1-s2.0-S156772492400093X-main

Mitochondrion 78 (2024) 101935
Contents lists available at ScienceDirect
Mitochondrion
journal homepage: www.elsevier.com/locate/mito
Review
Extracellular vesicles as carriers for mitochondria: Biological functions and

clinical applications
Zhiwei Liao 1 , Bide Tong 1 , Wencan Ke 1 , Cao Yang , Xinghuo Wu , Ming Lei *
Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
A R T I C L E I N F O A B S T R A C T
Keywords: In recent years, research has increasingly focused on the biogenesis of extracellular vesicles (EVs) and the sorting
Extracellular vesicles mechanisms for their contents. Mitochondria can be selectively loaded into EVs, serving as a way to maintain
Mitochondrial transfer cellular mitochondrial homeostasis. EV-mediated mitochondrial transfer has also been shown to greatly impact
Mitochondria-derived vesicles
the function of target cells. Based on the mechanism of EV-mediated mitochondrial transfer, therapies can be
Mitochondrial quality control
developed to treat human diseases. This review summarizes the recent advances in the biogenesis and molecular
composition of EVs. It also highlights the sorting and trafficking mechanisms of mitochondrial components into
EVs. Furthermore, it explores the current role of EV-mediated mitochondrial transfer in the development of
human diseases, as well as its diagnostic and therapeutic applications.
1. Introduction phospholipid compositions. They contain various enzymes, structural

proteins, and molecules related to energy metabolism. The mitochon
Extracellular vesicles (EVs) are membrane-structured particles drial DNA (mtDNA), which may have evolved from the bacterial
secreted by cells. They contain various bioactive substances that enable genome, comprises 37 intron-free polycistronic genes (Iovine et al.,
their application in disease diagnosis and treatment (Keshtkar et al., 2021). The mitochondrial DNA encodes 22 tRNAs, 2 rRNAs, and 13
2018). In the past decade, EVs have been used as a safe and effective cell- mRNAs that are essential for oxidative phosphorylation (OXPHOS)
free therapy, serving as a substitute for cells in tissue regenerative (Basu et al., 2020). Mitochondrial RNA (mtRNA) and mtDNA, along
medicine (Liao, 2023). Researches have shown that the biological ac with other mitochondrial contents, are known as endogenous damage-
tivity of stem cell-derived EVs is comparable to that of maternal stem associated molecular patterns (DAMPs) (Madreiter-Sokolowski, 2019).
cells, and they have greater potential for clinical translation. EVs have The integrity and normal function of mitochondrial membrane structure
lower immunogenicity and tumorigenicity compared to cellular com are essential for cells. Loss of mitochondrial membrane potential (MMP)
ponents, and they are more convenient for storage, transportation, and and disruption of membrane structure can cause leakage of mitochon
clinical treatment (Kim, 2022). Due to the low immunogenicity and high drial contents into the cytoplasm, activating the inflammatory signaling
cell affinity, EVs are considered a promising biological tool in nano- pathway (Vringer and Tait, 2023). The clearance of damaged mito
medicine. In clinical treatment, the application of EVs is usually chondria usually depends on mitophagy. Molecules such as PTEN-
restricted by the isolated and purified technology, as well as their induced putative kinase 1 (PINK1) and parkin mediate mitophagy,
limited production (Kimiz-Gebologlu and Oncel, 2022). To facilitate which selectively clears damaged mitochondria within cells, thereby
further research on EVs, it is beneficial to standardize their classification maintaining mitochondrial quality (Nguyen et al., 2016). When the
and use advanced separation techniques or equipment to obtain pure EV mitophagy pathway is inhibited, for example, when lysosomal function
components. is compromised, the secretory pathway can be activated, promoting the
Mitochondria are important organelles responsible for producing release of damaged mitochondria into the extracellular space (Liang,
ATP to fuel cellular functions (Dache and Thierry, 2023). They also serve 2023). However, more research is needed to understand the mechanism
as centers for metabolite processing, cellular signaling, and apoptosis. of mitochondrial secretion, as well as the fate and biological effects of
Mitochondria are enclosed by two separate membranes with distinctive the secreted mitochondria.
* Corresponding author.
E-mail addresses: wuxinghuo@hust.edu.cn (X. Wu), leiming2010@hust.edu.cn (M. Lei).
1
Zhiwei Liao, Bide Tong and Wencan Ke contributed equally to this work.
https://doi.org/10.1016/j.mito.2024.101935
Received 25 March 2024; Received in revised form 21 June 2024; Accepted 8 July 2024
Available online 11 July 2024
1567-7249/© 2024 Elsevier B.V. and Mitochondria Research Society. All rights are reserved, including those for text and data mining, AI training, and similar
technologies.
