Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer

Autor: Andrew J. Shepherd, Ronnie Trinh, Krystal English, Annemieke Kavelaars, Cobi J. Heijnen, Ndidi Ese Uzor
Jazyk: angličtina
Rok vydání: 2020
Předmět:
rho GTP-Binding Proteins
Cortical neurons
Synaptogenesis
Stimulation
Mitochondrion
lcsh:RC346-429
0302 clinical medicine
Membrane Potential
Mitochondrial
Neurons
Membrane potential
0303 health sciences
Chemistry
Optical Imaging
Mitochondrial Turnover
Neural stem cell
3. Good health
Cell biology
Mitochondria
medicine.anatomical_structure
Gene Knockdown Techniques
Neurotoxicity Syndromes
Astrocyte
medicine.drug
Cell Respiration
Primary Cell Culture
chemistry.chemical_element
Antineoplastic Agents
In Vitro Techniques
Calcium
Pathology and Forensic Medicine
Mitochondrial Proteins
03 medical and health sciences
Cellular and Molecular Neuroscience
Oxygen Consumption
Chemotherapy-Related Cognitive Impairment
medicine
Animals
Calcium Signaling
lcsh:Neurology. Diseases of the nervous system
030304 developmental biology
Miro-1
Cisplatin
Luminescent Agents
Research
Coculture Techniques
Rats
Luminescent Proteins
nervous system
Astrocytes
Neurology (clinical)
030217 neurology & neurosurgery
Zdroj: Acta Neuropathologica Communications, Vol 8, Iss 1, Pp 1-14 (2020)
Acta Neuropathologica Communications
ISSN: 2051-5960
DOI: 10.1186/s40478-020-00897-7
Popis: Neurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunction in vivo and in 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 an in vitro system 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 that were 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 neurons that had received mitochondria from astrocytes which underlines the importance of mitochondrial transfer. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. We show that siRNA-mediated knockdown of the Rho-GTPase Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics.In conclusion, we showed that transfer of mitochondria from astrocytes to neurons rescues neurons from the damage induced by cisplatin treatment. Astrocytes are far more resistant to cisplatin than cortical neurons. We propose that transfer of functional mitochondria from astrocytes to neurons is an important repair mechanism to protect the vulnerable cortical neurons against the toxic effects of cisplatin.
Databáze: OpenAIRE
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