Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

Rose, Jordan; Brian, Christian; Pappa, Aglaia; Panayiotidis, Mihalis Ι.; Franco, Rodrigo

doi:10.3389/fnins.2020.536682

Cited by 96 publications

(98 citation statements)

References 246 publications

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“…In case of high energy demand, PDH may be activated to convert pyruvate to acetyl-coenzyme A (acetyl-CoA), thus fueling the Krebs or tricarboxylic acid (TCA) cycle for ATP generation by oxidative phosphorylation. In this context, transport mechanisms for the uptake of free fatty acids from the blood and their oxidation, especially in astrocytes have been described (reviewed in [ 33 ]). Thus, astrocytic ATP production is not exclusively dependent on glycolysis.…”

Section: Energy Metabolism Of the Brainmentioning

confidence: 99%

Oxidative Stress and Energy Metabolism in the Brain: Midlife as a Turning Point

et al. 2021

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Neural tissue is one of the main oxygen consumers in the mammalian body, and a plentitude of metabolic as well as signaling processes within the brain is accompanied by the generation of reactive oxygen (ROS) and nitrogen (RNS) species. Besides the important signaling roles, both ROS and RNS can damage/modify the self-derived cellular components thus promoting neuroinflammation and oxidative stress. While previously, the latter processes were thought to progress linearly with age, newer data point to midlife as a critical turning point. Here, we describe (i) the main pathways leading to ROS/RNS generation within the brain, (ii) the main defense systems for their neutralization and (iii) summarize the recent literature about considerable changes in the energy/ROS homeostasis as well as activation state of the brain’s immune system at midlife. Finally, we discuss the role of calorie restriction as a readily available and cost-efficient antiaging and antioxidant lifestyle intervention.

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Section: Energy Metabolism Of the Brainmentioning

confidence: 99%

Oxidative Stress and Energy Metabolism in the Brain: Midlife as a Turning Point

et al. 2021

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Section: Introductionmentioning

confidence: 99%

“…Mitochondrial metabolism is important for energy production and survival of brain cells in brain [ 24 , 25 ]. Mitochondrial metabolism in astrocytes plays a role in brain bioenergetics, neurotransmission and redox balance [ 24 , 25 ]. In physiological or pathological conditions, mitochondrial metabolism is critical for the regulation of redox in astrocytes [ [26] , [27] , [28] ].…”

Section: Introductionmentioning

confidence: 99%

NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases

et al. 2021

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Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction is linked to oxidative stress and reactive oxygen species (ROS) in neurotoxicity during AD. Impaired mitochondrial metabolism has been associated with mitochondrial dysfunction in brain damage of AD. While the role of NADPH oxidase 4 (NOX4), a major source of ROS, has been identified in brain damage, the mechanism by which NOX4 regulates ferroptosis of astrocytes in AD remains unclear. Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD. The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD. We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes. Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes. Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes. These results suggest that NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in AD.

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“…The central nervous system (CNS) is a complex structure formed by distinct cell types organized in interacting substructures, whose development is dependent on the interactions between several single genes and non-genetic factors. Thus, CNS is highly susceptible to disturbances caused by genetic mutations that may be associated to external damaging factors (e.g., infection or vaccination), resulting in a broad range of disorders, including the so-called inherited metabolic disorders (IMDs) ( Rose et al, 2020 ; Schiller et al, 2020 ).…”

Section: Inherited Metabolic Disorders and Neurological Dysfunctionmentioning

confidence: 99%

“…vaccination), resulting in a broad range of disorders, including the so-called inherited metabolic disorders (IMDs) (Rose et al, 2020;Schiller et al, 2020).…”

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confidence: 99%

Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

Seminotti

Grings

Tucci

et al. 2021

Front. Cell. Neurosci.

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Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Since treatment for a large number of IMDs is limited, there is an urgent need to find novel therapeutical targets. Nuclear factor erythroid-related factor 2 (Nrf2) is a transcription factor that has a key role in controlling the intracellular redox environment by regulating the expression of antioxidant enzymes and several important genes related to redox homeostasis. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf2 signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.

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Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

Cited by 96 publications

References 246 publications

Oxidative Stress and Energy Metabolism in the Brain: Midlife as a Turning Point

Oxidative Stress and Energy Metabolism in the Brain: Midlife as a Turning Point

NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases

Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

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