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

Nature Neuroscience volume 22, pages 1635–1648 (2019)Cite this article

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An Author Correction to this article was published on 15 December 2020

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Abstract

In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into 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 glial cells. The propagation of the 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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Fig. 1: Inhibition of Drp1–Fis1-mediated mitochondrial fission in vivo reduces sustained microglia and astrocyte activation and subsequent proinflammatory responses in three models of neurodegenerative disease in mice.
Fig. 2: Drp1–Fis1-mediated mitochondrial fragmentation and dysfunction are required to induce microglial inflammatory responses in a model of HD (induced by cytotoxic Q73) or LPS activation in culture.
Fig. 3: Drp1–Fis1-mediated mitochondrial fragmentation and dysfunction are required to induce microglial inflammatory response in a model of ALS (by expressing cytotoxic SOD1-G93A) or in a model of AD (induced by treatment with oAβ1-42) in culture.
Fig. 4: Conditioned media of activated microglia with mitochondrial dysfunction propagate astrocyte activation to the A1 proinflammatory state and dysfunction of mitochondria in cultured astrocytes in multiple models of neurodegenerative diseases.
Fig. 5: Excessive mitochondrial fission and dysfunction occur in activated astrocytes.
Fig. 6: Dysfunctional extracellular mitochondria release from activated primary rat and mouse microglia or astrocytes or human primary monocyte-derived microglial cells occurs in a Drp1–Fis1-specific manner.
Fig. 7: Released (extracellular) glial mitochondria propagate mitochondrial dysfunction and cell death from activated microglia to neurons through astrocytes.
Fig. 8: WT or R6/2 astrocytes induce Drp1–Fis1-dependent propagation of neuronal mitochondrial dysfunction and neuronal cell death from R6/2 microglia to naive mouse cortical neurons.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

In memory of Ben Barres, whose advice and research inspired this study. This work was supported, in part, by a Stanford Discovery Innovation Award and R01 HL52141 to D.M.-R., a Paul & Daisy Soros Fellowship to P.S.M., a postdoctoral fellowship from the Australian National Health and Medical Research Council (GNT1052961) and the Glenn Foundation Glenn Award to S.A.L., RO1AG058047 to K.I.A., and R35 HL135736 to G.W.D. The authors thank N. Raju and S. Avolicino for assistance with immunohistochemistry and J. Perrino for technical support with electron microscopy.

Author information

Author notes

  1. Shane A. Liddelow

    Present address: Department of Neuroscience and Physiology and Neuroscience Institute, New York University Langone Medical Center, New York, NY, USA

  2. Shane A. Liddelow

    Present address: Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, Australia

Authors and Affiliations

  1. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA

    Amit U. Joshi, Bereketeab Haileselassie & Daria Mochly-Rosen

  2. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Paras S. Minhas & Katrin I. Andreasson

  3. Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA

    Shane A. Liddelow

  4. Department of Pediatrics Division of Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Bereketeab Haileselassie

  5. Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA

    Gerald W. Dorn II

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Contributions

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

Corresponding author

Correspondence to Daria Mochly-Rosen.

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Competing interests

Patents on P110 and its utility in HD, ALS and other neurodegenerative diseases have been filed by D.M.‐R. and A.U.J. The other authors declare no competing interests.

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Peer review information Nature Neuroscience thanks Robert Friedlander, Krista Spiller and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Integrated supplementary information

Supplementary Figure 1 Inhibition of excessive mitochondrial fission by treatment with P110 in vivo reduces sustained microglial-astrocytic activation and subsequent pro-inflammatory response in three mouse models of neurodegenerative diseases, AD, HD and ALS.

(a) Area occupied by GFAP immunoreactive astrocytes (brown) was quantified in hippocampus, striatum and spinal cord, in 5xFAD AD mice, in R6/2 HD mice and SOD1 G93A ALS mice, respectively, vehicle- or P110-treated with 3 mg/kg/day for the time indicated in (1a). (b) Area occupied by Iba-1 immunoreactive microglia (brown) was quantified in hippocampus, striatum and spinal cord, in 5xFAD AD mice, in R6/2 HD mice and SOD1 G93A ALS mice, respectively, vehicle- or P110-treated with 3 mg/kg/day for the time indicated in (1a; red rectangles). (n = 5 per group/ 2 sections per mice.). (c) Representative western blot staining for glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, Iba-1, a marker of microglial activation, NLRP3, a marker of inflammasome activation and COX-2, a marker of canonical inflammation in whole brain R6/2 HD mice at endpoint. (d) Representative western blot staining for glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, Iba-1, a marker of microglial activation, NLRP3, a marker of inflammasome activation and COX-2, a marker of canonical inflammation in spinal cord SOD1 G93A mice at endpoint. (e) Representative western blot staining for glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, Iba-1, a marker of microglial activation, NLRP3, a marker of inflammasome activation and COX-2, a marker of canonical inflammation in whole brain lysate in 5XFAD mice at endpoint. 1a. (n = 5 per group). β-actin was used as a loading control. (f) NLRP3 and (g) COX-2 protein levels (determined by quantitating immunostaining) in each mouse model, presented as ratio to the corresponding WT mice. Data were evaluated by one-way ANOVA and Tukey’s multiple comparisons test for multiple testing between each treatment group. All graphs represent mean ± s.d.

Supplementary Figure 2 Excessive mitochondrial fission and dysfunction linked with inflammasome activation in microglia.

