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Mitochondria in activated microglia in vitro

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Journal of Neurocytology

Abstract

In the CNS, microglia become activated, i.e. change their functional state and phenotype, in response to a wide variety of pathological stimuli. Since this activation is triggered at a very low threshold and at the same time remains territorially restricted, the spatial distribution of activated microglia can be used as a sensitive, generic measure of the anatomical localisation of ongoing disease processes. One protein complex, undetectable in resting microglia but highly up-regulated upon activation in vivo and in vitro, is the ‘peripheral benzodiazepine binding site’, as measured by binding of the isoquinoline derivate PK11195. Particularly numerous in the outer membrane of mitochondria, this binding site has also been referred to as the ‘mitochondrial benzodiazepine receptor’. The de novo expression of this receptor by activated microglia suggests that the process of activation may be associated with important qualitative changes in the state of mitochondria. Here, we provide confocal light- and electron microscopic evidence that the activation of microglia indeed entails conspicuous mitochondrial alterations. In cultured rat microglia stained with the fluorescent probe, JC-1, a sensitive indicator of mitochondrial membrane potential, we demonstrate that stimulation by bacterial lipopolysaccharide and interferon-γ increases the number of microglial mitochondrial profiles and leads to marked changes in their morphology. Prominent elongated, “needle-like” mitochondria are a characteristic feature of activated microglia in vitro. Electron microscopically, an abundance of abnormal profiles, including circular cristae or ring- and U-shaped membranes, are found. Our observations support the notion that the previously reported increase in microglial binding of PK11195, that labelled with carbon-11 ([11C] (R)-PK11195) has clinical use for the visualisation of activated microglia in vivo by positron emission tomography, may at least in part relate to an increased number and altered functional state of microglial mitochondria.

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Authors and Affiliations

  1. Chair of Medical Radiation Sciences, School of Medical Radiation Sciences, and Ramaciotti Centre for Brain Imaging (Brain-Mind Research Institute), University of Sydney, East Street PO Box 170, Lidcombe NSW 1825, Australia

    Richard B. Banati

  2. University Department of Neuropathology, Faculty of Medicine, Division of Neuroscience, Imperial College London, Charing Cross Campus, Fulham Palace Road, London, W6 8RF, UK

    B. Manuel &  Graeber

  3. Institute of Neuropathology, University of Münster, Domagkstr 19, D-48149, Münster, Germany

    Rupert Egensperger

  4. Institute of Pharmaceutical and Medical Chemistry, University of Münster, Hittorfstrasse 58-62, 48149, Münster, Germany

    Alexander Maassen

  5. Aurigon Life Science GmbH, Bahnhofstr. 9- 15, 82327, Tutzing, Germany

    Gerhard Hager

  6. Department of Neuromorphology, Max-Planck-Institute of Neurobiology, Am Klopferspitz 18a, 82152, Martinsried, Germany

    Georg W. Kreutzberg

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  1. Richard B. Banati
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  2. Rupert Egensperger
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  3. Alexander Maassen
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  4. Gerhard Hager
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  5. Georg W. Kreutzberg
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  6. B. Manuel
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  7. Graeber
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Correspondence to Graeber.

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Banati, R.B., Egensperger, R., Maassen, A. et al. Mitochondria in activated microglia in vitro. J Neurocytol 33, 535–541 (2004). https://doi.org/10.1007/s11068-004-0515-7

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  • DOI: https://doi.org/10.1007/s11068-004-0515-7

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