Changes in mitochondrial morphology modulate LPS-induced loss of calcium homeostasis in BV-2 microglial cells

Pereira, Osvaldo; Ramos, Vitor Miranda; Cabral-Costa, João Victor; Kowaltowski, Alicia J.

doi:10.1007/s10863-021-09878-4

Cited by 11 publications

(4 citation statements)

References 49 publications

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“…Evidence for a mitochondrial ROS‐mediated mechanism of post‐traumatic microglial/macrophage activation is currently lacking. Other mechanisms of mitochondrial dysfunction described in human TBI samples, such as excess calcium influx, reduced membrane potential and mitochondrial respiration (Carteri et al, 2019; Kilbaugh et al, 2015; Singh et al, 2006), are phenomena also observed in LPS‐stimulated BV2 microglia (Pereira Jr. et al, 2021). In addition, metabolic analysis of microglia co‐cultured with needle scratch‐injured neurons demonstrates an increase in glucose conversion to citrate, aconitate, and αKG, but not malate (Liu et al, 2023), indicating a disruption in the TCA cycle following injury.…”

Section: Oxidative Phosphorylation and Krebs Cycle Dysfunction Follow...mentioning

confidence: 95%

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Strogulski,

Portela,

Polster

et al. 2023

Journal of Neurochemistry

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Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain‐infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro‐ and anti‐inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro‐inflammatory activation is associated with decreased mitochondrial respiration, whereas anti‐inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post‐traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non‐resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post‐traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.image

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Section: Oxidative Phosphorylation and Krebs Cycle Dysfunction Follow...mentioning

confidence: 95%

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Strogulski,

Portela,

Polster

et al. 2023

Journal of Neurochemistry

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“…The dependence of immune functions on cellular metabolic pathways can be described using the term immunometabolism. Alongside changes in metabolism, activation of microglia can result in changes to mitochondrial structure, with LPS treatment shown to result in mitochondrial fragmentation, indicative of reduced OXPHOS [ 182 , 183 , 184 ].…”

Section: Microglial Immunometabolismmentioning

confidence: 99%

Assaying Microglia Functions In Vitro

Maguire

Connor-Robson

Shaw

et al. 2022

Cells

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Microglia, the main immune modulators of the central nervous system, have key roles in both the developing and adult brain. These functions include shaping healthy neuronal networks, carrying out immune surveillance, mediating inflammatory responses, and disposing of unwanted material. A wide variety of pathological conditions present with microglia dysregulation, highlighting the importance of these cells in both normal brain function and disease. Studies into microglial function in the context of both health and disease thus have the potential to provide tremendous insight across a broad range of research areas. In vitro culture of microglia, using primary cells, cell lines, or induced pluripotent stem cell derived microglia, allows researchers to generate reproducible, robust, and quantifiable data regarding microglia function. A broad range of assays have been successfully developed and optimised for characterizing microglial morphology, mediation of inflammation, endocytosis, phagocytosis, chemotaxis and random motility, and mediation of immunometabolism. This review describes the main functions of microglia, compares existing protocols for measuring these functions in vitro, and highlights common pitfalls and future areas for development. We aim to provide a comprehensive methodological guide for researchers planning to characterise microglial functions within a range of contexts and in vitro models.

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“…Generally, activated microglia cells switch from oxidative phosphorylation to glycolysis and form a fragmented mitochondria network 68 . Notably, microglia nodules in MS generally possess a more tubular and less fragmented mitochondrial network compared to microglia nodules in stroke.…”

mentioning

confidence: 99%

Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation

van den Bosch,

van der Poel,

Fransen

et al. 2023

Preprint

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Clusters of ramified HLA-DR+ cells, known as microglia nodules, are associated with brain pathology. Here we investigated if microglia nodules in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) are different from microglia nodules in white matter (WM) in stroke and whether they may relate to the start of demyelinating MS lesions. We studied the relation between microglia nodules and pathological severity in an MS autopsy cohort (n=167), and we compared frequency, size, and gene expression of microglia nodules in MS (n=7) and stroke (n=7). MS donors with microglia nodules (64%) had a higher lesion load and a higher proportion of active lesions compared to donors without microglia nodules (36%). We found altered expression of genes in microglia nodules in MS compared to stroke, including genes previously shown to be upregulated in MS lesions. Genes associated with lipid metabolism, presence and proliferation of T and B cells, production of and response to immunoglobulins and cytokines (specifically TNF and IFN), activation of the complement cascade, and metabolic stress were upregulated. Using immunohistochemistry, we confirmed that in MS, more than in stroke, microglia nodules are associated with membrane attack complexes, have phagocytosed oxidized phospholipids, and have a tubular mitochondrial network reflecting increased metabolic activity. Furthermore, in MS, some nodules encapsulated partially demyelinated axons. Taken together, we propose that activation of some microglia nodules in MS by pro-inflammatory cytokines and immunoglobulins in combination with phagocytosis of oxidized phospholipids may lead to a volatile phenotype prone to form MS lesions.

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Changes in mitochondrial morphology modulate LPS-induced loss of calcium homeostasis in BV-2 microglial cells

Cited by 11 publications

References 49 publications

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Assaying Microglia Functions In Vitro

Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation

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