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Review
. 2023 May 3;24(9):8181.
doi: 10.3390/ijms24098181.

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

Tommaso Di Mambro  1 , Giulia Pellielo  1 , Esther Densu Agyapong  1 , Marianna Carinci  1 , Diego Chianese  1 , Carlotta Giorgi  1 , Giampaolo Morciano  1 , Simone Patergnani  1 , Paolo Pinton  1   2 , Alessandro Rimessi  1   2
Affiliations
Review

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

Tommaso Di Mambro et al. Int J Mol Sci. .

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.

Keywords: extracellular vesicles; inflammation; inflammatory diseases; intercellular communication; mitochondria; mitochondria-derived vesicles; mitovesicles.

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Conflict of interest statement

The authors declare that there are no competing interests in relation to this work.

Figures

Figure 1
Figure 1
Several mtDAMPs contribute to mito-inflammation. The main mtDAMPs involved in mito-inflammation are ATP, cardiolipin, mtROS, Ca2+, and mtDNA. ATP-high intracellular levels lead to activation of P2X7 receptor, resulting in activation of NLRP3 inflammasome mediating K+-efflux; Cardiolipin modulates NLRP3 inflammasome activation when transferred to OMM or other cellular structures; mtROS at high levels stimulate production of proinflammatory cytokines and promote inflammasome activation; mitochondrial Ca2+ perturbation leads to mtROS production and consequent inflammasome activation; mtDNA release from mitochondria, also through mPTP-opening, leads to activation of inflammasomes (NLRP3 and NLRC4), TLR9 signaling, and cGAS-STING pathway. Created with BioRender.com.
Figure 2
Figure 2
Extracellular vesicles (EVs) biogenesis. Extracellular vesicles (EVs) are classified into three types: exosomes, vesicles enclose by the lumen of multivesicular bodies (MVB) that can either ensue the secretory pathway fusing with the PM to discharge its content as exosomes or ensue the lysosome pathway where MVB fuse with the lysosome for degradation; Microvesicles, which generate via budding of the PM; and Apoptotic bodies, PM blebbing by cells undergoing programmed cell death. Under stress conditions, mitochondrial components including mtDNA, ROS, cardiolipin, and proteins have enveloped into TOM20-positive “mitochondrial-derived vesicles” (MDVs). MDVs may be targeted to Tollip-positive endosome facilitating their trafficking to the lysosome or released outside direct to recipient cells. Created with BioRender.com.
Figure 3
Figure 3
Extracellular vesicles (EVs) release in inflammatory-related diseases. (A) In the pulmonary system of cystic fibrosis patients, the released EVs are higher respect to control, and this EV release increases with age of cystic fibrosis patients. In Chronic Obstructive Pulmonary Disease (COPD) patients, a higher release of EVs containing miRNAs is observed. In SARS-CoV-2 infection, patients showed an increased EVs release. (B) In the cardiovascular system, the EVs are enriched with mRNA, ATP, and mtDNA. The EVs incorporation in cardiomyocytes improved mitochondrial biogenesis during hypoxia and subsequent reoxygenation condition. EVs enriched with VDAC protein and fused with donor cells induced oxidative stress and inflammation by the expression of ICAM-1 and VCAM-1. (C) In the nervous system, EVs are involved in different diseases. An increased level of released EVs, containing mtROS, was observed in Parkinson Disease (PD). EVs containing RNA are higher in Alzheimer Disease (AD) patients respect to control. EVs containing mtDNA are increased in Huntington’s disease (HD) and Down Syndrome patients. an increased level of EVs containing a higher mitochondrial complex IV and a lower mitochondrial complex V activity was observed in Multiple Sclerosis (MS). (D) In cancers, Evs enriched in miRNAs, metabolites, and lncRNA regulated glucose metabolism. EVs containing mtDNA promoted the exit of breast cancer cells from dormancy. EVs enriched in metabolites supplied substances for TCA cycle. Created with BioRender.com.
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