(a) Schematic of the experimental design using primary rat microglia treated with LPS (10 ng/ml) for 3 hours, followed by nigericin (1.2µM)-treatment in the presence/ absence of P110 (1 µM added 15 minutes prior to LPS) for 21 hours in serum and antibiotic free DMEM (top). Cellular levels of phospho-p44/42, phosphorylated NFκB and phosphorylated c-Jun N-terminal kinase (JNK) were determined by immunoblotting, quantified and presented as fold-change of control in rat primary microglia; (n=3). (b) Levels of Il-1β and caspase1-p20 were determined in cultured media of these primary microglia by immunoblotting. β-actin in the cells from the corresponding cultures was used as a cell loading control; (n = 2.) (c) Mitochondrial NLRP3 and ASC levels were determined by immunoblotting of mitochondrial fraction, quantified and presented as fold-change of control in these primary microglia. Data were evaluated by one-way ANOVA and Holm-Sidak’s multiple comparisons test for multiple testing between each treatment group; (n=5) All graphs represent mean ± s.d.

Supplementary Figure 3 Transfer of conditioned media of primary rat microglia activates primary rat astrocytes in vitro in a process dependent on Drp1/Fis1 interaction in the microglia and results in Drp1 activation and mitochondrial dysfunction in the astrocytes.

(a) The protocol of cell treatments and media transfer (above). Levels of GFAP protein were determined in cell extracts by immunoblotting rat primary astrocytes treated with supernatant from activated rat primary microglia (MCM); β-actin was used as a loading control; n = 4 (b) IL-1α, IL-1β, TNFα in the culture media of the astrocytes were measured by ELISA; n = 6 and (c) C1q RNA levels in cell extracts were measured by qPCR in cells treated as described in a; n = 5 (d) Drp1 phosphorylation in astrocytes (as a measure of Drp1 activation) were determined by immunoblotting in primary astrocytes treated with supernatant from activated primary microglia; β-actin was used as a loading control; n=4. (e) Mitochondrial levels of NLRP3 and ASC were determined by immunoblotting in the primary astrocytes; β-actin was used as a loading control. Protein levels were quantified and are presented as fold-change of control; n = 3-6. (f) Quantitative PCR analysis of astrocyte-specific phagocytic receptors (multiple EGF-like domains 10, Megf10, and MER proto-oncogene, tyrosine kinase, Mertk) and bridging molecules (receptor tyrosine kinase, Axl, and its ligand, growth arrest-specific 6, Gas6) in primary astrocytes treated with conditioned media, as in a; n=4. (g) OXPHOS in primary astrocytes treated with conditioned media, as in a; n=4. Data were evaluated by one-way ANOVA and Holm-Sidak’s multiple comparisons test for multiple testing between each treatment group. All graphs represent mean ± s.d.

Supplementary Figure 4 Functional mitochondria expelled from astrocytes decrease neuronal death.

(a) Primary cortical rat neurons were treated with conditioned media of primary rat microglia treated as in described in Fig. 2l for 24 hours without (Con) or with LPS/Nig without (Veh) or with P110 (1 μM) and assessed for survival, using LDH release from the neurons. (n=12) (b) Protocol of injury propagation from primary rat microglia activated by LPS to primary cortical rat neurons by media from activated astrocytes (aACM), as in described in Fig. 7a. Where indicated, mitochondria were from the astrocytic media (aACM; filtration through 0.2-μm filters; MitoΔ) and neuronal cell death was determined using LDH release from the neurons. Removal of mitochondria from aACM decreased neuronal survival, indicating the neuroprotective role of functional extracellular mitochondria; (n=10). (c) Primary cortical rat neurons were treated with conditioned media of primary rat astrocytes treated as in described in Fig. 6j for 24 hours. Neuronal cell death was determined using LDH release from the neurons; n=5). (d) Neuroinflammation response propagated from activated microglia to astrocytes to cause cell death of naïve neurons in models of neurodegenerative diseases via expelled and damaged glial mitochondria. Both functional and dysfunctional mitochondria are expelled from both astrocytes and microglia cells. However, mitochondrial dysfunction in microglia triggers the release of more dysfunctional mitochondria relative to functional mitochondria, and these dysfunctional extracellular mitochondria propagate the injurious signal to neurons directly, as well as through inducing mitochondrial dysfunction, activation and neuroinflammation in the astrocytes (left). Inhibiting Drp1/Fis1-mediated pathological fission in the microglia, using a selective inhibitor, such as P110, greatly reduces neuroinflammation, propagation of mitochondrial dysfunction and neuronal cell death. Blocking Drp1Fis1-mediated mitochondrial fission in the microglia increased the transfer benefit to subsequent cell types, in part, by releasing healthier mitochondria into the neuronal milieu (right). Whether the neurons uptake the extracellular mitochondria remains to be determined. Data were evaluated by one-way ANOVA and Holm-Sidak’s multiple comparisons test for multiple testing between each treatment group. All graphs represent mean ± s.d.

Supplementary Figure 5 Image processing for mitochondrial structure analysis.

Images acquired were processed using a macro in Fiji (Image J).

Supplementary Figure 6

Source Data for Western Blots.

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Joshi, A.U., Minhas, P.S., Liddelow, S.A. et al. Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat Neurosci 22, 1635–1648 (2019). https://doi.org/10.1038/s41593-019-0486-0

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