Histone deacetylase inhibitors induce mitochondrial elongation

Abstract

Although various stimuli-inducing cell demise are known to alter mitochondrial morphology, it is currently debated whether alteration of mitochondrial morphology is per se responsible for apoptosis execution or prevention. This study was undertaken to examine the effect of histone deacetylase (HDAC) inhibitors on mitochondrial fusion-fission equilibrium. The mechanism underlying HDAC inhibitor-induced alteration of mitochondrial morphology was examined in various cells including primary cultured cells and untransformed and cancer cell lines treated with seven different HDAC inhibitors. Suberoylanilide hydroxamic acid (SAHA)-induced mitochondrial elongation in both Hep3B and Bcl-2-overexpressing Hep3B cells, apart from its apoptosis induction function. SAHA significantly decreased the expression of mitochondrial fission protein Fis1 and reduced the translocation of Drp1 to the mitochondria. Fis1 overexpression attenuated SAHA-induced mitochondrial elongation. In addition, depletion of mitochondrial fusion proteins, Mfn1 or Opa1, by RNA interference also attenuated SAHA-induced mitochondrial elongation. All of the HDAC inhibitors we examined induced mitochondrial elongation in all the cell types tested at both subtoxic and toxic concentrations. These results indicate that HDAC inhibitors induce mitochondrial elongation, irrespective of the induction of apoptosis, which may be linked to alterations of mitochondrial dynamics regulated by mitochondrial morphology-regulating proteins. Since mitochondria have recently emerged as attractive targets for cancer therapy, our findings that HDAC inhibitors altered mitochondrial morphology may support the rationale for these agents as novel therapeutic approaches against cancer. Further, the present study may provide insight into a valuable experimental strategy for simple manipulation of mitochondrial morphology.

Targeted inhibition of mitochondrial Hsp90 induces mitochondrial elongation in Hep3B hepatocellular carcinoma cells undergoing apoptosis by increasing the ROS level

“…However, some studies showed that apoptosis-inducing agents could result in mitochondrial elongation. A previous study reported that HDAC inhibitors, which induce apoptosis, caused mitochondrial elongation in various cells in addition to inducing apoptosis (24). Our data suggest that G-TPP induces mitochondrial elongation by reducing and inactivating the mitochondrial fission-regulating protein Drp1 and increasing the ROS level.…”

TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB–Dependent Activation of OPA1 Expression

“… 76 Histone deacetylase inhibitors have previously been reported to promote mitochondrial fusion, which can be abolished by either OPA1 or Mfn1 downregulation. 78 , 79 Thus, we could not totally exclude the possibility that histone deacetylase inhibitors played a role in modulating Stat3 acetylation levels in our study; nevertheless, our data strongly supported the idea that Stat3 acetylation and RelA play key roles in upregulating OPA1 expression and thus improving mitochondrial dynamics.…”

MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria

“…It is also worth noting that HDAC inhibitors have been shown to increase mitochondrial fusion under non-stressed conditions. However, this activity is independent of HDAC6 and involves down-modulation of DRP1 (Lee et al, 2012;Tailor et al, 2013).…”