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 - 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. K. Mizumura, M. J. Justice, and E. V. Berdyshev designed and performed experiments, analyzed data, and wrote the manuscript; K. S. Schweitzer and W. C. Hubbard performed experiments and analyzed data; S. Krishnan and I. Bronova performed experiments; Y. Pewzner‐Jung designed and performed experiments and analyzed data; A. H. Futerman and A. M. K. Choi designed experiments and analyzed data; and I. Petrache designed experiments, analyzed data, and wrote manuscript. Funding Information: U.S. National Institute of Health. National Heart, Lung, and Blood Institute. Grant Numbers: RO1HL077328, F31HL126459, P01HL114501, R01HL132198. Binational Science Foundation.
PY - 2018/4
Y1 - 2018/4
N2 - 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, Pinkl‐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 PINKl‐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.
AB - 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, Pinkl‐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 PINKl‐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.
UR - https://www.scopus.com/pages/publications/85044999285
U2 - 10.1096/fj.201700571R
DO - 10.1096/fj.201700571R
M3 - Article
SN - 0892-6638
VL - 32
SP - 1880
EP - 1890
JO - FASEB Journal
JF - FASEB Journal
IS - 4
ER -