Dataset Information

Mitochondria Released by Apoptotic Cell Death Initiate Innate Immune Responses.

ABSTRACT: In solid organ transplantation, cell death arising from ischemia/reperfusion leads to the release of several damage-associated molecular patterns derived from mitochondria. Mitochondrial damage-associated molecular patterns (mtDAMPs) initiate proinflammatory responses, but it remains unknown whether the mode of cell death affects the inflammatory properties of mitochondria. Murine and human cell lines induced to selectively undergo apoptosis and necroptosis were used to examine the extracellular release of mitochondria during programmed cell death. Mitochondria purified from healthy, apoptotic, and necroptotic cells were used to stimulate macrophage inflammasome responses in vitro and neutrophil chemotaxis in vivo. Inhibition of specific mtDAMPs was performed to identify those responsible for macrophage inflammasome activation. A rat liver transplant model was used to identify apoptotic and necroptotic cell death in graft tissue following ischemia/reperfusion. Both apoptotic and necroptotic cell death occur in parallel in graft tissue. Apoptotic cells released more mitochondria than necroptotic cells. Moreover, mitochondria from apoptotic cells were significantly more inflammatory in terms of macrophage inflammasome activation and neutrophil recruitment. Inhibition of cellular synthesis of cardiolipin, a mitochondria-specific lipid and mtDAMP, significantly reduced the inflammasome-activating properties of apoptosis-derived mitochondria. Mitochondria derived from apoptotic cells are potent activators of innate immune responses, whereas mitochondria derived from healthy or necroptotic cells are significantly less inflammatory. Cardiolipin appears to be a key mtDAMP-regulating inflammasome activation by mitochondria. Methods of inhibiting apoptotic cell death in transplant grafts may be beneficial for reducing graft inflammation and transplant allosensitization.

SUBMITTER: Zhu M

PROVIDER: S-EPMC6400482 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mitochondria Released by Apoptotic Cell Death Initiate Innate Immune Responses.

Zhu Minghua M Barbas Andrew S AS Lin Liwen L Scheuermann Uwe U Bishawi Muath M Brennan Todd V TV

ImmunoHorizons 20181201 11

In solid organ transplantation, cell death arising from ischemia/reperfusion leads to the release of several damage-associated molecular patterns derived from mitochondria. Mitochondrial damage-associated molecular patterns (mtDAMPs) initiate proinflammatory responses, but it remains unknown whether the mode of cell death affects the inflammatory properties of mitochondria. Murine and human cell lines induced to selectively undergo apoptosis and necroptosis were used to examine the extracellular ...[more]

PMID: 30847435

Similar Datasets

Project description:Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid β (Aβ) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Aβ impairs mitochondrial dynamics and function. Furthermore, mitochondrial Aβ accumulation has been detected in the AD brain. However, the underlying mechanism of how Aβ affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Aβ accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Aβ(1-42) treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Aβ(1-42)-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Aβ(1-42) in HT22 cells using Aβ(1-42) with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Aβ(1-42)-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Aβ(1-42) accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Aβ(1-42)-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Aβ(1-42) accumulation, which mimics the apoptosis process in exogenous Aβ(1-42)-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Aβ(1-42) accumulation is the necessary and sufficient condition for Aβ-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Aβ-mediated signaling alterations.

Dataset Information

Mitochondria Released by Apoptotic Cell Death Initiate Innate Immune Responses.

Publications

Mitochondria Released by Apoptotic Cell Death Initiate Innate Immune Responses.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets