TY - JOUR
T1 - Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure
AU - Mizumura, Kenji
AU - Justice, Matthew J.
AU - Schweitzer, Kelly S.
AU - Krishnan, Sheila
AU - Bronova, Irina
AU - Berdyshev, Evgeny V.
AU - Hubbard, Walter C.
AU - Pewzner-Jung, Yael
AU - Futerman, Anthony H.
AU - Choi, Augustine M.K.
AU - Petrache, Irina
N1 - Funding Information:
The authors acknowledge the support from U.S. National Institute of Health, National Heart, Lung, and Blood Institute Grants RO1HL077328 (to I.P.), F31HL126459 (to M.J.J.), and P01HL114501 and R01HL132198 (to A.M.K.C.); and support from the Binational Science Foundation (to I.P. and A.H.F.). K.M. and M.J.J. are cofirst authors on this manuscript. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
KW - Cell death
KW - Cell survival
KW - Ceramide
KW - Inflammation
KW - Sphingosine
UR - http://www.scopus.com/inward/record.url?scp=85044999285&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044999285&partnerID=8YFLogxK
U2 - 10.1096/fj.201700571R
DO - 10.1096/fj.201700571R
M3 - Article
C2 - 29196503
AN - SCOPUS:85044999285
SN - 0892-6638
VL - 32
SP - 1880
EP - 1890
JO - FASEB Journal
JF - FASEB Journal
IS - 4
ER -