Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6

Kamemura, Kazuo; Ogawa, Masamichi; Ohkubo, Saki; Ohtsuka, Yasuhiro; Shitara, Yu; Komiya, Tohru; Maeda, Satoko; Ito, Akihiro; Yoshida, Minoru

doi:10.1016/j.febslet.2012.03.060

Cited by 25 publications

(22 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This finding is in keeping with a previous study that showed that an HDAC6 inhibitor improved survival and reduced bacteremia in a murine sepsis model (35). Moreover, previous studies have linked HDAC6 to the control of mitochondrial function (43,44), and a very recent study reported that HDAC6 inhibition disrupted mitochondrial membrane potential and enhanced ROS production in melanoma cells (45). Collectively, these studies suggest that HDAC6 may have a regulatory role in controlling mitoROS production in infected macrophages such that inhibition of HDAC6 increases mitoROS concentrations to facilitate bacterial clearance.…”

Section: Discussionsupporting

confidence: 92%

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Ariffin

Gupta

Kapétanovic

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Broad-spectrum histone deacetylase inhibitors (HDACi) are used clinically as anticancer agents, and more isoform-selective HDACi have been sought to modulate other conditions, including chronic inflammatory diseases. Mouse studies suggest that HDACi downregulate immune responses and may compromise host defense. However, their effects on human macrophage antimicrobial responses are largely unknown. Here, we show that overnight pretreatment of human macrophages with HDACi prior to challenge with Salmonella enterica serovar Typhimurium or Escherichia coli results in significantly reduced intramacrophage bacterial loads, which likely reflect the fact that this treatment regime impairs phagocytosis. In contrast, cotreatment of human macrophages with HDACi at the time of bacterial challenge did not impair phagocytosis; instead, HDACi cotreatment actually promoted clearance of intracellular S. Typhimurium and E. coli. Mechanistically, treatment of human macrophages with HDACi at the time of bacterial infection enhanced mitochondrial reactive oxygen species generation by these cells. The capacity of HDACi to promote the clearance of intracellular bacteria from human macrophages was abrogated when cells were pretreated with MitoTracker Red CMXRos, which perturbs mitochondrial function. The HDAC6-selective inhibitor tubastatin A promoted bacterial clearance from human macrophages, whereas the class I HDAC inhibitor MS-275, which inhibits HDAC1 to -3, had no effect on intracellular bacterial loads. These data are consistent with HDAC6 and/or related HDACs constraining mitochondrial reactive oxygen species production from human macrophages during bacterial challenge. Our findings suggest that, whereas long-term HDACi treatment regimes may potentially compromise host defense, selective HDAC inhibitors may have applications in treating acute bacterial infections.

show abstract

Section: Discussionsupporting

confidence: 92%

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Ariffin

Gupta

Kapétanovic

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…We next investigated whether the fusion status affects mitochondrial activity. HDAC6 KO MEFs showed lower basal oxygen consumption in normal medium, consistent with a recent report (Kamemura et al, 2012). However, in response to glucose starvation, oxygen consumption in HDAC6 KO MEFs eventually elevated to a level comparable to that in wild-type MEFs (Fig.…”

Section: Mitochondrial Fusion Reduces Mitochondrial Ros Under Glucosesupporting

confidence: 91%

MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria

Lee

Kapur

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

Fasting and glucose shortage activate a metabolic switch that shifts more energy production to mitochondria. This metabolic adaptation ensures energy supply, but also elevates the risk of mitochondrial oxidative damage. Here, we present evidence that metabolically challenged mitochondria undergo active fusion to suppress oxidative stress. In response to glucose starvation, mitofusin 1 (MFN1) becomes associated with the protein deacetylase HDAC6. This interaction leads to MFN1 deacetylation and activation, promoting mitochondrial fusion. Deficiency in HDAC6 or MFN1 prevents mitochondrial fusion induced by glucose deprivation. Unexpectedly, failure to undergo fusion does not acutely affect mitochondrial adaptive energy production; instead, it causes excessive production of mitochondrial reactive oxygen species and oxidative damage, a defect suppressed by an acetylationresistant MFN1 mutant. In mice subjected to fasting, skeletal muscle mitochondria undergo dramatic fusion. Remarkably, fasting-induced mitochondrial fusion is abrogated in HDAC6-knockout mice, resulting in extensive mitochondrial degeneration. These findings show that adaptive mitochondrial fusion protects metabolically challenged mitochondria.

show abstract

“…The enzyme can be found in the cytoplasm as well as in the nucleus of cells, depending on the differentiation status (42). In the cytosol, many substrates and interacting proteins have been described, including cortactin, Hsp90, and peroxiredoxins (43)(44)(45)(46)(47)(48)(49). One of the most prominent and best characterized protein substrate is the a-subunit of tubulin (8,50), through which the enzyme regulates microtubule dynamics and vesicular transport (51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway

Dhanyamraju

Holz

Finkernagel

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Uncontrolled Hedgehog (Hh) signaling is the cause of several malignancies, including the pediatric cancer medulloblastoma, a neuroectodermal tumor affecting the cerebellum. Despite the development of potent Hh pathway antagonists, medulloblastoma drug resistance is still an unresolved issue that requires the identification of novel drug targets. Following up on our observation that histone deacetylase 6 (HDAC6) expression was increased in Hh-driven medulloblastoma, we found that this enzyme is essential for full Hh pathway activation. Intriguingly, these stimulatory effects of HDAC6 are partly integrated downstream of primary cilia, a known HDAC6-regulated structure. In addition, HDAC6 is also required for the complete repression of basal Hh target gene expression. These contrasting effects are mediated by HDAC6 0 s impact on Gli2 mRNA and GLI3 protein expression. As a result of this complex interaction with Hh signaling, global transcriptome analysis revealed that HDAC6 regulates only a subset of Smoothened-and Gli-driven genes, including all well-established Hh targets such as Ptch1 or Gli1. Importantly, medulloblastoma cell survival was severely compromised by HDAC6 inhibition in vitro and pharmacologic HDAC6 blockade strongly reduced tumor growth in an in vivo allograft model. In summary, our data describe an important role for HDAC6 in regulating the mammalian Hh pathway and encourage further studies focusing on HDAC6 as a novel drug target in medulloblastoma.

show abstract

Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6

Cited by 25 publications

References 25 publications

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria

Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway

Contact Info

Product

Resources

About