Histone deacetylase 8 protects human proximal tubular epithelial cells from
hypoxia-mimetic cobalt- and hypoxia/reoxygenation-induced mitochondrial fission
and cytotoxicity
#MMPMID30054507
Ha SD
; Solomon O
; Akbari M
; Sener A
; Kim SO
Sci Rep
2018[Jul]; 8
(1
): 11332
PMID30054507
show ga
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.
free
free
free
