Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure
dc.contributor.author | Mizumura, Kenji | |
dc.contributor.author | Justice, Matthew J. | |
dc.contributor.author | Schweitzer, Kelly S. | |
dc.contributor.author | Krishnan, Sheila | |
dc.contributor.author | Bronova, Irina | |
dc.contributor.author | Berdyshev, Evgeny V. | |
dc.contributor.author | Hubbard, Walter C. | |
dc.contributor.author | Pewzner-Jung, Yael | |
dc.contributor.author | Futerman, Anthony H. | |
dc.contributor.author | Choi, Augustine M. K. | |
dc.contributor.author | Petrache, Irina | |
dc.contributor.department | Medicine, School of Medicine | en_US |
dc.date.accessioned | 2019-08-05T17:28:16Z | |
dc.date.available | 2019-08-05T17:28:16Z | |
dc.date.issued | 2018-04 | |
dc.description.abstract | The mechanisms by which lung structural cells survive toxic exposures to cigarette smoke (CS) are not well defined but may involve proper disposal of damaged mitochondria by macro-autophagy (mitophagy), processes that may be influenced by pro-apoptotic ceramide (Cer) or its precursor dihydroceramide (DHC). Human lung epithelial and endothelial cells exposed to CS exhibited mitochondrial damage, signaled by phosphatase and tensin homolog-induced putative kinase 1 (PINK1) phosphorylation, autophagy, and necroptosis. Although cells responded to CS by rapid inhibition of DHC desaturase, which elevated DHC levels, palmitoyl (C16)-Cer also increased in CS-exposed cells. Whereas DHC augmentation triggered autophagy without cell death, the exogenous administration of C16-Cer was sufficient to trigger necroptosis. Inhibition of Cer-generating acid sphingomyelinase reduced both CS-induced PINK1 phosphorylation and necroptosis. When exposed to CS, Pink1-deficient ( Pink1-/-) mice, which are protected from airspace enlargement compared with wild-type littermates, had blunted C16-Cer elevations and less lung necroptosis. CS-exposed Pink1-/- mice also exhibited significantly increased levels of lignoceroyl (C24)-DHC, along with increased expression of Cer synthase 2 ( CerS2), the enzyme responsible for its production. This suggested that a combination of high C24-DHC and low C16-Cer levels might protect against CS-induced necroptosis. Indeed, CerS2-/- mice, which lack C24-DHC at the expense of increased C16-Cer, were more susceptible to CS, developing airspace enlargement following only 1 month of exposure. These results implicate DHCs, in particular, C24-DHC, as protective against CS toxicity by enhancing autophagy, whereas C16-Cer accumulation contributes to mitochondrial damage and PINK1-mediated necroptosis, which may be amplified by the inhibition of C24-DHC-producing CerS2.-Mizumura, K., Justice, M. J., Schweitzer, K. S., Krishnan, S., Bronova, I., Berdyshev, E. V., Hubbard, W. C., Pewzner-Jung, Y., Futerman, A. H., Choi, A. M. K., Petrache, I. Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure. | en_US |
dc.identifier.citation | Mizumura, K., Justice, M. J., Schweitzer, K. S., Krishnan, S., Bronova, I., Berdyshev, E. V., … Petrache, I. (2018). Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 32(4), 1880–1890. doi:10.1096/fj.201700571R | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/20188 | |
dc.language.iso | en_US | en_US |
dc.publisher | Federation of American Societies for Experimental Biology | en_US |
dc.relation.isversionof | 10.1096/fj.201700571R | en_US |
dc.relation.journal | FASEB journal | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | Ceramide | en_US |
dc.subject | Sphingosine | en_US |
dc.subject | Cell death | en_US |
dc.subject | Cell survival | en_US |
dc.subject | Inflammation | en_US |
dc.title | Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure | en_US |
dc.type | Article | en_US |
ul.alternative.fulltext | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893175/ | en_US |
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