Title

Histone deacetylase 8 protects human proximal tubular epithelial cells from hypoxia-mimetic cobalt- and hypoxia/reoxygenation-induced mitochondrial fission and cytotoxicity

Authors

Soon-Duck Ha, Department of Microbiology & Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario
Ori Solomon, Department of Microbiology & Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario
Masoud Akbari, Department of Microbiology & Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario & Department of Surgery, Schulich School of Medicine & Dentistry, University of Western Ontario
Alp Sener, Department of Microbiology & Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario & Department of Surgery, Schulich School of Medicine & Dentistry, University of Western Ontario
Sung Ouk Kim, Department of Microbiology & Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario

Document Type

Article

Publication Date

7-27-2018

Journal

Scientific Reports

Volume

8

URL with Digital Object Identifier

https://doi.org/10.1038/s41598-018-29463-x

Abstract

Cell death by hypoxia followed by reoxygenation (H/R) is responsible for tissue injury in multiple pathological conditions. Recent studies found that epigenetic reprogramming mediated by histone deacetylases (HDACs) is implicated in H/R-induced cell death. However, among 18 different isoforms comprising 4 classes (I-IV), the role of each HDAC in cell death is largely unknown. This study examined the role of HDAC8, which is the most distinct isoform of class I, in the hypoxia mimetic cobalt- and H/R-induced cytotoxicity of human proximal tubular HK-2 cells. Using the HDAC8-specific activator TM-2-51 (TM) and inhibitor PCI34051, we found that HDAC8 played a protective role in cytotoxicity. TM or overexpression of wild-type HDAC8, but not a deacetylase-defective HDAC8 mutant, prevented mitochondrial fission, loss of mitochondrial transmembrane potential and release of cytochrome C into the cytoplasm. TM suppressed expression of dynamin-related protein 1 (DRP1) which is a key factor required for mitochondrial fission. Suppression of DRP1 by HDAC8 was likely mediated by decreasing the level of acetylated histone H3 lysine 27 (a hallmark of active promoters) at the DRP1 promoter. Collectively, this study shows that HDAC8 inhibits cytotoxicity induced by cobalt and H/R, in part, through suppressing DRP1 expression and mitochondrial fission.

Notes

Histone deacetylase 8 protects human proximal tubular epithelial cells from hypoxia-mimetic cobalt- and hypoxia/reoxygenation-induced mitochondrial fission and cytotoxicity

Soon-Duck Ha et al

Scientific Reports

Springer Nature

Jul 27, 2018

Copyright © 2018, Springer Nature

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.