Z. Liao et al. Mitochondrion 78 (2024) 101935
In recent years, the transfer of mitochondria between cells mediated Alix protein (Larios et al., 2020). Alix combines with TSG101 of the
by EVs has attracted widespread attention. Researchers have discovered ESCRT-I complex and the ESCRT-III components, simultaneously. With
complete mitochondria and various mitochondrial components in EVs. the assistance of ESCRT and accessory proteins, ILV progressively ma
This review summarizes the relevant knowledge of EVs, including their tures and merges with the cytomembrane, releasing exosomes outward
classification, biological origins, and composition. An extensive litera (Juan and Fürthauer, 2018). However, recent studies also suggest that
ture review was conducted regarding EV-mediated mitochondrial the formation of ILVs and exosomes is independent of ESCRT machinery.
transfer. It summarizes the types of mitochondrial components loaded It has been discovered that RAB31 interacts with flotillin proteins to
by different types of EVs and the trafficking mechanisms. It also dis produce ILVs without the involvement of the ESCRT machinery (Wei,
cusses the biological effects produced by EVs in target cells. Finally, we 2021). RAB31 recruits GTPase-activating protein TBC1D2B to deacti
discuss the physiological or pathological role of EV-mediated mito vate RAB7, thus preventing the fusion of MVBs with lysosomes and
chondrial transfer in various human diseases. This review offers insights enabling the release of exosomes.
into the biological mechanisms of EV-mediated mitochondria transfer, Microvesicles. The formation of microvesicles (MVs) is associated
as well as provides potential therapeutic targets for human diseases. with the direct outward blebbing and pinching of the plasma membrane.
Similar to the exosomes, the formation of MVs also utilizes the endo
2. Origin and classification of EVs somal machinery, including the Ras-related GTPase ADP-ribosylation
factor 6 (ARF6) and the ESCRT components (Chen et al., 2023). The
2.1. Classification of EVs interaction of arrestin domain-containing protein-1 (ARRDC1) with
TSG101 of the ESCRT-I complex resulting in membrane curvature. The
Most cells can release EVs for intercellular communication and activation and phosphorylation of myosin light chain (MLC) is mediated
transfer of substances, or to remove excess components or membrane by ARF6 via a Rho-associated protein kinase (ROCK) signaling, which
structures within the cell (van Niel et al., 2018). These EVs are typically promotes the fission and release of MVs from the cell surface. The cargo
enclosed by lipid bilayers and contain specific nucleic acids, proteins, trafficking of MVs is not random, while the mechanism for selective
and lipid, among others (Zhang, 2022). EVs can be divided into three loading is currently unclear. Related studies have shown that ARF6 plays
categories based on their sizes and sources (Tzng et al., 2023; Bebelman an important role in this process. Clancy et al. found that the loading of
et al., 2018). The first category is exosomes (30–150 nm), which origi cellular DNA in MVs is dependent upon both ARF6 and the cytosolic
nate from multivesicular bodies (MVBs). The second category is DNA sensor cGAS (Clancy et al., 2022). If ARF6 or cGAS is inhibited, the
microvesicles or microparticles (100–1000 nm), which directly origi efflux of double-stranded DNA from tumor cells via MVs decreases
nate from the cell membrane. Another type is apoptotic bodies significantly.
(1000–5000 nm) that secreted by apoptotic cells. However, this classi Apoptotic bodies. Apoptotic bodies (ABs) are the special type of EVs
fication is still controversial. The International Society for Extracellular released by dying cells during apoptosis (Santavanond et al., 2021). One
Vesicles (ISEV) proposes categorizing based on the physical diameter of of the morphological features of apoptotic cells at the early stage is
EVs according to their latest guideline (Welsh, 2024). Usually, particles apoptotic volume decrease (Xu et al., 2019). During this stage, cell
with a diameter (<200 nm) are classified as small EVs (sEVs), while membranes tend to form bubbles known as membrane blebbing, which
those with a diameter (>200 nm) are classified as large or medium EVs consist of the reduction or contraction of cell volume. ABs arise from the
(lEVs or mEVs). Alternatively, they can be classified into three cate membrane blebbing with the package of cellular contents. Although
gories based on density (low, medium, and high). In fact, researchers there are differences between different types of cells, it is currently
should be aware of the limitations of each classification method and believed that there are many DNA components in Abs (Zhou, 2022; Tang
strive to define terminology as clearly as possible. Due to the complex et al., 2022). Besides, intracellular fragments alongside cellular organ
biological origins and varied sizes of EVs, there currently exists a lack of elles such as histones can be found in the ABs fraction. Compared to
a standard classification method. Some researchers tend to classify EVs other types of EVs, there is relatively less research on apoptotic bodies.
according to their donor cell origin, like astrocyte-derived EVs. The EV The ABs are considered as extremely heterogeneous particles. It has
subtypes can also be defined by specific molecular markers such as been suggested that only cells possessing the required machinerys for
CD63, CD9, CD81, and annexin A1 (Jeppesen, 2019). Furthermore, EV ABs biogenesis are capable of ABs release (Kakarla et al., 2020).
classification based on different cell culture conditions or pre-treatment, Furthermore, distinct cellular stresses resulting in apoptotic cell death
such as hypoxia or apoptosis, can also be employed (Shao, 2018). may be necessary to stimulate ABs release.
