ZnT6-mediated Zn Redistribution: Impact on Mitochondrial Fission and Autophagy in H9c2 Cells

Overview

Journal Mol Cell Biochem

Publisher Springer

Specialty Biochemistry

Date 2025 Mar 15

PMID 40087209

Authors

Erkan Tuncay

Yusuf Olgar

Leila Aryan

Suatnur Sik

Deniz Billur

Belma Turan

Affiliations

Soon will be listed here.

Abstract

Cytosolic free Zn⁺ level ([Zn⁺]) is tightly regulated by Zn⁺ transporters, under both physiological and pathological conditions. At the cellular level, dysregulated free Zn⁺ levels have been linked to metabolic and cardiovascular diseases, primarily through their association with various Zn⁺ 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⁺ 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⁺ level ([Zn⁺]) with a significant reduction in [Zn⁺], 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⁺ 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.

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