This review delves into the mechanisms of heavy metal toxicity, specifically focusing on the role of mitochondrial oxidative stress in inducing apoptosis. Previous research on heavy metal toxicity largely centered on isolated mitochondria. However, this review emphasizes the need to shift focus towards investigating various cellular systems in vitro and in vivo to gain a more comprehensive understanding of the complex interplay between heavy metals and cellular processes. The study highlights the significant role of mitochondria in the toxicity of heavy metals, with a particular emphasis on how these metals disrupt mitochondrial function and trigger apoptotic pathways. Understanding the precise mechanisms involved is critical for developing effective therapeutic strategies to mitigate the harmful effects of heavy metal exposure and prevent the development of associated diseases. The widespread use of heavy metals in industrial processes and their potential for environmental contamination underscore the importance of this research. By elucidating the intricate pathways by which heavy metals trigger cell death, this review contributes valuable insights into both the prevention and treatment of heavy metal-induced pathologies.

The review begins by summarizing past research on heavy metal toxicity, tracing the evolution of research methodologies from studies on isolated mitochondria to more recent in vitro and in vivo investigations. It examines previous findings on the effects of individual heavy metals on various cellular components and functions. This literature review provides a foundation for understanding the current state of knowledge concerning the toxic mechanisms of heavy metals and sets the stage for the review's analysis of the central role of mitochondrial oxidative stress in apoptosis induced by these metals.

The methodology employed in this review is a comprehensive analysis of existing literature related to heavy metal toxicity and mitochondrial function. The author conducted a thorough review of published research articles, focusing on studies that investigated the effects of different-valence heavy metals on cellular and mitochondrial processes, particularly apoptosis and oxidative stress. This approach involved a systematic search of relevant databases using keywords such as "heavy metals," "apoptosis," "oxidative stress," "mitochondria," and the specific names of the metals under investigation. The selected studies encompassed a range of experimental designs, including in vitro studies using isolated mitochondria and cells and in vivo studies conducted on animal models. The author critically evaluated the findings of these studies, paying particular attention to the experimental methods used, the consistency of the results across different studies, and the potential limitations of the research. The collected data on the effects of individual heavy metals on cellular and mitochondrial functions were then integrated to provide a holistic overview of the mechanisms by which heavy metals induce apoptosis and oxidative stress. The analysis pays special attention to the role of mitochondrial processes in the overall toxic response. The author then synthesizes these findings to determine common mechanistic themes and highlight any metal-specific effects. The review concludes by discussing the implications of the findings for understanding and addressing heavy metal-induced toxicity and suggests avenues for future research.

The review found that various heavy metals (Ag+, Tl+, Hg2+, Cd2+, Pb2+, Al3+, Ga3+, In3+, As3+, Sb3+, Cr6+, and U6+) induce apoptosis through a common mechanism involving mitochondrial oxidative stress. This process generally involves: (1) the disruption of mitochondrial function, leading to reduced ATP synthesis and decreased mitochondrial membrane potential; (2) an increase in the production of reactive oxygen species (ROS) and hydrogen peroxide (H2O2); (3) lipid peroxidation and the opening of the mitochondrial permeability transition pore (MPTP); (4) the release of cytochrome c into the cytoplasm, triggering caspase activation and subsequent apoptosis. However, there are notable metal-specific differences. Some metals, such as Ag+, Hg2+, Cd2+, Pb2+, As3+, and Sb3+, directly bind to thiol groups in mitochondrial respiratory complexes and the adenine nucleotide translocase, inhibiting their activity. Others, including Tl+, Al3+, Ga3+, In3+, Cr6+, and U6+, indirectly induce oxidative stress via ROS production, leading to thiol group oxidation and impairment of respiratory chain function. Thallium (Tl+) shows unique characteristics, exhibiting minimal affinity for thiol groups and not directly inducing MPTP opening in isolated mitochondria, yet still causing apoptosis in cells via increased cytoplasmic calcium. The increased toxicity of thallium compared to other metals might be due to its inability to be effectively detoxified by metallothioneins or its reversible oxidation to Tl3+ near ROS generation sites within the respiratory chain, resulting in reduced mitochondrial glutathione. The review also details the effects of each heavy metal on various cellular and mitochondrial parameters, providing specific data points from multiple studies that support the general conclusions.

The findings of this review strongly suggest that mitochondrial oxidative stress is a central mechanism underlying heavy metal-induced apoptosis. The consistent observation of mitochondrial dysfunction, ROS production, MPTP opening, and cytochrome c release across various heavy metals supports this conclusion. However, the metal-specific differences in their interactions with mitochondrial components highlight the complexities of heavy metal toxicity. While Tl+ presents a unique case with its low thiol affinity, the observed increase in cytoplasmic calcium and potential involvement in glutathione oxidation still points towards mitochondrial involvement in its toxicity. These findings are relevant to several fields including toxicology, environmental health, and medicine. Understanding the common mechanistic pathways can inform the development of therapeutic strategies targeting mitochondrial dysfunction to reduce the overall toxicity of heavy metals. The identification of metal-specific differences also allows for targeted interventions based on the specific metal involved. The review underscores the importance of further research into the interaction between heavy metals and cellular components, particularly the impact on mitochondrial function and redox state.

This review demonstrates that mitochondrial oxidative stress is a pivotal factor in apoptosis triggered by various heavy metals. While common pathways exist, specific mechanisms vary depending on the metal. Further research should explore metal-specific therapeutic targets and explore the complex interaction between different heavy metals in co-exposure scenarios to better understand and mitigate heavy metal toxicity. The development of more effective chelation therapies and strategies for enhancing cellular antioxidant defenses represent promising avenues for future research.

This review is limited to the currently available literature and may not encompass all published research on the topic of heavy metal toxicity and mitochondrial function. Future research may reveal more detailed insights and metal-specific variations in the complex mechanism of heavy metal toxicity. The review primarily relies on in vitro studies, while in vivo data is also presented, the extrapolation of in vitro findings to in vivo conditions requires caution due to differences in physiological factors and the complex systemic response of the organism.