Numerous studies have revealed that EVs perform various functions via
the delivery of cargoes, contributing to several physiological and path 3. Cargoes loaded in EVs
ological processes such as inflammation, immune response, cancer
progression and tissue degeneration (Sharma and Mukhopadhyay, 2024; EVs contain a diverse range of substances including nucleic acids,
György, 2011; Jeppesen et al., 2023). Therefore, it would be meaningful proteins and lipids (Rädler et al., 2023). Advanced techniques such as
to classify EVs based on specific molecular markers or the functional high-throughput sequencing, protein mass spectrometry, lipidomics and
cargoes that they carry. metabolomics can be utilized to analyze their compositions. The ultra
structure and molecular composition of EVs can be depicted via electron
2.2. Origin of EVs microscopy and immunolabeling. Nonetheless, investigating the sorting
mechanism of cargo in EVs still poses a challenge for researchers.
Exosomes. Exosomes are mostly derived from intracellular intra
luminal vesicles (ILVs) that are formed by inward budding of the early 3.1. Nucleic acids
endosomal membrane (Yang, 2022; Colombo et al., 2014). The initial
formation of ILVs is mediated by the interaction of several tetraspanins, There are abundant nucleic acids in EVs, including DNA, messenger
such as CD9 and CD63. Subsequently, the formation of ILVs is driven by RNA (mRNA), and noncoding RNAs. It is usually considered that EVs
endosomal sorting complexes required for transport (ESCRT) proteins, remove excess cytoplasmic DNA and gene fragments in order to main
which can be divided into ESCRT-0, − I, − II, and − III, and other acces tain cellular homeostasis (Vaidya and Sugaya, 2020). Studies have
sory proteins (Vietri et al., 2020). The ESCRT-0 complex identifies and confirmed the presence of genomic DNA in exosomes originating from
sequesters transmembrane proteins that are ubiquitinated in the early cancer cells, especially originating from cell micronuclei that represent
endosomal membrane, thereby prompting the recruitment of ESCRT-I genomic instability (Yokoi, 2019). These DNA contents are mainly
and ESCRT-II. ESCRT-III is recruited to ESCRT-I and II through the loaded into exosomes via the CD63 and Histone H2B complex. In recent
2
years, researchers have shown an interest in the diverse functions of mitochondria, lysosomes and peroxisomes (Wang, 2021). It appears that
non-coding RNAs in EVs (Spanos, 2023). These include microRNA EVs can serve as efficient mediators of intracellular waste disposal by
(miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA), releasing some organelle fragments outside the cell. In particular types
transfer RNA (tRNA), ribosomal RNA (rRNA), and others. Studies have of EVs, such as microvesicles, the entire mitochondrial components may
revealed that non-coding RNAs mediate the effect of EVs on the recipient be retained, preserving their functionalities (Liu, 2020; Thomas, 2022).
cells. Most of the nucleic acid components in EVs consist of small RNAs, However, the presence of certain protein components does not neces
especially miRNA (Babuta and Szabo, 2022). Compared to the parent sarily imply a complete organelle structure and function. Further
cells, the proportion of miRNA is much higher in the EVs fraction research is required to determine the presence of functional organelles
(Zhang, 2015). Exosomes and other EVs exert diverse functions in in EVs. Furthermore, the EV membrane comprises sialic acid, poly
recipient cells through the delivery of miRNAs. The loading of miRNAs lactosamine, heparan sulfate, and various surface carbohydrates,
in EVs is considered to be selective, with miRNAs containing a specific including mannose and different types of glycans (Batista et al., 2011).
motif (EXO-motif) being sorted into exosomes via heterogeneous nu These molecules may contribute to the structural composition and signal
clear ribonucleoproteins-dependent pathways (Liao, 2023; Zietzer, transduction of the EV membrane. Especially, the surface glycans in EVs
2020). are related to the cellular uptake of vesicles. Exosomes enriched with
sialic acid are preferred for internalization by binding to lectins in
3.2. Proteins recipient cells (Shimoda et al., 2017). Currently, most of the research on
organelles in EVs is related to mitochondria. We then summarize how
The proteins carried in EVs consist mainly of membrane proteins and specific mitochondria transport to mitochondria and how they affect the
cytoplasmic proteins. Membrane proteins, including tetraspanins, recipient cells through EVs in the following description.
integrins and so on, can serve as molecular markers of EVs (Pegtel and
Gould, 2019). Some membrane proteins are peripheral surface proteins 4. Trafficking mechanism of mitochondria in EVs
in EVs, such as wingless (Wnt) proteins, transforming growth factor
(TGF) receptor, tumor necrosis factor (TNF) receptor and so on, and One important mechanism by which EVs regulate mitochondrial
many of which are involved in signaling transduction (Gross and intercellular transfer is via mitochondria-derived vesicles (MDVs).
