TY - JOUR
T1 - Drp-1-Dependent Mitochondrial Fragmentation Contributes to Cobalt Chloride-Induced Toxicity in Caenorhabditis elegans
AU - Zheng, Fuli
AU - Chen, Pan
AU - Li, Huangyuan
AU - Aschner, Michael
N1 - Publisher Copyright:
© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Excess cobalt may lead to metallosis, characterized by sensorineural hearing loss, visual, and cognitive impairment, and peripheral neuropathy. In the present study, we sought to address the molecular mechanisms of cobalt-induced neurotoxicity, using Caenorhabditis elegans as an experimental model. Exposure to cobalt chloride for 2 h significantly decreased the survival rate and lifespan in nematodes. Cobalt chloride exposure led to increased oxidative stress and upregulation of glutathione S-transferase 4. Consistently, its upstream regulator skn-1, a mammalian homolog of the nuclear factor erythroid 2-related factor 2, was activated. Among the mRNAs examined by quantitative real-time polymerase chain reactions, apoptotic activator egl-1, proapoptotic gene ced-9, autophagic (bec-1 and lgg-1), and mitochondrial fission regulator drp-1 were significantly upregulated upon cobalt exposure, concomitant with mitochondrial fragmentation, as determined by confocal microscopy. Moreover, drp-1 inhibition suppressed the cobalt chloride-induced reactive oxygen species generation, growth defects, and reduced mitochondrial fragmentation. Our novel findings suggest that the acute toxicity of cobalt is mediated by mitochondrial fragmentation and drp-1 upregulation.
AB - Excess cobalt may lead to metallosis, characterized by sensorineural hearing loss, visual, and cognitive impairment, and peripheral neuropathy. In the present study, we sought to address the molecular mechanisms of cobalt-induced neurotoxicity, using Caenorhabditis elegans as an experimental model. Exposure to cobalt chloride for 2 h significantly decreased the survival rate and lifespan in nematodes. Cobalt chloride exposure led to increased oxidative stress and upregulation of glutathione S-transferase 4. Consistently, its upstream regulator skn-1, a mammalian homolog of the nuclear factor erythroid 2-related factor 2, was activated. Among the mRNAs examined by quantitative real-time polymerase chain reactions, apoptotic activator egl-1, proapoptotic gene ced-9, autophagic (bec-1 and lgg-1), and mitochondrial fission regulator drp-1 were significantly upregulated upon cobalt exposure, concomitant with mitochondrial fragmentation, as determined by confocal microscopy. Moreover, drp-1 inhibition suppressed the cobalt chloride-induced reactive oxygen species generation, growth defects, and reduced mitochondrial fragmentation. Our novel findings suggest that the acute toxicity of cobalt is mediated by mitochondrial fragmentation and drp-1 upregulation.
KW - Cobalt
KW - Drp-1
KW - Mitochondria fragmentation
KW - Oxidative stress
KW - Toxicity
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U2 - 10.1093/toxsci/kfaa105
DO - 10.1093/toxsci/kfaa105
M3 - Article
C2 - 32617571
AN - SCOPUS:85091127172
SN - 1096-6080
VL - 177
SP - 158
EP - 167
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
ER -