Intercellular transfer of mitochondria via tunneling nanotubes protects against cobalt nanoparticle-induced neurotoxicity and mitochondrial damage

Abstract

Broad applications of cobalt nanoparticles (CoNPs) have raised increased concerns regarding their potential toxicity. However, the underlining mechanisms of their toxicity have yet to be characterized. Here, we demonstrated that CoNPs reduced cell viability and induced membrane leakage. CoNPs induced oxidative stress, as indicated by the generation of reactive oxygen species (ROS) secondary to the increased expression of hypoxia-induced factor 1 alpha. Moreover, CoNPs led to mitochondrial damage, including generation of mitochondrial ROS, reduction in ATP content, morphological damage and autophagy. Interestingly, exogenous mitochondria were observed between neurons and astrocytes upon CoNPs exposure. Concomitantly, tunneling nanotubes (TNTs)-like structures were observed between neurons and astrocytes upon CoNPs exposure. These structures were further verified to be TNTs as they were found to be F-actin rich and lacking tubulin. We then demonstrated that TNTs were utilized for mitochondrial transfer between neurons and astrocytes, suggesting a novel crosstalk phenomenon between these cells. Moreover, we found that the inhibition of TNTs (using actin-depolymerizing drug latrunculin B) intensified apoptosis triggered by CoNPs. Therefore, we demonstrate, for the first time, that the inhibition of intercellular mitochondrial transfer via TNTs aggravates CoNPs-induced cellular and mitochondrial toxicity in neuronal cells, implying a novel intercellular protection mechanism in response to nanoparticle exposure.

Keywords:

• Cobalt nanoparticles (CoNPs)
• mitochondrial transfer
• tunneling nanotubes (TNTs)
• neurotoxicity
• astrocytes

Acknowledgements

The authors appreciate the technical assistance of Ling Lin, Junjin Lin, Zhihong Huang, Xiurong Zhong, Linying Zhou and Xi Lin from Public Technology Service Center, Fujian Medical University (Fuzhou, China).

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China under Grants [numbers 81903352, 81973083, 22006019], the Joint Funds for the Innovation of Science and Technology, Fujian province under Grant [number 2019Y9020], the Provincial Natural Science Foundation of Fujian Province under Grant [number 2019J05081], High-level personnel research start-up funding of Fujian medical university under Grant [number XRCZX2018002] and National Institutes of Health under Grants [numbers R01ES07331, R01ES10563].