Zelarayán, 2018; Sampey, 2016). The varieties of cytoplasmic proteins MDVs are single (outer) or double (inner and outer) membrane vesicles
are more diverse. Generally, EVs contain proteins related to the originating from mitochondria and containing certain mitochondrial
biogenesis and membrane trafficking, such as ESCRT proteins, soluble components (Sugiura et al., 2014). In terms of ultrastructure, MDVs
NSF attachment protein receptors (SNARE) proteins and Rab small have a restricted diameter of 80–150 nm and are characterized by a
GTPase found in exosomes (Wang, 2020). Complement components and double membrane-bound structure lacking cristae. According to Math
extracellular matrix (ECM) collagens are also enriched in EVs. ECM eoud et al. (Matheoud, 2016), MDVs engage in mitochondrial antigen
proteins such as fibronectin, tenascin, collagens and so forth, are also presentation by interacting with late endosomes or lysosomes that are
involved in signaling and adhesion (Purushothaman, 2016). Moreover, mediated by Rab7 and Rab9. It reveals that the formation of MDVs re
EVs contain a variety of enzymes that may be involved in the recipient quires the recruitment of Snx9 and Rab9 to mitochondria. Ultrastruc
cells metabolism or biological processes, such as lipases, RNA editing tural analysis revealed Tom20-positive structures within the MVBs,
enzymes, CD73, and metabolic enzymes (Nolte-’t Hoen et al., 2016; indicating MDVs as a vesicle transport route between the mitochondria
Zhang, 2018). Besides, mitochondrial, ribosomal, and nuclear proteins and lysosomes (Soubannier, 2012). Todkar et al. discovered that mito
are detected in EVs and enriched in specific EV subtypes (Cheruiyot chondrial proteins, such as TOM20, mtHSP70, and OPA1 are enriched in
et al., 2018). EVs, and these proteins can be targeted by MDVs to EVs (Todkar, 2021).
It appears that pink1-parkin-mediated mitophagy affects the outcome of
3.3. Lipids MDVs. During normal mitophagy activity, lysosome-targeted MDVs
block the release of oxidized mitochondrial components via EVs (Tod
Using high-throughput and high-sensitivity mass spectrometry- kar, 2021). The secretion of mitochondrial proteins might serve as a
based approaches, including liquid and gas chromatography combined quality control mechanism in which cells transport damaged mito
with mass spectrometry, this method provides the characterization and chondria to distant cells for degradation (Mahrouf-Yorgov, 2017; Joshi,
quantification of lipid species in EVs. The majority of lipid components 2019). The mechanism of damaged mitochondria efflux is also known as
originate from the EV membrane. Lipids, such as cholesterol, sphingo transmitophagy (Davis and Marsh-Armstrong, 2014). For instance,
myelin, glycosphingolipids, phosphatidylethanolamine (PE), phospha Davis et.al. found that retinal ganglion cell axons shed cellular mito
tidylcholine (PC), phosphatidylserine (PS) and so on, are enriched in chondria and these mitochondria are internalized and degraded by
exosomes (Llorente, 2013; Choi et al., 2013; Haraszti, 2016). Several adjacent astrocytes (Davis, et al., 2014). However, there is currently a
studies indicate that exosomes released from various cell lines exhibit a paucity of research investigating the potential association between
similar composition of lipid classes. This is likely due to the similarity in transmitophagy and EVs.
the composition of exosome membrane structure. PE and PS are notably EVs transferring mitochondrial components are considered a strat
expressed in the bilayer of exosomes, particularly in the outer leaflet egy for maintaining mitochondrial quality by dealing with damaged
(Booth, 2006). In contrast to parental cells, EVs have analogous lipid mitochondria. Choong et al. found that disrupting both Parkin-mediated
composition types but differ significantly in proportion, which may and Parkin-independent pathways for mitophagy increased the number
indicate the biogenesis of EVs (Skotland et al., 2017). Among these, the of depolarized mitochondria in the released EVs fraction (Choong,
sphingolipid ceramides are also enriched in exosomes, and they play a 2021). The extracellular release of mitochondria operates in parallel
role in enhancing the production of exosomes (Trajkovic, 2008). with mitophagy to sustain mitochondrial homeostasis. When the
Currently, there is insufficient research on EV lipidomics, and further mitophagy system is obstructed, the mechanism of mitochondria
quantitative lipidomic studies of exosomes and their lipid specifications transfer via EVs may compensate for insufficient mitophagy capacity
are required. (Choong, 2021). On the other hand, the extracellular release of mito
chondria in donor cells may serve as warning signals to the cells
3.4. Organelles and others receiving them (Mahrouf-Yorgov, 2017). It has been reported that
mesenchymal stem cells (MSCs) engulf mitochondria derived from
The results from the mass spectrometry analysis suggest that EVs endothelial cells, resulting in the induction of the cytoprotective enzyme
contain multiple organelle components, including proteins derived from heme oxygenase-1 and stimulation of mitochondrial biogenesis in MSCs
3
