ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

Hong, Sung Il; Pedersen, Peter L.

doi:10.1128/mmbr.00016-08

Cited by 275 publications

(313 citation statements)

References 449 publications

(524 reference statements)

Supporting

Mentioning

302

Contrasting

Order By: Relevance

“…ATPase and reduced its intrinsic ATPase activity, leading to increased oxidative stress and increased sensitivity to respiratory inhibitors (15,16,(23)(24)(25)(26). However, the role of ATP/GDP-binding protein motif A (P-loop) in the virulence of brucellae is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Protective Property of Brucella abortuscydCandlooPMutants

Truong¹,

Cho²,

Barate³

et al. 2014

Clin. Vaccine Immunol.

View full text Add to dashboard Cite

bBrucella abortus readily multiplies in professional or nonprofessional phagocytes in vitro and is highly virulent in mice. Isogenic mutants of B. abortus biovar 1 strain IVKB9007 lacking the ATP/GDP-binding protein motif A (P-loop) (named looP; designated here the IVKB9007 looP::Tn5 mutant) and the ATP-binding/permease protein (cydC; designated here the IVKB9007 cydC::Tn5 mutant) were identified and characterized by transposon mutagenesis using the mini-Tn5Km2 transposon. Both mutants were found to be virtually incapable of intracellular replication in both murine macrophages (RAW264.7) and the HeLa cell line, and their virulence was significantly impaired in BALB/c mice. Respective complementation of the IVKB9007 looP::Tn5 and IVKB9007 cydC::Tn5 mutants restored their ability to survive in vitro and in vivo to a level comparable with that of the wild type. These findings indicate that the cydC and looP genes play important roles in the virulence of B. abortus. In addition, intraperitoneal immunization of mice with a dose of the live IVKB9007 looP::Tn5 and IVKB9007 cydC::Tn5 mutants provided a high degree of protection against challenge with pathogenic B. abortus strain 544. Both mutants should be evaluated further as a live attenuated vaccine against bovine brucellosis for their ability to stimulate a protective immune response. Brucella abortus, the causative agent of bovine brucellosis, causes abortion and reduced fertility in cattle and undulant fever in humans (1). Unlike other pathogenic bacteria, brucellae do not have classical virulence factors. A key aspect of the virulence of B. abortus is its ability to invade, survive, and proliferate within host phagocytic cells; it successfully bypasses the bactericidal activities of phagocytes and thereby establishes long-lasting chronic infections (2, 3). The B. abortus vaccine strains S19 and RB51 have been used worldwide for the prevention of brucellosis in cattle but have several drawbacks, including interference with diagnosis, residual virulence, and some pathogenicity for humans as well as cattle (4, 5). Therefore, understanding the virulence of B. abortus on a genetic level and the host response against B. abortus will provide important information for the development of a new vaccine for controlling brucellosis.Transposon mutagenesis is an extensively used approach for the identification of genes involved in the virulence of bacterial pathogens (6-8). To understand the sustained intracellular residence of brucellae in host cells, a transposon-based approach has been employed to identify genes in brucellae that are critically required for lipopolysaccharide biosynthesis, metabolic processes, stress responses, nutrient deprivation, and invasion of and survival in host cells. Mutations in these genes led to the attenuation of Brucella compared with the virulence of the parental strain; attenuation was recognized by the reduced intracellular survival and replication or rapid clearance of the mutants from both macrophages and mice (6-11). However, these atten...

show abstract

Section: Discussionmentioning

confidence: 99%

Characterization and Protective Property of Brucella abortuscydCandlooPMutants

Truong¹,

Cho²,

Barate³

et al. 2014

Clin. Vaccine Immunol.

View full text Add to dashboard Cite

show abstract

“…Other immune diseases and certain neoplastic conditions possess similar phenotypic changes that should sensitize them to the mechanism identified here (Rommel et al, 2007;Samuels et al, 2004). Such observations suggest that development of small molecule modulators of the F 0 F 1 -ATPase based on the Bz-423 pharmacophore may have broad therapeutic potential (Hong and Pedersen, 2008).…”

Section: Discussionmentioning

confidence: 96%

Apoptotic Signaling Activated by Modulation of the F₀F₁-ATPase: Implications for Selective Killing of Autoimmune Lymphocytes

