TMEM14A inhibits N-(4-hydroxyphenyl)retinamide-induced apoptosis through the stabilization of mitochondrial membrane potential

Woo, Im Sun; Jin, Hana; Kang, Eun Sil; Kim, Hye Jung; Lee, Jae Heun; Chang, Ki Churl; Park, Jae Yong; Choi, Wan Sung; Seo, Han Geuk

doi:10.1016/j.canlet.2011.05.031

Cited by 31 publications

(25 citation statements)

References 24 publications

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“…However, this work was done on isolated mitochondria. Other reports suggest that the regulation of mitochondrial potential can also be independent of ROS (27). To confirm the increase in mitochondrial potential in isoprenoid-deficient monocytes, we used a different probe, TMRM.…”

Section: Resultsmentioning

confidence: 99%

Defects in Mitochondrial Clearance Predispose Human Monocytes to Interleukin-1β Hypersecretion

Burgh

Nijhuis

Pervolaraki

et al. 2014

Journal of Biological Chemistry

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Background: Periodic fever syndromes are caused by deregulation of interleukin-1␤ release. Results: Defective autophagy leads to accumulation of damaged mitochondria in monocytes. Conclusion: Mitochondrial components in the cytosol cause priming of monocytes for interleukin-1␤ release. Significance: The molecular mechanism behind deregulated cytokine secretion provides new clues for intervention.Most hereditary periodic fever syndromes are mediated by deregulated IL-1␤ secretion. The generation of mature IL-1␤ requires two signals: one that induces synthesis of inflammasome components and substrates and a second that activates inflammasomes. The mechanisms that mediate autoinflammation in mevalonate kinase deficiency, a periodic fever disease characterized by a block in isoprenoid biosynthesis, are poorly understood. In studying the effects of isoprenoid shortage on IL-1 ␤ generation, we identified a new inflammasome activation signal that originates from defects in autophagy. We find that hypersecretion of IL-1␤ and IL-18 requires reactive oxygen species and is associated with an oxidized redox status of monocytes but not lymphocytes. IL-1␤ hypersecretion by monocytes involves decreased mitochondrial stability, release of mitochondrial content into the cytosol and attenuated autophagosomal degradation. Defective autophagy, as established by ATG7 knockdown, results in prolonged cytosolic retention of damaged mitochondria and increased IL-1␤ secretion. Finally, activation of autophagy in healthy but not mevalonate kinase deficiency patient cells reduces IL-1␤ secretion. Together, these results indicate that defective autophagy can prime monocytes for mitochondria-mediated NLRP3 inflammasome activation, thereby contributing to hypersecretion of IL-1␤ in mevalonate kinase deficiency.Periodic fever syndromes are characterized by inflammation that occurs in the absence of apparent infection or high titer autoantibodies (1, 2). In most periodic fever syndromes, the generalized inflammation is driven by IL-1␤ generated through proteolytic cleavage by the NLRP3 inflammasome. An additional feature associated with inflammation is the production of reactive oxygen species (ROS) 3 (3, 4). During infection, ROS produced by NADPH-oxidase subunits at the plasma membrane are beneficial because ROS in phagosomes contribute to the killing of intracellular pathogens (5). In several inflammatory diseases, including periodic fever syndromes, ROS levels are increased in the cytosol and contribute to pathology (6). ROS play roles as intracellular second messengers and have immediate effects on the intracellular redox status. In TNF receptor 1-associated periodic syndrome (TRAPS), for example, mitochondria-derived ROS facilitate inflammatory cytokine production (7). Mitochondria are believed to be the main source of ROS in several autoinflammatory disorders (8).ROS are normally generated within mitochondria as byproducts of oxidative phosphorylation, but when liberated in the cytosol ROS can facilitate activation of the NLRP3 inflammas...

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Section: Resultsmentioning

confidence: 99%

Defects in Mitochondrial Clearance Predispose Human Monocytes to Interleukin-1β Hypersecretion

Burgh

Nijhuis

Pervolaraki

et al. 2014

Journal of Biological Chemistry

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“…Whereas TMEM14C was identified to coexpress with the core machinery of heme biosynthesis and its knockdown causes anemia in zebrafish [12], TMEM14A was described to stabilize mitochondrial membrane potential and thereby inhibit apoptosis in a yeast system [13]. However, their exact biological function is still unknown.…”

Section: Discussionmentioning

confidence: 99%

FAX1, a Novel Membrane Protein Mediating Plastid Fatty Acid Export

et al. 2015

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Fatty acid synthesis in plants occurs in plastids, and thus, export for subsequent acyl editing and lipid assembly in the cytosol and endoplasmatic reticulum is required. Yet, the transport mechanism for plastid fatty acids still remains enigmatic. We isolated FAX1 (fatty acid export 1), a novel protein, which inserts into the chloroplast inner envelope by α-helical membrane-spanning domains. Detailed phenotypic and ultrastructural analyses of FAX1 mutants in Arabidopsis thaliana showed that FAX1 function is crucial for biomass production, male fertility and synthesis of fatty acid-derived compounds such as lipids, ketone waxes, or pollen cell wall material. Determination of lipid, fatty acid, and wax contents by mass spectrometry revealed that endoplasmatic reticulum (ER)-derived lipids decreased when FAX1 was missing, but levels of several plastid-produced species increased. FAX1 over-expressing lines showed the opposite behavior, including a pronounced increase of triacyglycerol oils in flowers and leaves. Furthermore, the cuticular layer of stems from fax1 knockout lines was specifically reduced in C29 ketone wax compounds. Differential gene expression in FAX1 mutants as determined by DNA microarray analysis confirmed phenotypes and metabolic imbalances. Since in yeast FAX1 could complement for fatty acid transport, we concluded that FAX1 mediates fatty acid export from plastids. In vertebrates, FAX1 relatives are structurally related, mitochondrial membrane proteins of so-far unknown function. Therefore, this protein family might represent a powerful tool not only to increase lipid/biofuel production in plants but also to explore novel transport systems involved in vertebrate fatty acid and lipid metabolism.

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“…TMEM14A has been shown to play a functional role in the suppression of apoptosis by inhibiting the pro-apoptotic protein Bax and by regulating mitochondrial membrane potential [18]. TMEM14A may also play a role in the regulation of planar cell polarity by trafficking planar cell polarity proteins to the membrane including VANGL2 [19], a protein that promotes migration and invasion in human cancer cells [20].…”

Section: Resultsmentioning

confidence: 99%

Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

Penrod

Moore

2014

BMC Systems Biology

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BackgroundThe demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets.ResultsWe use this approach to prioritize genes as drug target candidates in a set of ER + breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER + breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process.ConclusionsInfluence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use.

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TMEM14A inhibits N-(4-hydroxyphenyl)retinamide-induced apoptosis through the stabilization of mitochondrial membrane potential

Cited by 31 publications

References 24 publications

Defects in Mitochondrial Clearance Predispose Human Monocytes to Interleukin-1β Hypersecretion

Defects in Mitochondrial Clearance Predispose Human Monocytes to Interleukin-1β Hypersecretion

FAX1, a Novel Membrane Protein Mediating Plastid Fatty Acid Export

Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

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