(Mahrouf-Yorgov, 2017). The receipt of mitochondria activates the 5.1. Intact mitochondria
rescue properties of MSCs, ultimately improving cell survival in
ischemic environments. Crewe and colleagues discovered that adipo Several studies have confirmed the presence of intact mitochondria
cytes, in response to oxidative stress, release EVs containing damaged in EVs. The intact mitochondria retain the original function of energy
mitochondria (Crewe, 2021). These mitochondria-enriched EVs activate metabolism, which may be involved in energy transfer between cells
the antioxidant system in cardiomyocytes and provide protection (Liu, 2021). Souza et al. found that MVs deliver intact mitochondria to
against ischemia-induced injury. Multiple studies have demonstrated brain endothelial cell; and the mitochondrial transfer increases the ATP
that MDV represents an important origin of mitochondria-embeded EVs level by 200-fold compared with untreated cells (D’Souza, 2021). Sup
(Sugiura et al., 2014; Todkar, 2021; Collier et al., 2023). MDVs appear to ply of intact mitochondria increases the ATP level of the recipient cells
sprout from the mitochondrial structure, acting as a selective transporter and improves their antioxidant stress capacity, which contributes to the
of damaged mitochondrial components to the lysosomal system. adaptation to stressful environments (Liu, 2022; Dave, 2023). According
From a perspective of physical size, MVs are more inclined to load to Thomas et al. (Thomas, 2022), intercellular transfer of healthy
complete mitochondrial structures. The presence of mitochondria in mitochondria via EVs augments mitochondrial content and function of
MVs has been established by a number of studies (Haraszti, 2016; chondrocytes, which presents a therapeutic approach for poorly-healing
Phinney, 2015; D’Souza, 2021). Hayakawa et al. discovered that the cartilage. It could be also being explored as a potential treatment for
calcium-dependent release of extracellular mitochondria in MVs was various ischemic or degenerative diseases. Although some research
facilitated by CD38 signaling (Hayakawa, 2016). Furthermore, the for suggests that intact mitochondria transfer is linked to the inflammatory
mation of MVs was inhibited by a specific inhibitor, which led to a response (Puhm, 2019; Boudreau, 2014), it is important to note that
decrease in the extracellular release of mitochondria (Zhang, 2020). mitochondria membrane structure remains intact, preventing the
According to Anand et al., MVs from wildtype cells showed an enrich leakage of their contained DAMPs and generally avoiding immune re
ment of mitochondrial proteins, whereas MVs from ARRDC1-knockout sponses in the recipient cells. Indeed, several studies have suggested the
cells were enriched with proteins related to meiotic recombination anti-inflammatory role of transferred intact mitochondria. According to
and DNA methylation (Anand, 2018). Souza and colleagues discovered Jametti et al.’s research, the incorporation of mitochondria from EVs
that endothelial cell-derived MVs contain a high concentration of into inflammatory mononuclear phagocytes reinstated mitochondrial
ATP5A, a subunit of the mitochondrial ATP synthase protein (D’Souza, dynamics and decreased the expression of pro-inflammatory markers
2021). These MVs deliver mitochondria through MV/ATP5A complexes. (Peruzzotti-Jametti, 2021). Mitochondrial supplementation can
Their findings suggest that cationic ATP5A protein interacts with improve the energy supply of cells and is of great significance for tissue
negatively-charged MVs membranes through electrostatic interactions repair. The mitochondria delivered by vesicles are more easily ingested
to form a complex (D’Souza, 2021). Mitochondria contained within MVs by cells or tissues, and have inhibitory effects on the progression of acute
can be pro-inflammatory in certain instances. For instance, Puhm et al. and chronic inflammation (Nascimento-dos-Santos et al., 2021; Hu,
found that mitochondria-embedded MVs stimulates the TNF and type I 2023) (Fig. 1).
IFN responses, as well as the release of IL-1 and IL-8 in endothelial cells
(Puhm, 2019). The depletion of TOM22-positive MVs subsequently 5.2. Mitochondrial fragment
limits the ability of MVs to incite inflammatory pathways, effectively
highlighting the significant contribution of mitochondria within MVs to Several studies have reported the presence and function of mito
the immune response. chondrial fragments in EVs, mostly damaged or depolarized mitochon
Currently, some scholars consider migrasomes to be a novel form of dria (Choong, 2021). However, incomplete structure of mitochondria
EVs (Ardalan, 2022). Migrasomes are large vesicle with pomegranate- does not necessarily imply a lack of functionality. Crewe et al. have
like structures, approximately 500–3000 nm in size, that are linked to shown that oxidative stress-treated adipocytes secrete sEVs rich in
cell migration. Cellular contents can be actively transported into the damaged mitochondria (Crewe, 2021). And, the release of damaged
migrasome, which mediates intercellular communication and substance mitochondria can alleviate the stress level of maternal adipocytes.
