Mitochondria Are a Subset of [EVs] Released by Activated Monocytes and Induce Type I IFN and TNF Responses in Endothelial Cells, 2019, Binder et al

[Andy]

Abstract
Rationale:
Extracellular vesicles, including microvesicles, are increasingly recognized as important mediators in cardiovascular disease. The cargo and surface proteins they carry are considered to define their biological activity, including their inflammatory properties. Monocyte to endothelial cell signaling is a prerequisite for the propagation of inflammatory responses. However, the contribution of microvesicles in this process is poorly understood.

Objective:
To elucidate the mechanisms by which microvesicles derived from activated monocytic cells exert inflammatory effects on endothelial cells.

Methods and Results:
LPS (lipopolysaccharide)-stimulated monocytic cells release free mitochondria and microvesicles with mitochondrial content as demonstrated by flow cytometry, quantitative polymerase chain reaction, Western Blot, and transmission electron microscopy. Using RNAseq analysis and quantitative reverse transcription-polymerase chain reaction, we demonstrated that both mitochondria directly isolated from and microvesicles released by LPS-activated monocytic cells, as well as circulating microvesicles isolated from volunteers receiving low-dose LPS-injections, induce type I IFN (interferon), and TNF (tumor necrosis factor) responses in endothelial cells. Depletion of free mitochondria significantly reduced the ability of these microvesicles to induce type I IFN and TNF-dependent genes. We identified mitochondria-associated TNFα and RNA from stressed mitochondria as major inducers of these responses. Finally, we demonstrated that the proinflammatory potential of microvesicles and directly isolated mitochondria were drastically reduced when they were derived from monocytic cells with nonrespiring mitochondria or monocytic cells cultured in the presence of pyruvate or the mitochondrial reactive oxygen species scavenger MitoTEMPO.

Conclusions:
Mitochondria and mitochondria embedded in microvesicles constitute a major subset of extracellular vesicles released by activated monocytes, and their proinflammatory activity on endothelial cells is determined by the activation status of their parental cells. Thus, mitochondria may represent critical intercellular mediators in cardiovascular disease and other inflammatory settings associated with type I IFN and TNF signaling.

Open access at https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.314601

 

[Susan K]

Open access at https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.314601

Oh, very cool Andy.
Stuck in my foggy brain was the vague idea that chronic diseases other than ME have mitochrondrial dysfunction in affected cell types. Did not realize that there exists "microvesicle-embedded mitochondria"

This is from this Circ. Research article you posted above:

"What Is Known?

• Microvesicles, a subtype of extracellular vesicles, contribute to monocyte-endothelial cell signaling.
  
  
• Cargo and surface proteins are considered to define the inflammatory properties of microvesicles.
  
  
• Mitochondria are a source of damage-associated molecular patterns.
  
  
• Altered mitochondrial activity and cellular metabolism contribute to cardiovascular disease and other pathologies.
• 
  
• What New Information Does This Article Contribute?

• Lipopolysaccharide-activated monocytic cells release mitochondria and mitochondria embedded in microvesicles.
  
  
• Both free mitochondria and microvesicle-embedded mitochondria contribute to the ability of microvesicles to activate endothelial cells.
  
  
• This proinflammatory capacity is determined by the mitochondrial activity of parental cells rather than the mere presence of mitochondrial content.
  
  
• Mitochondria-associated TNF (tumor necrosis factor) and interferonogenic mitochondrial RNA are the major proinflammatory mediators of microvesicles released from activated monocytic cells."