The Tricky Connection between Extracellular Vesicles and Mitochondria in Inflammatory-Related Diseases

Abstract

Mitochondria are organelles present in almost all eukaryotic cells, where they represent the main site of energy production. Mitochondria are involved in several important cell processes, such as calcium homeostasis, OXPHOS, autophagy, and apoptosis. Moreover, they play a pivotal role also in inflammation through the inter-organelle and inter-cellular communications, mediated by the release of mitochondrial damage-associated molecular patterns (mtDAMPs). It is currently well-documented that in addition to traditional endocrine and paracrine communication, the cells converse via extracellular vesicles (EVs). These small membrane-bound particles are released from cells in the extracellular milieu under physio-pathological conditions. Importantly, EVs have gained much attention for their crucial role in inter-cellular communication, translating inflammatory signals into recipient cells. EVs cargo includes plasma membrane and endosomal proteins, but EVs also contain material from other cellular compartments, including mitochondria. Studies have shown that EVs may transport mitochondrial portions, proteins, and/or mtDAMPs to modulate the metabolic and inflammatory responses of recipient cells. Overall, the relationship between EVs and mitochondria in inflammation is an active area of research, although further studies are needed to fully understand the mechanisms involved and how they may be targeted for therapeutic purposes. Here, we have reported and discussed the latest studies focused on this fascinating and recent area of research, discussing of tricky connection between mitochondria and EVs in inflammatory-related diseases.

Alcohol and e-cigarette damage alveolar-epithelial barrier by activation of P2X7r and provoke brain endothelial injury via extracellular vesicles

“…In the mouse brain, cocaine-induced inflammation promotes the release of small EVs (exosomes) loaded with mtDAMPs, including misfolded mito-proteins, eATP, ROS, and degraded mtDNA [ 83 ]. When released, these mtDAMPs can activate numerous proinflammatory autocrine and paracrine signaling in recipient cells, producing several inflammation-associated diseases [ 84 ]. In our studies ETH, ALD, or e-Cig (1.8% nicotine) exposure increased eATP cargo in EVs.…”

Utilizing Extracellular Vesicles for Eliminating ‘Unwanted Molecules’: Harnessing Nature’s Structures in Modern Therapeutic Strategies

“…This damage can lead to an increase in mtROS levels, particularly during mitochondrial malfunctioning. Elevated mtROS levels can activate redox-sensitive transcription factors, such as NF-kB, which may result in the production of pro-inflammatory cytokines [ 115 , 116 , 117 ].…”

Immunometabolism, extracellular vesicles and cardiac injury

“…EVs can also transport mitochondrial enzymes, mitochondrial DNA, parts of the electron transport chain, mitochondrial fragments, and whole mitochondria ( 61 ). The role of these “mitoEVs” carry many implications for inflammatory pathways, which are tightly regulated by mitochondrial function ( 62 ). For example, mitochondrial damage-associated molecular patterns (mtDAMPs), which are released from damaged heart muscle, can trigger inflammation via the cGAS/STING/NF-κB pathway ( 62 ).…”

“…The role of these “mitoEVs” carry many implications for inflammatory pathways, which are tightly regulated by mitochondrial function ( 62 ). For example, mitochondrial damage-associated molecular patterns (mtDAMPs), which are released from damaged heart muscle, can trigger inflammation via the cGAS/STING/NF-κB pathway ( 62 ). Delivery of whole mitochondria to macrophages via EVs also plays a critical role in macrophage polarization ( 63 ).…”