transfer (Jiang, 2023). Tetraspanins (TSPANs) are involved in the for Mitophagy is an essential mechanism for cellular degradation under
mation of migrasomes (Zhang et al., 2023). Specifically, the initial stage stress (Ashrafi and Schwarz, 2013). It has been suggested that EVs
of migrasomes formation is the membrane tension, which leads to the deliver damaged mitochondria, which serve as the mechanism to out
local swellings on the tubular retraction fibers. TSPANs, particularly source mitophagy (Phinney, 2015). The transferred depolarized mito
TSPAN4, stabilize TSPAN-based membrane domains and transform chondria can enhance the bioenergetics of macrophages. On the other
these swellings into migrasomes (Dharan, 2023). Migrasome-mediated hand, mitochondrial fragments are taken up by surrounding cells
transfer of mitochondria is believed to alleviate cellular mitochondrial through sEVs, thereby improving the antioxidant response of recipient
stress, thereby maintaining mitochondrial quality and viability in neu cells (Crewe, 2021). Intercellular transmission of damaged mitochon
trophils. This process is referred to as mitocytosis, according to Jiao dria has become an important self-regulated mechanism for adaptation
et al.’s research (Jiao, 2021). During mitocytosis, damaged mitochon to injury (Fairley et al., 2022). Additionally, Suh et al. found that frag
dria are transported to the cell periphery by the inward motor protein mented mitochondria are secreted extracellularly by osteoblasts, and
dynein and the outward motor kinesin 1. Research on migrasomes is still these mitochondrial fragments accelerate osteogenesis (Suh, 2023). This
in its early stages and requires further investigation. also reveals the possibility of MDVs carrying mitochondrial fragments.
5. Transfer of mitochondrial component in EVs 5.3. mtDNA
Mitochondria are closely associated with immune responses and Several studies have demonstrated that EVs mediate inflammatory
inflammation. Many studies have implicated that intact mitochondria or responses by delivering mtDNA. Currently, the detection of mtDNA in
mitochondrial components can be transferred via EV-dependent EVs from peripheral blood (cell-free DNA) may serve as a molecular
pathway (Table 1). However, the role of intercellular mitochondrial diagnostic method for many diseases (Nikanjam et al., 2022; Song,
transfer varies across different diseases, and there still lacks systematic 2022). It has been shown that elevated levels of mtDNA in EVs indicate
research into the underlying mechanisms. inflammatory diseases or tumour progression (Vikramdeo, 2022;
Byappanahalli, 2023). The release of mtDNA into EVs is suggested to
coincide with an increase in the expression of markers associated with
DNA damage, proinflammatory cytokines, and senescence (Giordano,
4
Table 1
The mechanism and function of mitochondria transfer in EVs.
EV types Extraction methods Mitochondrial components Biogenesis mechanism Effects on the Recipient cells
MVs Centrifugation, 18 K g Intact mitochondria Associated with lipopolysaccharide To induce proinflammatry activity associated with type
stimulation I IFN and TNF signaling (Puhm, 2019)
MVs Centrifugation, 20 K g Intact mitochondria The binding between MVs and ATP5A To increase mitochondrial function and facilitate
via electrostatic interactions endothelial cell survival under ischemic conditions (
D’Souza, 2021)
MVs Centrifugation, 10 K g Depolarized mitochondria Arrestin domain-containing protein 1- To enhance macrophage bioenergetics (Phinney, 2015)
mediated mitochondria loading at cell
surface
Microparticles N/A Intact mitochondria Associated with actin contribution To promote inflammatory response and leukocyte
and independently of microtubules activation (Boudreau, 2014)
Microparticles Centrifugation, 17.8 K g Intact mitochondria N/A To regulate metabolic reprogramming (Gharib et al.,
2023)
sEVs Ultracentrifugation, 100 K g Mitochondrial proteins Associated with plasma membrane P2 To drive the accumulation of ATP into the tumor
receptor microenvironment (Vultaggio-Poma, 2022)
sEVs Ultracentrifugation, 100 K g Mitochondrial fragments Originating from MDVs and affected To induce a transient state of oxidative stress, which
by parkin-mediated mitophagy triggers an antioxidant response (Crewe, 2021)
sEVs Ultracentrifugation, 120 K g Mitochondrial N/A To restore TFAM protein and TFAM-mtDNA complex
transcription factor A stability, thereby reversing mtDNA deletion and
(TFAM) mRNA and mtDNA mitochondrial oxidative phosphorylation (Zhao, 2021)
sEVs Exo-Spin, commercial kit Mitochondrial proteins Sorting nexin 6 and 9-dependent To suppress the host antiviral response and facilitate
MDVs formation viral infection (Lee and Shin, 2023)
sEVs Ultracentrifugation, 110 K g Mitochondrial fragments N/A To transfer mtDNA with a metastasis-enhancing
and mtDNA pathogenic mutation (Takenaga et al., 2021)
mEVs and Centrifugation, 20 K g Intact mitochondria Associated with mitochondria To increase relative ATP levels and mitochondrial
