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      Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration


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          In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here, we show that expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to trigger death of naïve neurons directly and to propagate neuronal death through activation of naïve astrocytes to A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria to the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glia cells. The propagation of inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration – one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.

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          Most cited references 25

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          Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization.

          Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.
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            A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity.

            Excessive mitochondrial fission is associated with the pathology of a number of neurodegenerative diseases. Therefore, inhibitors of aberrant mitochondrial fission could provide important research tools in addition to potential leads for drug development. Using a rational approach, we designed a novel and selective peptide inhibitor, P110, of excessive mitochondrial fission. P110 inhibits Drp1 enzyme activity and blocks Drp1/Fis1 interaction in vitro and in cultured neurons, whereas it has no effect on the interaction between Drp1 and other mitochondrial adaptors, as demonstrated by co-immunoprecipitation. Furthermore, using a model of Parkinson's disease (PD) in culture, we demonstrated that P110 is neuroprotective by inhibiting mitochondrial fragmentation and reactive oxygen species (ROS) production and subsequently improving mitochondrial membrane potential and mitochondrial integrity. P110 increased neuronal cell viability by reducing apoptosis and autophagic cell death, and reduced neurite loss of primary dopaminergic neurons in this PD cell culture model. We also found that P110 treatment appears to have minimal effects on mitochondrial fission and cell viability under basal conditions. Finally, P110 required the presence of Drp1 to inhibit mitochondrial fission under oxidative stress conditions. Taken together, our findings suggest that P110, as a selective peptide inhibitor of Drp1, might be useful for the treatment of diseases in which excessive mitochondrial fission and mitochondrial dysfunction occur.
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              Is Open Access

              The role of astroglia in neuroprotection

              Astrocytes are the main neural cell type responsible for the maintenance of brain homeostasis. They form highly organized anatomical domains that are interconnected into extensive networks. These features, along with the expression of a wide array of receptors, transporters, and ion channels, ideally position them to sense and dynamically modulate neuronal activity. Astrocytes cooperate with neurons on several levels, including neurotransmitter trafficking and recycling, ion homeostasis, energy metabolism, and defense against oxidative stress. The critical dependence of neurons upon their constant support confers astrocytes with intrinsic neuroprotective properties which are discussed here. Conversely, pathogenic stimuli may disturb astrocytic function, thus compromising neuronal functionality and viability. Using neuroinflammation, Alzheimer's disease, and hepatic encephalopathy as examples, we discuss how astrocytic defense mechanisms may be overwhelmed in pathological conditions, contributing to disease progression.

                Author and article information

                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                6 August 2019
                23 September 2019
                October 2019
                23 March 2020
                : 22
                : 10
                : 1635-1648
                [1 ]Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA;
                [2 ]Department of Neurology & Neurological Sciences, Stanford School of Medicine, Stanford, CA;
                [3 ]Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA (Current address: Department of Neuroscience and Physiology; Neuroscience Institute; Department of Neuroscience and Physiology, NYU Langone Medical Center, NY; Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Australia);
                [4 ]Department of Pediatrics division of Critical Care Medicine, Stanford University School of Medicine, Stanford, CA;
                [5 ]Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis MO USA
                Author notes

                Author Contributions

                A.U.J and D.M-R generated the hypothesis and experimental design. A.U.J, D.M-R and G.W.D contributed to manuscript preparation. K.I.A contributed to experimental design. A.U.J performed isolations of neurons, microglia and astrocytes, collected, analyzed and interpreted the results from earlier mouse studies, qPCR, ELISA, immunoblots, and mitochondrial assays. P.S.M. performed isolations of human MDMs, neurons, microglia and astrocytes, collected data from seahorse experiments and helped with data analysis. B.H. performed mitochondrial assays, ELISA and immunoblots and helped with data analysis. S.A.L isolated microglia and performed Microfluidic qPCR and helped with data analysis. All the authors reviewed and edited the manuscript.

                [* ] Corresponding author: Daria Mochly-Rosen, Department of Chemical & Systems Biology, School of Medicine, Stanford University, CA, USA, mochly@ 123456stanford.edu Tel: 650-255-1053

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