Transfer of mitochondria from astrocytes to neurons after stroke.

Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, Ji X, Lo EH

Nature 2016

Neurons can release damaged mitochondria and transfer them to astrocytes for disposal and recycling. 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.

14 Figures Extracted

Fig. 1

Astrocytic CD38 and extracellular mitochondria a, Transmission electron microscopy (TEM) of extracellular mitochondria in astrocyte-conditioned mediu...

Fig. 2

Astrocytic extracellular mitochondria and neuroprotection a, Experimental schematic to test neuroprotective effects of astrocyte conditioned media (A...

Fig. 3

Astrocytic mitochondria and neuroplasticity after ischemic stress a, Confocal microscopy revealed that astrocytic mitochondria (red, Mitotracker Red ...

Fig. 4

Effects of CD38 siRNA in focal cerebral ischemia a, Male C57Bl6 mice were subjected to transient 60 min focal ischemia and control siRNA or CD38 siRN...

Extended Data Figure 1

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Astrocytic mitochondria particle detection a, Electron microscopic analysis demonstrated that mitochondria were detected within extracellular astrocy...

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Characteristics of astrocytic mitochondria particle in FACS analysis a, Mitochondrial particles were identified by FACS. b, Of these mitochondrial ...

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Production of astrocytic mitochondria particle in a Ca 2+ -dependent mechanism a, The known CD38 downstream signal, cADPR increased intracellular cal...

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Summary of experiment on Figure 2c a , We repeated the experiment in Fig. 2c with n=4 independent primary cultures per group. Similar results were ...

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Role of astrocytic CD38 in mitochondria transfer during starvation in vitro a, Immunocytochemistry in neuron-astrocyte co-cultures demonstrated that ...

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Metabolic inhibition in astrocyte causes neuronal cell death and retards neurite outgrowth in vitro a, Astrocytic aconitase was inhibited by fluoroci...

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FACS analysis using E17 FVB/N-Tg (GFAPGFP)14Mes/J transgenic mice a, Cortical neurons were isolated from E17 FVB/N-Tg (GFAPGFP)14Mes/J transgenic mic...

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Effects of CD38 suppression with siRNA in vivo and in vitro a, Western blot showed that CD38 expression was increased in peri-infarct cortex at days ...

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Neuronal purity confirmed by FACS analysis in vivo To be sure about our FACS findings, we used two different standard approaches that have been publis...

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Involvement of integrin-mediate src/syk mechanisms in astrocytic mitochondrial entry into neurons in vitro a and b, Cultured rat cortical astrocytes ...