lEVs electron transport complex V function (Dave, 2023)
lEVs Size-based filtration, ExoTIC Intact mitochondria N/A To reduce ROS production and preserve mitochondrial
biogenesis and function (O’Brien, 2021)
EVs Ultracentrifugation, 100 K g Intact mitochondria Associated with superoxide To reverse the metabolic function and maintain ATP
accumulation and mitophagy supply (Hu, 2023)
EVs Ultracentrifugation, 100 K g Intact mitochondria N/A To induce mitochondrial fusion and repair the
mitochondrial function (Lu, 2022)
EVs Qiagen Exoeasy, commercial Mitochondrial proteins Associated with radiation stimulation To reprogram mitochondrial homeostasis and enhance
kit cell survival (Miller, 2022)
EVs Ultracentrifugation, 100 K g Mitochondrial proteins and Originating from Optic Atrophy 1 and To activate an inflammatory response (Todkar, 2021)
mtDNA sorting nexin 9-dependent MDVs
EVs Ultracentrifugation, 100 K g Intact mitochondria N/A To enhance macrophage oxidative phosphorylation (
Morrison, 2017)
EVs Total Exosome Isolation, mtDNA N/A To upregulate the expression of pro-inflammatory
commercial kit cytokines (Giordano, 2022)
EVs ExoQuick, commercial kit Intact mitochondria N/A To augment mitochondrial content and function (
Thomas, 2022)
EVs Sucrose gradient Mitochondrial proteins Originating from MDVs Serve as biomarkers during mitochondrial stress and
centrifugation, 151 K g related pathologies (Vasam, 2021)
EVs Ultracentrifugation, 150 K g Mitochondrial proteins Originating from MDVs To deliver ATP synthase and produce ATP (Hazan Ben-
Menachem, 2023)
EVs Ultracentrifugation, 100 K g Mitochondrial proteins N/A To regulate thermogenesis activity (Camino, 2022)
EVs Ultracentrifugation, 100 K g mtDNA PINK1-dependent interaction To promote endosomal trafficking and invasiveness (
between mitochondria and late Rabas, 2021)
endosomes
EVs Ultracentrifugation, 100 K g mRNA N/A To restore of bioenergetics and mitochondrial
biogenesis (Ikeda, 2021)
EVs Centrifugation, 13 K g Mitochondrial fragments The formation of MDVs via CD38/ To modulate mitochondrial morphology and enhance
cyclic ADP ribose signaling osteoblast maturation (Suh, 2023)
EVs Size exclusion mtDNA N/A To serve as damage-associated molecular pattern
chromatography (DAMP) molecules (Byappanahalli, 2023)
EVs Sucrose gradient and mtDNA N/A To remold tumor microenvironment and promotes
ultracentrifugation, 150 K g macrophages shift to pro‑inflammatory phenotype (
Liu, 2023)
EVs Centrifugation, 5 K g Mitochondrial proteins N/A To prevent endothelial reactive oxygen species
accumulation (Bao, 2022)
EVs Centrifugation, 10 K g Intact mitochondria Associated with small GTPase Rab7 Captured by macrophages without activating
and lysosomal function inflammation (Liang, 2023)
Exosomes Ultracentrifugation, 100 K g mtDNA Associated with caspase-1 To promote a strong inflammatory response (Konaka,
2023)
Exosomes N/A mtRNA Associated with protein kinase R To activate Toll-like receptor 3 and inflammatory
activation pathway (Kim, 2022)
Exosomes Polyethyleneglycol Mitochondrial proteins N/A To restore mitochondrial function and alleviate
precipitation and oxidative stress (Sayeed and Sugaya, 2022)
centrifugation, 10 K g
Exosomes Ultracentrifugation, 100 K g Intact mitochondria N/A To co-localize with the mitochondrial network and
generate reactive oxygen species (Hough, 2018)
Exosomes Ultracentrifugation, 110 K g mtDNA The mtDNA-binding and packaging To improve mitochondrial integrity and oxidative
protein TOM20 and NDUFV2 bolster phosphorylation level, and enable macrophages
the mtDNA loading shifting to anti-inflammatory phenotype (Xia, 2022)
(continued on next page)
5
Table 1 (continued )
EV types Extraction methods Mitochondrial components Biogenesis mechanism Effects on the Recipient cells
Exosomes Sucrose gradient Intact mitochondria CD9 and CD63-dependent pathway To restore normal mitochondrial dynamics and reduce
centrifugation, 100 K g the expression of pro-inflammatory markers (
Peruzzotti-Jametti, 2021)
Exosomes Ultracentrifugation, 100 K g Intact mitochondria The inhibition of dynamin-related To inhibit mitochondria-mediated apoptosis pathway
protein-1/Fission 1‑mediated and alleviate mitochondria-mediated neuronal damage
mitochondrial fission
Exosomes ExoQuick, commercial kit mtRNA MtRNA that escapes into the To activate toll-like receptor 3 and stimulate IL-1β
cytoplasm and MVBs depends on production (Lee, 2020)
polynucleotide phosphorylase
Exosomes ExoQuick, commercial kit Intact mitochondria N/A To improve the recovery of mtDNA content and
oxidative phosphorylation (Yang, 2023)
Exosomes ExoQuick, commercial kit Mitochondrial proteins and Originating from MDVs and N/A
mtDNA mitophagy-associated (Wang, 2022)
Exosomes Ultracentrifugation, 100 K g mtRNA N/A To serve as potential predictors of inflammation (
Ranches, 2022)
Abbreviations: MVs, microvesicles; s/m/l EVs, small/ medium/large extracellular vesicles; MDVs, mitochondria-derived vesicles; mtDNA/RNA, mitochondrial DNA/
RNA.