Sundberg¹,

Swenson²,

Wahl³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

7-Chloro-5-(4-hydroxyphenyl)-1-methyl-3-(napthalen-2-ylmetyl)-4,5,-dihydro-1H-benzo [b][1,4]diazepin-2(3H)-one (Bz-423) is a proapoptotic 1,4-benzodiazepine that potently suppresses disease in the murine model of lupus by selectively killing pathogenic lymphocytes. In MRL/MpJ-Fas lpr (MRL-lpr) mice, Bz-423 overcomes deficient expression of the Fas death receptor and hyperactivation of antiapoptotic phosphatidylinositol 3-kinase (PI3K)-Akt signaling to specifically kill pathogenic CD4 ϩ T cells. Bz-423 binds to the oligomycin-sensitivity-conferring protein component of the mitochondrial F 0 F 1 -ATPase, which modulates the enzyme leading to formation of superoxide by the mitochondrial respiratory chain. Scavenging this reactive oxygen species blocks all subsequent components of the apoptotic cascade. To gain insight into how apoptotic signaling activated by Bz-423-induced superoxide contributes to the selective depletion of MRL-lpr CD4 ϩ T cells, we characterized the death mechanism in a CD4 ϩ T cell leukemia line (Jurkat). Although Bz-423-induced superoxide indirectly inactivates Akt, this response is not required for T cell death. Apoptosis instead results from parallel increases in levels of the proapoptotic Bcl-2 proteins Noxa and Bak leading to specific activation of Bak, mitochondrial outer membrane permeabilization, and a commitment to apoptosis. By directly up-regulating proteins that trigger loss of mitochondrial outer membrane integrity, Bz-423 bypasses defective Fas function and antiapoptotic PI3K-Akt signaling in MRL-lpr CD4 ϩ T cells. Moreover, because disease-associated abnormalities should sensitize autoreactive CD4 ϩ T cells to transcriptional up-regulation of Noxa by redox signals and to Bak-dependent apoptosis, the apoptotic mechanism elucidated in Jurkat cells provides important clues into the cell-type-and disease-selective effects of Bz-423 in MRLlpr mice.Human and murine lupus is mediated by autoreactive lymphocytes that survive abnormally and are chronically activated because of persistent stimulation with endogenous autoantigens (Hoffman, 2004;Santiago-Raber et al., 2004). Bz-423 is a proapoptotic 1,4-benzodiazepine with therapeutic properties in murine models of lupus that are linked to specific apoptosis of disease-causing lymphocytes (Blatt et al., 2002;Bednarski et al., 2003). In MRL/MpJ-Fas lpr (MRL-lpr) mice, Bz-423 selectively kills splenic CD4 ϩ T cells, which is the lymphoid subset responsible for disease in this model (Bednarski et al., 2003). Treatment is not associated with opportunistic infections, and Bz-423 does not reduce lymphocyte numbers or alter immune function in normal mice, which indicates that this agent is not globally immunosuppressive.Bz-423 binds to the oligomycin-sensitivity-conferring protein subunit of the mitochondrial F 0 F 1 -ATPase, which induces a state 3-to-state 4 respiratory transition and promotes formation of superoxide (O 2 . ) by the mitochondrial respiratory chain (Johnson et al., 2005 . , superoxide; PI, propidium iodide; PBS, phospha...

show abstract

“…The ATP synthase subunit β (34) and the cytochrome b-c1 complex subunit 1 (35) are mitochondrial proteins associated with ATP production. Consequently, both proteins (36,37) are virtually expressed in all tissues and cells, which probably would make them very unspecific markers. In addition, the two proteins are not known to be glycosylated.…”

Section: Discussionmentioning

confidence: 99%

Identification of proteins with the CDw75 epitope in human colorectal cancer

2017

View full text Add to dashboard Cite

Abstract. The CDw75 epitope is an α(2,6) sialylated antigen overexpressed in colorectal cancer (CRC), where its expression correlates with the progression of the disease. The CDw75 epitope is located mainly in N-glycoproteins, whose identity remains unknown. The aim of the present study was to identify proteins with the CDw75 epitope as a strategy to deepen the understanding of molecular pathogenesis of CRC and to identify novel biomarkers for this disease. For this purpose, a two-dimensional electrophoresis approach was employed. Protein spots in the gels were matched to the corresponding CDw75 positive spots in the immunoblotted polyvinylidene difluoride membranes, and further identification of the protein species was performed by mass spectrometry. Additionally, one-dimensional western blotting experiments were performed to verify the expression of these candidate proteins in the colorectal tissue and their coincidence in molecular mass with the CDw75-positive bands. The findings of the present study indicate that haptoglobin and the keratins 8 (K8) and 18 (K18) are proteins with the CDw75 epitope in the colorectal tissue from CRC patients and also suggest novel functions and cellular locations for these proteins in the colorectal tissue and in relation to CRC.

show abstract

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

Cited by 275 publications

References 449 publications

Characterization and Protective Property of Brucella abortuscydCandlooPMutants

Characterization and Protective Property of Brucella abortuscydCandlooPMutants

Apoptotic Signaling Activated by Modulation of the F₀F₁-ATPase: Implications for Selective Killing of Autoimmune Lymphocytes

Identification of proteins with the CDw75 epitope in human colorectal cancer

Contact Info

Product

Resources

About

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

Cited by 275 publications

References 449 publications

Characterization and Protective Property of Brucella abortuscydCandlooPMutants

Characterization and Protective Property of Brucella abortuscydCandlooPMutants

Apoptotic Signaling Activated by Modulation of the F0F1-ATPase: Implications for Selective Killing of Autoimmune Lymphocytes

Identification of proteins with the CDw75 epitope in human colorectal cancer

Contact Info

Product

Resources

About

Apoptotic Signaling Activated by Modulation of the F₀F₁-ATPase: Implications for Selective Killing of Autoimmune Lymphocytes