RRC ID 67646
Author Unuma K, Aki T, Funakoshi T, Hashimoto K, Uemura K.
Title Extrusion of mitochondrial contents from lipopolysaccharide-stimulated cells: Involvement of autophagy.
Journal Autophagy
Abstract Sepsis/endotoxemia is elicited by the circulatory distribution of pathogens/endotoxins into whole bodies, and causes profound effects on human health by causing inflammation in multiple organs. Mitochondrial damage is one of the characteristics of the cellular degeneration observed during sepsis/endotoxemia. Elimination of damaged mitochondria through the autophagy-lysosome system has been reported in the liver, indicating that autophagy should play an important role in liver homeostasis during sepsis/endotoxemia. An increased appearance of mitochondrial DNA and proteins in the plasma is another feature of sepsis/endotoxemia, suggesting that damaged mitochondria are not only eliminated within the cells, but also extruded through currently unknown mechanisms. Here we provide evidence for the secretion of mitochondrial proteins and DNA from lipopolysaccharide (LPS)-stimulated rat hepatocytes as well as mouse embryonic fibroblasts (MEFs). The secretion of mitochondrial contents is accompanied by the secretion of proteins that reside in the lumenal space of autolysosomes (LC3-II and CTSD/cathepsin D), but not by a lysosomal membrane protein (LAMP1). The pharmacological inhibition of autophagy by 3MA blocks the secretion of mitochondrial constituents from LPS-stimulated hepatocytes. LPS also stimulates the secretion of mitochondrial as well as autolysosomal lumenal proteins from wild-type (Atg5(+/+)) MEFs, but not from atg5(-/-) MEFs. Furthermore, we show that direct exposure of purified mitochondria activates polymorphonuclear leukocytes (PMNs), as evident by the induction of IL1B/interlekin-1β, a pro-inflammatory cytokine. Taken together, the data suggest the active extrusion of mitochondrial contents, which provoke an inflammatory response of immune cells, through the exocytosis of autolysosomes by cells stimulated with LPS.
Volume 11(9)
Pages 1520-36
Published 2015-1-1
DOI 10.1080/15548627.2015.1063765
PMID 26102061
PMC PMC4590602
MeSH Adenine / analogs & derivatives Adenine / pharmacology Animals Autophagy / drug effects* Autophagy / genetics Autophagy-Related Protein 5 Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism Cell Nucleus / drug effects Cell Nucleus / metabolism DNA, Mitochondrial / metabolism Fibroblasts / drug effects Fibroblasts / metabolism Gene Expression Regulation / drug effects Hepatocytes / drug effects Hepatocytes / metabolism Hepatocytes / ultrastructure Lipopolysaccharides / pharmacology* Lysosomes / drug effects Lysosomes / genetics Male Mice Microtubule-Associated Proteins / metabolism Mitochondria / drug effects Mitochondria / metabolism* Mitochondrial Proteins / metabolism Models, Biological Neutrophil Activation / drug effects Phagosomes / drug effects Phagosomes / metabolism Protein Transport / drug effects Rats, Sprague-Dawley Subcellular Fractions / metabolism Vacuoles / drug effects Vacuoles / metabolism
IF 9.77
Human and Animal Cells Atg5^(+/+)MEF(RCB2710) Atg5^(-/-)MEF(RCB2711)