Cadmium induced Drp1-dependent mitochondrial fragmentation by disturbing calcium homeostasis in its hepatotoxicity

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.

Apelin Attenuates Oxidative Stress in Human Adipocytes

“…Mitochondria morphology in live adipocytes can be resolved by confocal microscopy using the specific mitochondriastaining dye (MitoTracker) (51)(52)(53). As shown in Fig.…”

Retraction: Protective effect of SENP3-mediated SUMOylation against cadmium toxicity

“…Chronic exposure to cadmium leads to accumulation in various tissues and resultant toxicity. In particular, cadmium promotes mitochondrial dysfunction (Xu et al, 2013) and can promote mitochondrial-dependent apoptosis (Adiele et al, 2011). More specifi cally, cadmium inhibits the electron transport chain complexes, resulting in mitochondrial uncoupling via mitochondrial permeability transition and increased generation of ROS (Templeton and Liu, 2010) and oxidative stress (Adiele et al, 2011;Onukwufor et al, 2014).…”

“…Chronic exposure waste. Chronic exposure umulation in various tissues and tion in various ti particular, cadmium promotes mit cadmium promote ion (Xu et al, 2013) There ar There ar mamma m for th for t ty ty PERK and the lysosomal enzyme cathepsin B. A key target for SENP3-mediated deSUMOylation is the GTPase Drp1, which plays a major role in regulating mitochondrial morphology and integrity (Zungu et al, 2011).…”

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

“…These data indicate that uptake of calcium into the mitochondrial matrix and the opening of the mPTP plays a critical role in the mitochondrial morphology defects observed in sel-12 mutants. Furthermore, ER-mediated calcium release and subsequent mitochondrial calcium uptake can impact the activity of Drp1, a mitochondrial fission protein (Cribbs and Strack 2007;Cereghetti et al 2008;Xu et al 2013). To determine whether DRP-1 is involved in the increased mitochondrial fragmentation observed in sel-12 mutants, we used RNAi to knock down DRP-1 and examined mitochondrial morphology in both wild-type and sel-12(ty11) animals.…”