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<p>Elevated levels of heavy metals in cells lead to an imbalance of cellular redox homeostasis which is also seen in zinc and lead ion mediated toxicity. Human peroxiredoxins (<i>hPrxI</i> and <i>hPrxII</i>) are central regulators of redox balance; however, their role in mitigating heavy metal-induced stress remains unclear. Previously, we showed that the <i>Saccharomyces</i> <i>cerevisiae</i> model lacking <i>TSA1</i> and <i>TSA2</i> (<i>tsa1tsa2Δ</i>) showed growth defects in the presence of redox stressors that can be rescued by expressing <i>hPrxI</i> and <i>hPrxII</i>. In the present study, we utilized the <i>tsa1tsa2Δ</i> strain to understand the role of human homologs metal ion-induced stress. Growth assays demonstrated that ZnCl<sub>2</sub> and PbCl<sub>2</sub> markedly impaired the growth of <i>tsa1tsa2</i>Δ cells, whereas plasmid-based expression of <i>hPrxI</i> restored growth under both conditions. In contrast, <i>hPrxII</i> expression conferred protection only against ZnCl<sub>2</sub> toxicity. Measurements of intracellular reactive oxygen species (ROS) revealed significant accumulation upon ZnCl<sub>2</sub> and PbCl<sub>2</sub> exposure, which was alleviated by either <i>hPrxI</i> or <i>hPrxII</i> expression. Immunoblotting analyses indicated that <i>hPrxI</i> undergoes a monomer to dimer transition under heavy metal stress, suggesting redox-dependent structural modulation. Notably, catalytic mutants of both <i>hPrxI</i> and <i>hPrxII</i> partially restored growth and reduced ROS levels, demonstrating that their catalytic residues are not essential for conferring protection. These findings highlight isoforms specific and catalysis-independent roles of human peroxiredoxins in counteracting heavy metal-induced oxidative stress.</p>

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Deciphering the role of human peroxiredoxins for combating lead and zinc mediated cellular toxicity using a yeast model

  • 期刊论文

  • 发表日期：

    2026年5月8日

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  • Rahul Thakur,
  • Reena V. Saini,
  • Sasanka Chakrabarti,
  • Adesh K. Saini

摘要

Elevated levels of heavy metals in cells lead to an imbalance of cellular redox homeostasis which is also seen in zinc and lead ion mediated toxicity. Human peroxiredoxins (hPrxI and hPrxII) are central regulators of redox balance; however, their role in mitigating heavy metal-induced stress remains unclear. Previously, we showed that the Saccharomyces cerevisiae model lacking TSA1 and TSA2 (tsa1tsa2Δ) showed growth defects in the presence of redox stressors that can be rescued by expressing hPrxI and hPrxII. In the present study, we utilized the tsa1tsa2Δ strain to understand the role of human homologs metal ion-induced stress. Growth assays demonstrated that ZnCl2 and PbCl2 markedly impaired the growth of tsa1tsa2Δ cells, whereas plasmid-based expression of hPrxI restored growth under both conditions. In contrast, hPrxII expression conferred protection only against ZnCl2 toxicity. Measurements of intracellular reactive oxygen species (ROS) revealed significant accumulation upon ZnCl2 and PbCl2 exposure, which was alleviated by either hPrxI or hPrxII expression. Immunoblotting analyses indicated that hPrxI undergoes a monomer to dimer transition under heavy metal stress, suggesting redox-dependent structural modulation. Notably, catalytic mutants of both hPrxI and hPrxII partially restored growth and reduced ROS levels, demonstrating that their catalytic residues are not essential for conferring protection. These findings highlight isoforms specific and catalysis-independent roles of human peroxiredoxins in counteracting heavy metal-induced oxidative stress.