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Signaling role of cardiolipin externalization in elimination of damaged mitochondria in lung epithelial cells.

Kagan VE; Jiang J; Huang Z; Tyruin VA; Tyruina Y; Stolz D; Watkins S; Mallampalli R
Toxicologist 2014 Mar; 138(1):261
Bacterial pneumonia triggers an exuberant host response characterized by excessive inflammation, oxidative stress, and epithelial cell damage culminating in the acute respiratory distress syndrome (ARDS). In ARDS, virulent bacterial pathogens directly damage host cells, activate innate immune responses, and trigger a burst in reactive oxygen species resulting in epithelial cell death. However, specific pathways involved in the evolution of epithelial injury with attendant release of novel damage signals remain elusive. We suggested that one critical damage signal is mitochondrial cardiolipin (CL). We found that mitophagy and reduced levels of distal mitochondrial protein markers were detectable in murine models of bacterial pneumonia. In addition, we demonstrated that early on after bacterial infection of murine lung epithelial cells (MLE15), CL transmigrates from the IMM to OMM; the unmasked externalized CL serves as a novel signal for mitophagy. A typical inducer of mitophagy, carbonyl cyanide m-chlorophenylhydrazone (CCCP) - acting as a protonophoric uncoupler - induced CL externalization to the OMM in MLE15 cells. This was evidenced by a robust decrease of the ratio of CL in the IMM and OMM from 18.6+/-0.3 in control MLE15 cells to 3.7+/-1.4 after treatment with CCCP. The externalization of CL was accompanied by activation of autophagy (LC3-I/II conversion) and decreased levels of mitochondrial marker proteins (TOM40, TIM23 and MnSOD) - consistent with mitophagy activation. CCCP-induced mitophagy in MLE was also confirmed by co-localization of mitochondria and lysosomes. Manipulations of CL levels or proteins involved in CL externalization (PLSR3) affected sensitivity of MLE to pro-mitophageal stimulation. These data are compatible with a hypothesis that externalized CL acts as an "eat-me" signal in depolarized mitochondria.
Toxicology; Cell-function; Cellular-function; Cell-damage; Immunology; Immune-system; Respiration; Respiratory-system-disorders; Pulmonary-disorders; Pulmonary-function; Pulmonary-system; Pulmonary-system-disorders; Bacteria; Bacterial-cultures; Lung; Proteins
Publication Date
Document Type
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Identifying No.
Grant-Number-R01-OH-008282; M032014
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Source Name
The Toxicologist. Society of Toxicology 53rd Annual Meeting and ToxExpo, March 23-27, 2014, Phonex, Arizona
Performing Organization
University of Pittsburgh at Pittsburgh
Page last reviewed: September 2, 2020
Content source: National Institute for Occupational Safety and Health Education and Information Division