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

• Published in: Scientific reports 2018-07, Vol.8 (1), p.11332-13, Article 11332
• Main Authors: Ha, Soon-Duck, Solomon, Ori, Akbari, Masoud, Sener, Alp, Kim, Sung Ouk
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/31; 13/44; 13/89; 14/34; 14/63; 38; 38/77; 42; 631/80/82; 64; 692/308/153; 82; 96; Acetylation; Apoptosis; Benzamides - pharmacology; Cell death; Cell Death - drug effects; Cell Hypoxia - drug effects; Cell Line; Cobalt; Cobalt - toxicity; Cytochrome c; Cytoplasm; Cytoprotection - drug effects; Cytotoxicity; Dynamin; Dynamins; Epithelial cells; Gene Expression Regulation - drug effects; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Histone deacetylase; Histone Deacetylases - metabolism; Histone H3; Histones - metabolism; Humanities and Social Sciences; Humans; Hypoxia; Isoforms; Kidney Tubules, Proximal - pathology; Lysine; Lysine - metabolism; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondrial Dynamics - drug effects; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - metabolism; Mortality; multidisciplinary; Oxygen - pharmacology; Phenylthiourea - analogs & derivatives; Phenylthiourea - pharmacology; Promoter Regions, Genetic - genetics; Quinazolinones - pharmacology; Repressor Proteins - metabolism; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-29463-x

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.