Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure

Kenji Mizumura, Matthew J. Justice, Kelly S. Schweitzer, Sheila Krishnan, Irina Bronova, Evgeny V. Berdyshev, Walter C. Hubbard, Yael Pewzner-Jung, Anthony H. Futerman, Augustine M.K. Choi, Irina Petrache

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Themechanismsbywhich lung structural cells survive toxic exposures to cigarettesmoke (CS) are notwell defined but may involve proper disposal of damagedmitochondria bymacro-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 exhibitedmitochondrial damage, signaled by phosphatase and tensin homologinduced putative kinase 1 (PINK1) phosphorylation, autophagy, and necroptosis.Although cells responded toCS by rapid inhibition of DHC desaturase, which elevated DHC levels, palmitoyl (C16)-Cer also increased in CS-exposed cells. WhereasDHCaugmentation triggered autophagywithout cell death, the exogenous administration ofC16-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 (Pink12/2)mice, which are protected from airspace enlargement compared with wild-Type littermates, had blunted C16-Cer elevations and less lung necroptosis. CS-exposed Pink12/2 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 highC24-DHC and lowC16-Cer levels might protect againstCS-induced necroptosis. Indeed, CerS22/2 mice, which lack C24-DHC at the expense of increased C16-Cer, were more susceptible to CS, developing airspace enlargement following only 1month of exposure. These results implicate DHCs, in particular, C24-DHC, as protective against CS toxicity by enhancing autophagy,whereasC16-Cer accumulation contributes to mitochondrial damage and PINK1-mediated necroptosis, which may be amplified by the inhibition of C24-DHC-producing CerS2.

Original languageEnglish (US)
Pages (from-to)1880-1890
Number of pages11
JournalFASEB Journal
Volume32
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

Fingerprint

Mitochondrial Degradation
Sphingolipids
Smoke
Tobacco Products
Ceramides
Epithelial Cells
Lung
Autophagy
Phosphorylation
Sphingomyelin Phosphodiesterase
Poisons
Endothelial cells
Cell death
dihydroceramide
Phosphoric Monoester Hydrolases
Toxicity
Cell Death
Phosphotransferases
Endothelial Cells
Acids

Keywords

  • Cell death
  • Cell survival
  • Ceramide
  • Inflammation
  • Sphingosine

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

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, 32(4), 1880-1890. https://doi.org/10.1096/fj.201700571R

Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure. / Mizumura, Kenji; Justice, Matthew J.; Schweitzer, Kelly S.; Krishnan, Sheila; Bronova, Irina; Berdyshev, Evgeny V.; Hubbard, Walter C.; Pewzner-Jung, Yael; Futerman, Anthony H.; Choi, Augustine M.K.; Petrache, Irina.

In: FASEB Journal, Vol. 32, No. 4, 01.04.2018, p. 1880-1890.

Research output: Contribution to journalArticle

Mizumura, K, Justice, MJ, Schweitzer, KS, Krishnan, S, Bronova, I, Berdyshev, EV, Hubbard, WC, Pewzner-Jung, Y, Futerman, AH, Choi, AMK & Petrache, I 2018, 'Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure', FASEB Journal, vol. 32, no. 4, pp. 1880-1890. https://doi.org/10.1096/fj.201700571R
Mizumura K, Justice MJ, Schweitzer KS, Krishnan S, Bronova I, Berdyshev EV et al. Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure. FASEB Journal. 2018 Apr 1;32(4):1880-1890. https://doi.org/10.1096/fj.201700571R
Mizumura, Kenji ; Justice, Matthew J. ; Schweitzer, Kelly S. ; Krishnan, Sheila ; Bronova, Irina ; Berdyshev, Evgeny V. ; Hubbard, Walter C. ; Pewzner-Jung, Yael ; Futerman, Anthony H. ; Choi, Augustine M.K. ; Petrache, Irina. / Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure. In: FASEB Journal. 2018 ; Vol. 32, No. 4. pp. 1880-1890.
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