Astrocytes improve neuronal health after cisplatin treatment through mitochondrial transfer

AbstractNeurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunctionin vivoandin vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially, mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health. We used anin vitrosystem in which astrocytes containing mito-mCherry-labeled mitochondria were co-cultured with primary cortical neurons damaged by cisplatin. Culture of primary cortical neurons with cisplatin reduced neuronal survival and depolarized neuronal mitochondrial membrane potential. Cisplatin induced abnormalities in neuronal calcium dynamics characterized by increased resting calcium levels, reduced calcium responses to stimulation with KCl, and slower calcium clearance. The same dose of cisplatin that caused neuronal damage did not affect astrocyte survival or astrocytic mitochondrial respiration. Co-culture of cisplatin-treated neurons with astrocytes increased neuronal survival, restored neuronal mitochondrial membrane potential, and normalized neuronal calcium dynamics especially in those neurons that had received mitochondria from astrocytes. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. The Rho-GTPase Miro-1 is known to contribute to mitochondrial motility and transfer. We show that siRNA-mediated knockdown of Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics.In conclusion, we identified transfer of mitochondria from astrocytes to neurons damaged by cisplatin as an important repair mechanism to protect cortical neurons against the toxic effects of this chemotherapeutic.Significance statementChemotherapy-induced neurotoxicity is a serious health problem and little is known about the underlying mechanisms. Especially neurons are very sensitive to cisplatin treatment. We show that astrocytes can protect neurons damaged by cisplatin by improving neuronal survival, mitochondrial health, and calcium dynamicsin vitro. This beneficial effect of astrocytes is dependent on the transfer of mitochondria from astrocytes to the damaged neurons. Our findings provide evidence for an important endogenous protective neuro-glial mechanism that could contribute to prevention of neuronal death as a result of cisplatin treatment and thereby aid in sustaining brain health of patients during chemotherapy.