Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer

Abstract

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.

Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups

“…This suggests that the cisplatin is not lowering the mitochondrial membrane potential, which agrees with Kleih and colleagues who observed that ovarian cancer cells treated with cisplatin also maintained their mitochondrial membrane potential ( Cocetta, Ragazzi & Montopoli, 2019 ; Kleih et al, 2019 ). Similarly, English et al found that cisplatin-treated neuronal cells could maintain and restore their mitochondrial membrane potential through the uptake of cisplatin-resistant mitochondria from astrocytes ( English et al, 2020 ).…”

ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity

“…Under normal physiological conditions, bidirectional intercellular transfers of cellular materials via permanent cell fusion and temporal tunneling nanotube formations lead to tissue development and repair [ 17 , 18 , 19 ]. However, under pathological conditions such as viral infection, chronic inflammation, diabetes, and cancer, the intercellular transfers of biological materials (including chromosomal and extrachromosomal genetic materials, cellular organelles, viruses) via permanent and temporal cell fusions lead to de novo cell transformations and tissue heterogeneity, and thus to the development of drug resistance and disease progression [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”

“…Hypoxia, mechanical stress, chronic inflammation, cytotoxic stress, and oncometabolites associated with free radical formations are reported to potentiate intercellular membrane fusion events, and these conditions are often associated with the glioma microenvironment [ 14 , 20 , 21 , 22 , 23 , 27 , 35 , 44 , 45 , 46 , 47 ]. The mRNA-binding protein of ELAV-family HuR is a valuable biomarker of brain tumor progression [ 48 , 49 , 50 , 51 ] and is involved in the regulation of the key cell-signaling pathways responsible for the inflammatory glioma microenvironment, the hypoxia-related stress response, the transitions of classic and proneural glioma subtypes to the mesenchymal subtype, the metabolic stress, and the reactive oxygen species (ROS) generation associated with D-2HG oncometabolite production in low-grade gliomas harboring single alleles with IDH1-R132H/C/S mutations [ 52 , 53 , 54 , 55 ].…”

Peer Review #1 of "Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups (v0.2)"

“…Similarly, English et. al found that cisplatintreated neuronal cells could maintain and restore their mitochondrial membrane potential through the uptake of cisplatin-resistant mitochondria from astrocytes (English et al 2020).…”