Identification of novel modulators of mitochondrial function by a genome-wide RNAi screen in <i>Drosophila melanogaster</i>

Chen, Jian; Shi, Xiaoying; Padmanabhan, Ranjani; Wang, Qiong; Wu, Zhidan; Stevenson, Susan C.; Hild, Marc; Garza, Dan; Li, Hao

doi:10.1101/gr.6940108

Cited by 57 publications

(44 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

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: 81%

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: 81%

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

“…It has been proposed that mitochondria contain two of the cAMP effectors, EPAC and PKA (Schwoch et al, 1990; Sardanelli et al, 2006; Chen et al, 2008). EPAC appears to localize to the mitochondria in a cell cycle-dependent manner; however, its precise submitochondrial localization and its actions are still unknown (Qiao et al, 2002).…”

Section: Cyclic Amp Microdomainsmentioning

confidence: 99%

cAMP signaling in subcellular compartments

Lefkimmiatis

Zaccolo

2014

Pharmacology & Therapeutics

172

149

View full text Add to dashboard Cite

In the complex microcosm of a cell, information security and its faithful transmission are critical for maintaining internal stability. To achieve a coordinated response of all its parts to any stimulus the cell must protect the information received from potentially confounding signals. Physical segregation of the information transmission chain ensures that only the entities able to perform the encoded task have access to the relevant information. The cAMP intracellular signaling pathway is an important system for signal transmission responsible for the ancestral ‘flight or fight’ response and involved in the control of critical functions including frequency and strength of heart contraction, energy metabolism and gene transcription. It is becoming increasingly apparent that the cAMP signaling pathway uses compartmentalization as a strategy for coordinating the large number of key cellular functions under its control. Spatial confinement allows the formation of cAMP signaling “hot spots” at discrete subcellular domains in response to specific stimuli, bringing the information in proximity to the relevant effectors and their recipients, thus achieving specificity of action. In this report we discuss how the different constituents of the cAMP pathway are targeted and participate in the formation of cAMP compartmentalized signaling events. We illustrate a few examples of localized cAMP signaling, with a particular focus on the nucleus, the sarcoplasmic reticulum and the mitochondria. Finally, we discuss the therapeutic potential of interventions designed to perturb specific cAMP cascades locally.

show abstract

“…In the ovary, they both localize to NC and oocyte plasma membranes and to the inner rim of the ring canals (Dodson et al, 1998;Takahashi et al, 2005). Notably, SPOON/Yu (CG3249) and src42A were recently picked up in a genomewide iRNA screen for modulators of mitochondrial function (Chen et al, 2008), suggesting that they may fulfill roles similar to those of their mammalian counterparts.…”

Section: Functions Of Mitochondrial Src/ptpd1 Complexmentioning

confidence: 96%

Drosophila spoonbill encodes a dual-specificity A-kinase anchor protein essential for oogenesis

Hadad

Bresler-Musikant

Neuman-Silberberg

2011

Mechanisms of Development

View full text Add to dashboard Cite

spoonbill is a Drosophila female-sterile mutation, which interferes with normal egg patterning during oogenesis. Previous analyzes linked the mutation to a number of seemingly unrelated pathways, including GRK/EGFR and DPP, two major pathways essential for Drosophila and vertebrate development. Further work suggested that spoonbill may also function in actin polymerization and border-cell migration. Here we describe the molecular cloning of the spoonbill gene and characterize new mutant alleles, further demonstrating that spoonbill's function is essential during oogenesis. We found spoonbill to be allelic to CG3249 (also known as yu), which encodes the only known dual-specificity A-kinase anchor protein in Drosophila. Our data indicate that similar to mammalian AKAPs, Spoonbill protein contains a number of potential kinase and phosphatase binding motifs, and is targeted, in the ovary, to mitochondria and Golgi. Finally, we address some of spoonbill's mutant phenotypes from the perspective of the published data on the AKAP protein family.

show abstract

Identification of novel modulators of mitochondrial function by a genome-wide RNAi screen in Drosophila melanogaster

Cited by 57 publications

References 87 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

cAMP signaling in subcellular compartments

Drosophila spoonbill encodes a dual-specificity A-kinase anchor protein essential for oogenesis

Contact Info

Product

Resources

About