Sufficient to increase lung inflammation and trigger tissue remodeling. ThisSphingolipid Homeostasis

Sufficient to increase lung inflammation and trigger tissue remodeling. ThisSphingolipid Homeostasis Impact on Airway Functionillustrates the importance of determining ceramide species in experimental models of lung disease, as previously suggested by observational studies of altered species distribution during ceramide-dependent lung cell apoptosis [12]. Finally, CerS2 deficiency alone was associated with increased airways resistance, which in light of recent genomic studies of asthma could provide useful functional significance of the de novo sphingolipid pathway in this common disease.AcknowledgmentsWe thank Lee Albee, for help with the CerS qRT-PCR and Mariam Qureshi for assistance with BCA assays.Author ContributionsConceived and designed the experiments: IP YPJ AHF. Performed the experiments: KK CP ELL KSS MVD MJJ WCH. Analyzed the data: IP KK CP YPJ ELL KSS WH AHF. Contributed reagents/materials/ analysis tools: IP WCH AHF. Wrote the paper: IP YPJ AHF.GSK1059615
Mitochondria are essential for bioenergetics, coordination of cell metabolism through signaling and cells life and death decisions.Roxadustat Production of reactive oxygen species (ROS) [1, 2] and peroxidation of a mitochondria-specific phospholipid, cardiolipin (CL) are essential events in the execution of the mitochondrial stage of the intrinsic apoptotic program [3].PMID:23489613 These mitochondrial events develop as delayed responses commonly occurring hours after the exposure to chemical or physical pro-apoptotic factors, and thus offer a therapeutic window for protective and mitigative modalities [60]. During the initial stages of apoptosis, translocation of CL from the inner to the outer mitochondrial membrane [11] allows its interaction with an intermembrane space hemoprotein, cytochrome (cyt) c. In the resulting complex, cyt c loses its electron-transporting function but gains a peroxidase activity towards polyunsaturated species of CL [3, 12]. Oxidation of CL is essential for further transduction of apoptotic signals by facilitating detachment of cyt c from the mitochondrial membrane and formation of the mitochondrial permeability transition pore that leads to the release of pro-apoptotic factors from mitochondria into the cytosol [13]. This suggests that peroxidase activity of cyt c/CL complexes represents a promising target for anti-apoptotic drug discovery. Normally, cyt c has a very low peroxidase activity due to the stable hexacoordinate structure of the heme iron [14, 15]. The distal ligand, Met80, is located only 2.5 away from Fe, thus precluding access to the heme in the native protein by hydrogen peroxide (H2O2) or other peroxides [3]. Upon binding and partial unfolding of cyt c by CL, Met80 moves away from the heme Fe-atom and releases the sixth iron coordination bond, resulting in enhanced access of the heme catalytic site to small molecules like H2O2. One can assume that “locking” of the heme-iron coordination bond with a strong ligand delivered through the hydrophobic channel into immediate proximity of the heme catalytic site would block the peroxidase activity, inhibit CL peroxidation and prevent the progressions of apoptosis [16, 17]. As a proof of principle, we designed and synthesized imidazole-substituted derivativesFree Radic Biol Med. Author manuscript; available in PMC 2015 June 01.Jiang et al.Pageof stearic and oleic acids in which the imidazole group was attached to the 12th carbon. The carboxyl group of these derivatives likely interacted with one of the critical Lys re.