ReviewThe existence and function of mitochondrial component in extracellular vesicles
Introduction
Over the past decades, a new frontier about the intercellular and inter-organ communication exerting by extracellular vesicle (EVs) and its hints for diagnostics and therapeutics has attracted great attentions (Stahl and Raposo, 2019). EVs are secreted by most type of cells and classified into two types, exosomes and microvesicles, by their biogenesis (Monguio-Tortajada et al., 2019, Shi et al., 2019). Exosomes are originated through invagination of the endosomal membrane, forming multivesicular bodies (MVB), and then fusing with the plasma membrane in an exocytic manner (Shojaei et al., 2019). Microvesicles are generated by budding and shedding directly from the plasma membrane (Amoruso et al., 2018). Some researches use alternative terms for microvesicles, e.g. ectosomes or microparticles, we collectively refer to microvesicles herein.
In addition to their disparate biogenesis, exosomes and microvesicles differ in the respects of size and some biomarkers (Haraszti et al., 2016). The size of exosomes vary from 40 to 120 nm, microvesicles vary from 50 to 1000 nm, a wider range compared with exosomes (Nair et al., 2018, Romero et al., 2017). Although microvesicles are generally considered larger than exosomes, parts of the microvesicles size are overlapped with exosomes. It is difficult and unconvincing to separate them merely basing on their sizes, which restrict the validation of specific biomarkers distinguish exosomes and microvesicles. A recent study reveals that annexin A1 might be a specific marker of microvesicles different from exosomes. Annexin A1 is expressed in both small (<150 nm) and large (<1000 nm) EVs, and absent from exosomes purified by direct immunoaffinity capture (DIC) with magnetic beads targeting canonical exosomal tetraspanins, CD9, CD63, and CD81. Furthermore, structured illumination microscopy detects that annexin A1-positive vesicles shed directly from the plasma membrane of human colon cancer DKO-1 cells (Jeppesen et al., 2019).
Due to the reason that microvesicles and exosomes are not possible to fully separated from each other with current isolation methods, some research does not separate them purposely, integrally regard them as EVs, as recommended by Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV2018) guidelines (Thery et al., 2018). In this review, we used the terms of microvesicles or exosomes as referred to by the corresponding original research.
Mitochondria constitute the intracellular cores for energy and viability (Hayakawa et al., 2016). Mitochondria contain mitochondrial nucleic acids and specified proteins, e.g. components of mitochondrial electron transport chain (El-Hattab and Scaglia, 2016). Here we review recent research on the existence and function of intact mitochondria or mitochondrial constituent transferred through EVs. We also summarize and analyze the underlying mechanism about why and how mitochondrial components are encapsulated and transferred through EVs.
Section snippets
How EVs transfer mitochondrial components
Previous studies have demonstrated that mitochondria-derived vesicles (MDV) are involved in many aspects of mitochondrial mechanism. The germination of mitochondria in a manner independent mitochondrial fission machinery (Matheoud et al., 2016, Soubannier et al., 2012b). Delivery of mitochondrial cargo to endolysosomal system for mitochondrial quality control (MQC). Steady generation of MDV from mitochondria observed in nonstimulated cells (Soubannier et al., 2012a). These findings may support
Why EVs transfer mitochondrial components
Besides mitophagy, exosomes transferring mitochondrial components from MDV is also regarded as mitochondrial quality control strategy to deal with damaged mitochondria (Picca et al., 2019a, Soto-Heredero et al., 2017). In response to mitochondrial reactive oxygen species (ROS), the formation and turnover of MDV precedes mitophagy in Hela cells. Mitochondrial discharge by exosomes operates as the first line of defense against partial depolarized mitochondria, prior to total depolarization (
The existence and function of mtDNA associated with EVs
Mitochondrion has its own genome, a circular DNA approximately 16.5 kb long, independent of nuclear genome (Hanna et al., 2019, Kaufman et al., 2019). It is pointed that mtDNA rather than chromosomal DNA released into the cytoplasm in response to cellular stress plays a vital role in the pathogenesis of different kinds of diseases (Fang et al., 2016). mtDNA is a well-known damage-associated molecular patterns (DAMP), that is suggested to stimulate innate immunity (Boyapati et al., 2018, Peng et
The existence and function of mtRNA in EVs
Human mtDNA comprise 37 genes that are required for oxidative phosphorylation, codifying 2 rRNA, twenty two tRNA, and 13 proteins (Barchiesi and Vascotto, 2019, Jourdain et al., 2017). In addition to mtDNA, mtRNA is recently classified as a novel DAMP in mice and human (Ilic et al., 2019, Linder and Hornung, 2018). Compared with mtDNA, an even stronger proinflammatory response is triggered by mtRNA in primary mouse macrophages (Saxena et al., 2017).
Microvesicles released from lipopolysaccharide
The existence and function of other mitochondrial components associated with EVs
ATP synthase, an enzyme complex that generate the majority of intracellular ATP, is distributed mainly within mitochondria (Pereira et al., 2018). The exosomes proteome profile of the human urinary exosomes displays the existence of representative proteins from all of the five respiratory complexes. ATP synthase subunit is found to be specifically located on the surface of urinary exosomes. Urinary exosomes consume oxygen, and the oxygen consumption is coupled to ATP synthesis, suggesting the
The existence and function of intact mitochondria transferred by EVs
Under oxidative stress (21% oxygen treatment), human MSC extrudes partially depolarized mitochondria into microvesicles. The mitochondria in microvesicles are engulfed and reutilized by human macrophages to enhance their bioenergetics (Phinney et al., 2015).
Compared with healthy controls, the bronchoalveolar lavage fluid (BALF) of asthmatics has larger portions of mitochondria-containing EVs that express human leukocyte antigen – antigen D related (HLA-DR), a major histocompatibility complex
Conclusions and perspectives
This review has supplied a summarisation of current advances in the role of EVs, including microvesicles and exosomes, in intercellular transfer of mitochondria and mitochondrial components. Given that intact mitochondria and its components are transferred through EVs involved in the changes in the function of receipt cells and given that there are positive or negative roles involved in the pathogenesis of metabolic disorders, intact mitochondria and its components carried by EVs are
Author contributions
Study concept and design by Xiaofeng Yao, literature collection and writing by Dan Liu and Zhanchen Dong, figures and table preparation by Jinling Wang and Ye Tao, revision by Xiaofeng Yao and Xiance Sun.
Funding
This work was supported by the National Natural Science Foundation of China (NSFC, 81602881), China Postdoctoral Science Special Foundation (2018T110226), China Postdoctoral Science Foundation (2017M611239).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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The first two authors contributed equally to this work.