Mitochondrial Oxidative Stress Is the General Reason for Apoptosis Induced by Different-Valence Heavy Metals in Cells and Mitochondria

Abstract

This review analyzes the causes and consequences of apoptosis resulting from oxidative stress that occurs in mitochondria and cells exposed to the toxic effects of different-valence heavy metals (Ag+, Tl+, Hg2+, Cd2+, Pb2+, Al3+, Ga3+, In3+, As3+, Sb3+, Cr6+, and U6+). The problems of the relationship between the integration of these toxic metals into molecular mechanisms with the subsequent development of pathophysiological processes and the appearance of diseases caused by the accumulation of these metals in the body are also addressed in this review. Such apoptosis is characterized by a reduction in cell viability, the activation of caspase-3 and caspase-9, the expression of pro-apoptotic genes (Bax and Bcl-2), and the activation of protein kinases (ERK, JNK, p53, and p38) by mitogens. Moreover, the oxidative stress manifests as the mitochondrial permeability transition pore (MPTP) opening, mitochondrial swelling, an increase in the production of reactive oxygen species (ROS) and H2O2, lipid peroxidation, cytochrome c release, a decline in the inner mitochondrial membrane potential (ΔΨmito), a decrease in ATP synthesis, and reduced glutathione and oxygen consumption as well as cytoplasm and matrix calcium overload due to Ca2+ release from the endoplasmic reticulum (ER). The apoptosis and respiratory dysfunction induced by these metals are discussed regarding their interaction with cellular and mitochondrial thiol groups and Fe2+ metabolism disturbance. Similarities and differences in the toxic effects of Tl+ from those of other heavy metals under review are discussed. Similarities may be due to the increase in the cytoplasmic calcium concentration induced by Tl+ and these metals. One difference discussed is the failure to decrease Tl+ toxicity through metallothionein-dependent mechanisms. Another difference could be the decrease in reduced glutathione in the matrix due to the reversible oxidation of Tl+ to Tl3+ near the centers of ROS generation in the respiratory chain. The latter may explain why thallium toxicity to humans turned out to be higher than the toxicity of mercury, lead, cadmium, copper, and zinc.

Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement

“…Further, annexin/propidium iodide staining evaluated with FACS analysis indicates a strong increase in both early and late apoptosis upon miconazole 30 µM treatment for 24 h. Under this respect, differences between A375 and SK-MEL-28 may depend on their different growth kinetics. A mitochondrial-dependent apoptosis mediated by caspase3/7 is well known in several pathogenic setups [63][64][65][66], further supporting the role mitochondria play in the antiproliferative effects reported in the present study. Therefore, the collected evidences indicate that miconazole induces apoptosis in melanoma, likely via an early mitochondria disregulation evident at 6 h treatment.…”

Delivery of dental pulp stem cells by an injectable ROS-responsive hydrogel promotes temporomandibular joint cartilage repair via enhancing anti-apoptosis and regulating microenvironment

“…The activation of Cleaved caspase3 serves as a definitive indicator of apoptosis, while the dysregulated equilibrium between the expression levels of anti-apoptotic protein Bcl2 and pro-apoptotic protein Bax can instigate the initiation of the caspase cascade reaction to orchestrate apoptotic processes. 58 Our study confirmed that the activation of Bax by H 2 O 2 , a pro-apoptotic protein in the Bcl2 family, antagonized the anti-apoptotic protein Bcl2, leading to the alteration of the mitochondrial outer membrane permeabilization. This process resulted in the release of cytochrome C, which then promoted apoptosome formation, triggering Caspase-3-mediated substrate degradation and ultimately inducing apoptosis.…”