Abstract
Mitochondria are critical targets in the hepatotoxicity of cadmium (Cd). Abnormal mitochondrial dynamics have been increasingly implicated in mitochondrial dysfunction in pathophysiological conditions. Therefore, our study aimed to investigate the effects and underlying mechanism of Cd on mitochondrial dynamics during hepatotoxicity. In the L02 liver cell lines, 12 μM cadmium chloride (CdCl2) exposure induced excessive mitochondrial fragmentation as early as 3 h post-treatment with Cd, which preceded the mitochondrial dysfunction such as reactive oxygen species (ROS) overproduction, mitochondrial membrane potential (ΔΨm) loss and ATP reduction. Concurrent to mitochondrial fragmentation, CdCl2 treatment increased the protein levels of dynamin-related protein (Drp1) and promoted the recruitment of Drp1 into mitochondria. Strikingly, mitochondrial fragmentation also occurred in the liver tissue of rats exposed to CdCl2, accompanied by enhanced recruitment of Drp1 into mitochondria. Moreover, in L02 cells, Drp1 silencing could effectively reverse Cd-induced mitochondrial fragmentation and mitochondrial dysfunction. Furthermore, the increased expression and mitochondrial recruitment of Drp1 were tightly related to the disturbance of calcium homeostasis, which could be prevented by both chelating [Ca2+]i and inhibiting [Ca2+]m uptake. Overall, our study indicated that Cd induced Drp1-dependent mitochondrial fragmentation by disturbing calcium homeostasis to promote hepatotoxicity. Manipulation of Drp1 may be the potential avenue for developing novel strategies to protect against cadmium-induced hepatotoxicity.
Highlights
Mitochondria have proved to be highly dynamic organelles that undergo constant fission and fusion, activities that are orchestrated by large dynamin-related GTPases.[14]
To explore the effects of Cd on mitochondrial dynamics in liver injuries, mitochondrial morphology was examined in the human normal liver cell line L02 following exposure to 12 mM cadmium chloride (CdCl2)
In addition to mitochondrial dysfunction, cell viability in the CdCl2-treated L02 cells underwent a time-dependent reduction (Figure 2d). These results indicated that mitochondrial fragmentation occurred before mitochondrial dysfunction in Cd hepatotoxicity in vitro
Summary
Mitochondria have proved to be highly dynamic organelles that undergo constant fission and fusion, activities that are orchestrated by large dynamin-related GTPases.[14]. Impairments in mitochondrial dynamics markedly contribute to mitochondrial dysfunction in various pathophysiological conditions and mitochondria-associated diseases.[15,16] Accumulating evidence has indicated that abnormal mitochondrial fission, mediated by dynamin-related protein 1 (Drp1), leads to excessive mitochondrial fragmentation, which is a common pathway that leads to mitochondrial dysfunction critical to cellular death.[17,18,19] In light of the profound impact of mitochondrial dynamics have on mitochondrial function, the present study aims to provide insight into the effects and underlying mechanism of Cd on mitochondrial dynamics in its hepatotoxicity
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