zhou

et al. 2015

Experimental Neurology

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“…In fact, TRPV1-mediated modulation of presynaptic neurotransmitter release is partly dependent on mitochondrial calcium signaling, and TRPV1 activation can enhance mitochondrial function [231,232]. That TRPV1 can both enhance and inhibit mitochondrial function can be reconciled by the fact that calcium tightly controls mitochondrial function and biogenesis such that a small amount can stimulate function but too much can induce apoptosis [212,233]. Finally, vanillin-induced TRPV1 activation reduced markers of oxidative stress in model of HD and improved motor function, suggesting further validity for this target in relation to CBD [234].…”

Section: Cbd Ion Channels Targets In Neurodegenerationmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

447

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…On the whole, Ca 2? -activation of MAS through aralar/AGC1 would provide the neurons (or any cell) with the capacity to increase respiration on pyruvate if needed, acting as a gas pedal [16,17].…”

Section: Introductionmentioning

confidence: 99%

Fluctuations in Cytosolic Calcium Regulate the Neuronal Malate–Aspartate NADH Shuttle: Implications for Neuronal Energy Metabolism

Satrústegui

Bak

2015

Neurochem Res

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The malate-aspartate NADH shuttle (MAS) operates in neurons and other cells to translocate reducing equivalents from the cytosol to the mitochondrial matrix, thus allowing a continued flux through the glycolytic pathway and metabolism of extracellular lactate. Recent discoveries have taught us that MAS is regulated by fluctuations in cytosolic Ca 2? levels, and that this regulation is required to maintain a tight coupling between neuronal activity and mitochondrial respiration and oxidative phosphorylation. At cytosolic Ca 2? fluctuations below the threshold of the mitochondrial calcium uniporter, there is a positive correlation between Ca 2? and MAS activity; however, if cytosolic Ca 2? increases above the threshold, MAS activity is thought to be reduced by an intricate mechanism. The latter forces the neurons to partly rely on anaerobic glycolysis producing lactate that may be metabolized subsequently, by neurons or other cells. In this review, we will discuss the evidence for Ca 2? -mediated regulation of MAS that have been uncovered over the last decade or so, together with the need for further verification, and examine the metabolic ramifications for neurons.

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

Cited by 57 publications

References 104 publications

In vivo protein targets for increased quinoprotein adduct formation in aged substantia nigra

In vivo protein targets for increased quinoprotein adduct formation in aged substantia nigra

Molecular Targets of Cannabidiol in Neurological Disorders

Fluctuations in Cytosolic Calcium Regulate the Neuronal Malate–Aspartate NADH Shuttle: Implications for Neuronal Energy Metabolism

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