Letter | Published:

Transfer of mitochondria from astrocytes to neurons after stroke

Nature volume 535, pages 551555 (28 July 2016) | Download Citation

  • A Corrigendum to this article was published on 14 September 2016

Abstract

Neurons can release damaged mitochondria and transfer them to astrocytes for disposal and recycling1. This ability to exchange mitochondria may represent a potential mode of cell-to-cell signalling in the central nervous system. Here we show that astrocytes in mice can also release functional mitochondria that enter neurons. Astrocytic release of extracellular mitochondrial particles was mediated by a calcium-dependent mechanism involving CD38 and cyclic ADP ribose signalling. Transient focal cerebral ischaemia in mice induced entry of astrocytic mitochondria into adjacent neurons, and this entry amplified cell survival signals. Suppression of CD38 signalling by short interfering RNA reduced extracellular mitochondria transfer and worsened neurological outcomes. These findings suggest a new mitochondrial mechanism of neuroglial crosstalk that may contribute to endogenous neuroprotective and neurorecovery mechanisms after stroke.

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References

  1. 1.

    et al. Transcellular degradation of axonal mitochondria. Proc. Natl Acad. Sci. USA 111, 9633–9638 (2014)

  2. 2.

    & Glial regulation of the cerebral microvasculature. Nat. Neurosci. 10, 1369–1376 (2007)

  3. 3.

    et al. Glial and neuronal control of brain blood flow. Nature 468, 232–243 (2010)

  4. 4.

    & Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942–952 (2015)

  5. 5.

    & Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci. Lett. 103, 162–168 (1989)

  6. 6.

    & Pyruvate released by astrocytes protects neurons from copper-catalyzed cysteine neurotoxicity. J. Neurosci. 21, 3322–3331 (2001)

  7. 7.

    et al. Astrocyte-enriched miR-29a targets PUMA and reduces neuronal vulnerability to forebrain ischemia. Glia 61, 1784–1794 (2013)

  8. 8.

    et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat. Neurosci. 10, 615–622 (2007)

  9. 9.

    et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat. Biotechnol. 29, 824–828 (2011)

  10. 10.

    , , & Inhibition of mitochondrial function in astrocytes: implications for neuroprotection. J. Neurochem. 102, 1383–1394 (2007)

  11. 11.

    , , & The dynamics of the mitochondrial organelle as a potential therapeutic target. J. Cereb. Blood Flow Metab. 33, 22–32 (2013)

  12. 12.

    et al. Astrocytes shed large membrane vesicles that contain mitochondria, lipid droplets and ATP. Histochem. Cell Biol. 139, 221–231 (2013)

  13. 13.

    et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat. Med. 18, 759–765 (2012)

  14. 14.

    , , & Regulation of intracellular levels of NAD: a novel role for CD38. Biochem. Biophys. Res. Commun. 345, 1386–1392 (2006)

  15. 15.

    & NAADP: a universal Ca2+ trigger. Sci. Signal. 1, re10 (2008)

  16. 16.

    et al. Glutamate-mediated overexpression of CD38 in astrocytes cultured with neurones. J. Neurochem. 89, 264–272 (2004)

  17. 17.

    et al. CD38 facilitates recovery from traumatic brain injury. J. Neurotrauma 26, 1521–1533 (2009)

  18. 18.

    et al. Social memory, amnesia, and autism: brain oxytocin secretion is regulated by NAD+ metabolites and single nucleotide polymorphisms of CD38. Neurochem. Int. 61, 828–838 (2012)

  19. 19.

    et al. CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia. PLoS One 6, e19046 (2011)

  20. 20.

    et al. Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol. 11, e1001604 (2013)

  21. 21.

    et al. The phagocytic capacity of neurones. Eur. J. Neurosci. 25, 2947–2955 (2007)

  22. 22.

    , & Central nervous system pericytes in health and disease. Nat. Neurosci. 14, 1398–1405 (2011)

  23. 23.

    et al. Microglial and macrophage polarization—new prospects for brain repair. Nat. Rev. Neurol. 11, 56–64 (2015)

  24. 24.

    et al. Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse. PLoS One 5, e9027 (2010)

  25. 25.

    , , , & Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery. Proc. Natl Acad. Sci. USA 109, 7505–7510 (2012)

  26. 26.

    et al. Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor. Int. J. Mol. Med. 21, 63–67 (2008)

  27. 27.

    , , & The role of astrocytes in mediating exogenous cell-based restorative therapy for stroke. Glia 62, 1–16 (2014)

  28. 28.

    Degeneration and repair in central nervous system disease. Nat. Med. 16, 1205–1209 (2010)

  29. 29.

    & Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery. Prog. Neurobiol. (2016)

  30. 30.

    , , , & Activation of CD38 by interleukin-8 signaling regulates intracellular Ca2+ level and motility of lymphokine-activated killer cells. J. Biol. Chem. 280, 2888–2895 (2005)

  31. 31.

    , , , & Enzymatic synthesis and characterizations of cyclic GDP-ribose. A procedure for distinguishing enzymes with ADP-ribosyl cyclase activity. J. Biol. Chem. 269, 30260–30267 (1994)

  32. 32.

    et al. Cortical glial fibrillary acidic protein-positive cells generate neurons after perinatal hypoxic injury. J. Neurosci. 31, 9205–9221 (2011)

  33. 33.

    et al. New technologies for examining the role of neuronal ensembles in drug addiction and fear. Nat. Rev. Neurosci. 14, 743–754 (2013)

  34. 34.

    et al. Quantitative sizing of nano/microparticles with a tunable elastomeric pore sensor. Anal. Chem. 83, 3499–3506 (2011)

  35. 35.

    et al. Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 30, 871–882 (2010)

  36. 36.

    , & Role of ERK map kinase and CRM1 in IL-1β-stimulated release of HMGB1 from cortical astrocytes. Glia 58, 1007–1015 (2010)

  37. 37.

    , , & NeuriteQuant: an open source toolkit for high content screens of neuronal morphogenesis. BMC Neurosci. 12, 100 (2011)

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Acknowledgements

This work was supported in part by grants from the National Institutes of Health (NIH), the Rappaport Foundation, and the China National Natural Science Foundation Award For Distinguished Young Scholars. Electron microscopy was performed in the Center for Systems Biology. Cytometric assessments were supported by the Department of Pathology Flow and Image Cytometry Core. The authors thank J. Felton and J. Zwicker for assistance with qNano analysis.

Author information

Affiliations

  1. Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA

    • Kazuhide Hayakawa
    • , Elga Esposito
    • , Xiaohua Wang
    • , Yasukazu Terasaki
    • , Yi Liu
    • , Changhong Xing
    •  & Eng H. Lo
  2. Cerebrovascular Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China

    • Xiaohua Wang
    • , Yi Liu
    •  & Xunming Ji

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Contributions

K.H. contributed to manuscript preparation, hypothesis generation, experimental design/analysis and conducted experiments. E.E., X.W., Y.T., Y.L. and C.X. conducted experiments and helped with data analysis. X.J. and E.H.L. contributed to manuscript preparation, hypothesis generation and experimental design.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kazuhide Hayakawa or Xunming Ji or Eng H. Lo.

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DOI

https://doi.org/10.1038/nature18928

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