Scholarlink

<p>Cytosolic free Zn<sup>2</sup>⁺ level ([Zn<sup>2</sup>⁺]<sub>Cyt</sub>) is tightly regulated by Zn<sup>2</sup>⁺ transporters, under both physiological and pathological conditions. At the cellular level, dysregulated free Zn<sup>2</sup>⁺ levels have been linked to metabolic and cardiovascular diseases, primarily through their association with various Zn<sup>2</sup>⁺ transporters. However, the role and localization of ZnT6 in cardiomyocytes remain unclear. Previous studies have shown a significant increase in ZnT6 expression in insulin-resistant cardiomyocytes, suggesting a potential link between ZnT6 dysregulation and cardiac cell dysfunction. Therefore, here, we investigated the impact of ZnT6 overexpression (ZnT6-OE) on cellular Zn<sup>2</sup>⁺ distribution, mitochondrial dynamics, and autophagy-induced apoptosis in H9c2 cardiomyocytes. Using confocal imaging, biochemical assays, and electron microscopy, we demonstrated the mitochondrial localization of ZnT6 and its role in H9c2 cells. Our findings showed that ZnT6 overexpression led to a significant increase in mitochondrial free Zn<sup>2</sup>⁺ level ([Zn<sup>2</sup>⁺]<sub>Mit</sub>) with a significant reduction in [Zn<sup>2</sup>⁺]<sub>Cyt</sub>, which seems to be associated with enhanced numbers of mitochondria and mitochondrial fission process. Specifically, the ZnT6-OE cells exhibited increased dynamin-related protein 1 (DRP1) translocation to mitochondria which is an indication of excessive fission activity. We also determined severe mitochondrial dysfunction in ZnT6-OE cells, such as depolarization in mitochondrial membrane potential, production of excessive reactive oxygen species (ROS), reduced ATP levels, and autophagosome accumulation. Furthermore, these impairments were accompanied by elevated apoptotic markers, indicating autophagy-induced apoptosis. Our findings highlight ZnT6 as a critical regulator of mitochondrial dynamics and function in cardiomyocytes, contributing to disruption Zn<sup>2</sup>⁺ homeostasis by its overexpression, triggering excessive DRP1-mediated mitochondrial fission and leading to mitochondrial dysfunction, oxidative stress, and apoptotic cell death, suggesting an important impact of ZnT6 dysregulation on cardiomyocyte pathophysiology in metabolic disorders.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

ZnT6-mediated Zn2+ redistribution: impact on mitochondrial fission and autophagy in H9c2 cells

  • 期刊论文

  • 发表日期：

    2025年3月14日

查看全文
  • Erkan Tuncay,
  • Yusuf Olgar,
  • Leila Aryan,
  • Suatnur Şık,
  • Deniz Billur,
  • Belma Turan

摘要

Cytosolic free Zn2⁺ level ([Zn2⁺]Cyt) is tightly regulated by Zn2⁺ transporters, under both physiological and pathological conditions. At the cellular level, dysregulated free Zn2⁺ levels have been linked to metabolic and cardiovascular diseases, primarily through their association with various Zn2⁺ transporters. However, the role and localization of ZnT6 in cardiomyocytes remain unclear. Previous studies have shown a significant increase in ZnT6 expression in insulin-resistant cardiomyocytes, suggesting a potential link between ZnT6 dysregulation and cardiac cell dysfunction. Therefore, here, we investigated the impact of ZnT6 overexpression (ZnT6-OE) on cellular Zn2⁺ distribution, mitochondrial dynamics, and autophagy-induced apoptosis in H9c2 cardiomyocytes. Using confocal imaging, biochemical assays, and electron microscopy, we demonstrated the mitochondrial localization of ZnT6 and its role in H9c2 cells. Our findings showed that ZnT6 overexpression led to a significant increase in mitochondrial free Zn2⁺ level ([Zn2⁺]Mit) with a significant reduction in [Zn2⁺]Cyt, which seems to be associated with enhanced numbers of mitochondria and mitochondrial fission process. Specifically, the ZnT6-OE cells exhibited increased dynamin-related protein 1 (DRP1) translocation to mitochondria which is an indication of excessive fission activity. We also determined severe mitochondrial dysfunction in ZnT6-OE cells, such as depolarization in mitochondrial membrane potential, production of excessive reactive oxygen species (ROS), reduced ATP levels, and autophagosome accumulation. Furthermore, these impairments were accompanied by elevated apoptotic markers, indicating autophagy-induced apoptosis. Our findings highlight ZnT6 as a critical regulator of mitochondrial dynamics and function in cardiomyocytes, contributing to disruption Zn2⁺ homeostasis by its overexpression, triggering excessive DRP1-mediated mitochondrial fission and leading to mitochondrial dysfunction, oxidative stress, and apoptotic cell death, suggesting an important impact of ZnT6 dysregulation on cardiomyocyte pathophysiology in metabolic disorders.