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2015 ; 11
(9
): 1520-36
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Extrusion of mitochondrial contents from lipopolysaccharide-stimulated cells:
Involvement of autophagy
#MMPMID26102061
Unuma K
; Aki T
; Funakoshi T
; Hashimoto K
; Uemura K
Autophagy
2015[]; 11
(9
): 1520-36
PMID26102061
show ga
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-1?, 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.
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