AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival

Muraleedharan, Ranjithmenon; Gawali, Mruniya V.; Tiwari, Durgesh; Sukumaran, Abitha; Oatman, Nicole; Anderson, Jane L.; Nardini, Diana; Bhuiyan, Mohammad Alfrad Nobel; Tkáč, Ivan; Ward, Amber L.; Kundu, Mondira; Waclaw, Ronald R.; Chow, Lionel M.L.; Groß, Christina; Rao, Raghavendra; Schirmeier, Stefanie; Dasgupta, Biplab

doi:10.1016/j.celrep.2020.108092

Cited by 79 publications

(69 citation statements)

References 79 publications

(117 reference statements)

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“…However, even though AMPK seems poised for the integration of two signals derived from acute neuronal stimulation, its inhibition did not prevent the glycolytic NADH CYT transients in the soma of DGCs. Overall, AMPK seems irrelevant for neuronal lactate production, as observed in cultured cortical neurons ( Muraleedharan et al, 2020 ), however, it promotes glucose uptake and glycolysis during prolonged periods of activity in synaptic terminals ( Ashrafi et al, 2017 ), suggesting that AMPK signaling may be tailored to cope with local energy demands.…”

Section: Discussionmentioning

confidence: 99%

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

Díaz‐García

Meyer

Nathwani

et al. 2021

eLife

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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.

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Section: Discussionmentioning

confidence: 99%

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

Díaz‐García

Meyer

Nathwani

et al. 2021

eLife

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“…In the brain tissues of humans with chronic seizures and animals with acute and chronic seizures, the protein expression of AMPK is reduced [ 252 ] (Table 1 ). In addition, AMPK-null mice were reported to have increased seizure susceptibility through unregulated mTOR signaling [ 179 ]. Consistently, pharmacological activation of AMPK by metformin, one of the most extensively prescribed antidiabetic drugs, attenuated seizure activity in a pilocarpine-induced epileptic model, with inhibited mTOR phosphorylation [ 172 ].…”

Section: Introductionmentioning

confidence: 99%

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

Chang

Lin

et al. 2021

J Biomed Sci

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In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progressively become greater socioeconomic burdens. To date, despite the tremendous effort devoted to understanding neurodegenerative diseases in recent decades, treatment to delay disease progression is largely ineffective and is in urgent demand. The development of new strategies targeting these pathological features is a timely topic. It is important to note that most degenerative diseases are associated with the accumulation of specific misfolded proteins, which is facilitated by several common features of neurodegenerative diseases (including poor energy homeostasis and mitochondrial dysfunction). Adenosine is a purine nucleoside and neuromodulator in the brain. It is also an essential component of energy production pathways, cellular metabolism, and gene regulation in brain cells. The levels of intracellular and extracellular adenosine are thus tightly controlled by a handful of proteins (including adenosine metabolic enzymes and transporters) to maintain proper adenosine homeostasis. Notably, disruption of adenosine homeostasis in the brain under various pathophysiological conditions has been documented. In the past two decades, adenosine receptors (particularly A1 and A2A adenosine receptors) have been actively investigated as important drug targets in major degenerative diseases. Unfortunately, except for an A2A antagonist (istradefylline) administered as an adjuvant treatment with levodopa for Parkinson’s disease, no effective drug based on adenosine receptors has been developed for neurodegenerative diseases. In this review, we summarize the emerging findings on proteins involved in the control of adenosine homeostasis in the brain and discuss the challenges and future prospects for the development of new therapeutic treatments for neurodegenerative diseases and their associated disorders based on the understanding of adenosine homeostasis.

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“…AMPK activation has recently been shown to regulate the translocation of GLUT1 to the plasma membrane from internal stores by destabilizing the thioredoxininteracting protein (TXNIP). This enhances astrocytic glucose uptake and glycolysis and enables proper regulation of the astrocyte-neuron lactate shuttle (ANLS), which preserves neuronal metabolic functionality [74]. This could explain the beneficial effects of AMPK activation by metformin on PTZ-induced seizures in mice on a high-fat diet, since after treatment with metformin, a normalization in the expression levels of GLUT1 and GLUT3 was observed [75].…”

Section: Epilepsymentioning

confidence: 99%

Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease

Sanz

Serratosa

Sánchez

2021

IJMS

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Metformin is a drug in the family of biguanide compounds that is widely used in the treatment of type 2 diabetes (T2D). Interestingly, the therapeutic potential of metformin expands its prescribed use as an anti-diabetic drug. In this sense, it has been described that metformin administration has beneficial effects on different neurological conditions. In this work, we review the beneficial effects of this drug as a neuroprotective agent in different neurological diseases, with a special focus on epileptic disorders and Lafora disease, a particular type of progressive myoclonus epilepsy. In addition, we review the different proposed mechanisms of action of metformin to understand its function at the neurological level.

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AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival

Cited by 79 publications

References 79 publications

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

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

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease

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