Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity

Ioannou, Maria S.; Jackson, Jesse; Sheu, Shu-Hsien; Chang, Chi‐Lun; Weigel, Aubrey V.; Liu, Hui; Pasolli, H. Amalia; Xu, Chengpei; Pang, Song; Matthies, Doreen; Hess, Harald F.; Lippincott‐Schwartz, Jennifer; Liu, Zhe

doi:10.1016/j.cell.2019.04.001

Cited by 413 publications

(471 citation statements)

References 62 publications

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“…Interestingly, proliferation of neuronal stem cells during oxidative stress has been shown to involve LD biogenesis in adjacent nice glia cells that sequestered PUFAs to limit ROS and lipid peroxidation 45 . Along these lines, another recent report described a metabolic coupling of neuron-astrocytes engaging LD formation and oxidative metabolism, thereby protecting neurons from fatty acid toxicity 46 .…”

Section: Discussionmentioning

confidence: 99%

Cell density-dependent ferroptosis in breast cancer is induced by accumulation of polyunsaturated fatty acid-enriched triacylglycerides

Panzilius

Holstein

Dehairs

et al. 2018

Preprint

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Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent phospholipid peroxidation. It can be induced by inhibiting glutathione peroxidase 4 (GPX4), the key enzyme for efficiently reducing peroxides within phospholipid bilayers.Recent data suggest that cancer cells undergoing EMT (dedifferentiation) and those resistant to standard therapy expose a high vulnerability toward ferroptosis. Although recent studies have begun to identify and characterize the metabolic and genetic determinants underlying ferroptosis, many mechanisms that dictate ferroptosis sensitivity remain unknown. Here, we show that low cell density sensitizes primary mammary epithelial and breast cancer cells to ferroptosis induced by GPX4 inhibition, whereas high cell density confers resistance. These effects occur irrespective of oncogenic signaling, cellular phenotype and expression of the fatty acid ligase acyl-CoA synthetase long chain family member 4 (ACSL4). By contrast, we show that a massive accumulation of neutral triacylglycerides (TAG) enriched with polyunsaturated fatty acids (PUFA) is induced at low cell density. In addition, de novo lipogenesis and desaturation pathways were found to be reduced at low cell density, indicative of increased fatty acid uptake. Our study suggests that PUFA-mediated toxicity is limited by the enrichment in TAGs that in turn might pose a vulnerability towards ferroptosis. Conclusively, cell density regulates lipid metabolism of breast epithelial and cancer cells, which results in a ferroptosis-sensitive cell state with the potential to be exploited therapeutically during metastatic dissemination.

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Section: Discussionmentioning

confidence: 99%

Cell density-dependent ferroptosis in breast cancer is induced by accumulation of polyunsaturated fatty acid-enriched triacylglycerides

Panzilius

Holstein

Dehairs

et al. 2018

Preprint

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“…Fatty acids and KBs form the second metabolic compartment between neurons and astroglia (Fig. ) . KBs, consisting of acetoacetate (AA), acetone, and β‐hydroxybutyrate (BHB), are alternative substrates for glucose.…”

Section: Fatty Acid and Kbmentioning

confidence: 99%

“…4). [126][127][128][129][130][131] KBs, consisting of acetoacetate (AA), acetone, and β-hydroxybutyrate (BHB), are alternative substrates for glucose. KBs, rather than glucose, are the main energy substrates in the brains of infants.…”

Section: Kbs Produced From Fatty Acids Serve As Energy Substrates Formentioning

confidence: 99%

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

Takahashi

2020

Neuropathology

152

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Astroglia or astrocytes, the most abundant cells in the brain, are interposed between neuronal synapses and microvasculature in the brain gray matter. They play a pivotal role in brain metabolism as well as in the regulation of cerebral blood flow, taking advantage of their unique anatomical location. In particular, the astroglial cellular metabolic compartment exerts supportive roles in dedicating neurons to the generation of action potentials and protects them against oxidative stress associated with their high energy consumption. An impairment of normal astroglial function, therefore, can lead to numerous neurological disorders including stroke, neurodegenerative diseases, and neuroimmunological diseases, in which metabolic derangements accelerate neuronal damage. The neurovascular unit (NVU), the major components of which include neurons, microvessels, and astroglia, is a conceptual framework that was originally used to better understand the pathophysiology of cerebral ischemia. At present, the NVU is a tool for understanding normal brain physiology as well as the pathophysiology of numerous neurological disorders. The metabolic responses of astroglia in the NVU can be either protective or deleterious. This review focuses on three major metabolic compartments: (i) glucose and lactate; (ii) fatty acid and ketone bodies; and (iii) D‐ and L‐serine. Both the beneficial and the detrimental roles of compartmentalization between neurons and astroglia will be discussed. A better understanding of the astroglial metabolic response in the NVU is expected to lead to the development of novel therapeutic strategies for diverse neurological diseases.

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“…Glia are fixed, and the appearance of Red-C12 in astrocytic lipid droplets is imaged and quantified. This figure is reproduced fromIoannou et al (2019).…”

mentioning

confidence: 99%

“…Recipient cells (glia) are treated with depleted supernatant (sup) and analyzed for the appearance of labeled fatty acids. This schematic is reproduced fromIoannou et al (2019). (B) If centrifugation does not affect the appearance of labeled fatty acids in glia, then fatty acid transfer is mediated by free fatty acids.…”

mentioning

confidence: 99%

A Neuron‐Glia Co‐culture System for Studying Intercellular Lipid Transport

2019

Self Cite

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Neurons and glia operate in a highly coordinated fashion in the brain. Although glial cells have long been known to supply lipids to neurons via lipoprotein particles, new evidence reveals that lipid transport between neurons and glia is bidirectional. Here, we describe a co‐culture system to study transfer of lipids and lipid‐associated proteins from neurons to glia. The assay entails culturing neurons and glia on separate coverslips, pulsing the neurons with fluorescently labeled fatty acids, and then incubating the coverslips together. As astrocytes internalize and store neuron‐derived fatty acids in lipid droplets, analyzing the number, size, and fluorescence intensity of lipid droplets containing the fluorescent fatty acids provides an easy and quantifiable measure of fatty acid transport. © 2019 The Authors.

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Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity

Cited by 413 publications

References 62 publications

Cell density-dependent ferroptosis in breast cancer is induced by accumulation of polyunsaturated fatty acid-enriched triacylglycerides

Cell density-dependent ferroptosis in breast cancer is induced by accumulation of polyunsaturated fatty acid-enriched triacylglycerides

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

A Neuron‐Glia Co‐culture System for Studying Intercellular Lipid Transport

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