Fig. 1. The mechanisms and function of EV-mediated mitochondria transfer. Mitochondria-loading EVs are produced in the donor cells (left panel). The intact and
damaged mitochondria, as well as mitochondrial contents, including mtDNA, proteins and mtRNA are selectively loaded into intracellular vesicles. In addition to
being degraded by lysosomes, they can escape outward in the form of EVs, including MDVs, MVs or exosomes. Following the engulfment of mitochondria or
mitochondrial fragments by recipient cells (right panel), mitochondrial dynamics, energy supply and oxidative phosphorylation levels undergo a series of changes.
Besides, EV-mediated mitochondrial transfer could activate or regulate cellular inflammatory responses in the recipient cells. MV, microvesicles; MDV, mitochondria-
derived vesicle; P2X7R, plasma membrane P2 receptor; ARRDC1, arrestin domain-containing protein-1; OPA1, Optic Atrophy 1; NDUFV2, NADH dehydrogenase
(ubiquinone) flavoprotein 2; PNPase, polynucleotide phosphorylase; MVB, multivesicular bodies; PINK1, PTEN induced putative kinase 1; TLR, Toll-like receptors;
cGAS, cyclic GMP-AMP synthase; AIM2, absent in melanoma 2; ROS, Reactive oxygen species.
2022). Byappanahalli et al. proposed that mtDNA within EVs serve as a receiving exogenous mtDNA-containing EVs (Zhao, 2021). Xia et al. also
risk factor for frail individuals (Byappanahalli, 2023). Their investiga suggested that EVs transfer mtDNA to enable macrophages shifting to
tion suggested a significant correlation between EV mtDNA levels and anti-inflammatory phenotype, thereby increasing the production of anti-
the presence of inflammatory proteins. Mechanically; activation of inflammatory cytokines (Xia, 2022).
caspase-1 leads to mtDNA leakage from the mitochondria into the
cytoplasm (Konaka, 2023). It also induces the formation of ILVs, sub 5.4. mtRNA
sequently promoting the mtDNA trafficking into exosomes, and these
mtDNA-loading exosomes promotes a strong inflammatory response in Currently, there is limited research on the function of mtRNA in EVs.
the recipient cells. However, it has been suggested that mtDNA in EVs However, multiple tRNAs and rRNAs are important DAMPs involved in
may have anti-inflammatory effects. The recipient cells showed signifi the occurrence of inflammation (Di Florio et al., 2020; Koupenova et al.,
cant improvement in mtDNA deletion and OXPHOS defects after 2018). It is suggested that the content of mtRNA in exosomes can serve
6
as a diagnostic marker for sensing kidney inflammation (Ranches, compartments, including outer and inner membrane, intermembrane
2022). After delivering mtRNA to target cells, EV can activate Toll-like space and matrix, are found to be enriched in MVs and exosomes (Zor
receptors on the cell surface and elicit inflammatory pathways (Lee, ova, 2022). It has been suggested that EVs deliver functional mito
2020). According to Kim et al., polynucleotide phosphorylase (PNPase) chondrial proteins, such as ATP synthase and mitochondrial membrane
facilitates the release of mtRNA through the BAX-BAK1 pores on the proteins, to perform specific functions (Hazan Ben-Menachem, 2023).
mitochondrial membrane (Kim, 2022). As a result, the removal of Miller et al. discovered that EVs contain high levels of mitochondrial
cytosolic mtRNAs improves mitochondrial stress. Additionally, the antioxidant proteins, including peroxiredoxin 3 and glutathione perox
extracellular efflux of mtRNAs activates the innate immune system and idase 4, which promote the survival of prostate cancer cells (Miller,
promotes the development of osteoarthritis. Lee et al. suggested that the 2022). Additionally, EVs transport superoxide dismutase 2 to prevent
trafficking of mtRNA into exosomes is associated with mitochondrial the accumulation of reactive oxygen species in endothelial cells and
RNA helicase SUV3 and PNPase (Lee, 2020). Studies have shown that alleviate endothelial dysfunction (Bao, 2022). Sayeed et al. proposed
under conditions of stress, cells secrete more mtRNA components in EVs, that exosomes can restore mitochondrial function and alleviate oxida
and the authors speculate that these mtRNAs may originate from tive stress by delivering TOM40 (Hazan Ben-Menachem, 2023). Their
mitochondrial fragments of damaged cells (Kim, 2020). The changes in findings reveal that functional ATP synthase subunits are enriched in
mtRNA content in EVs may be clinically significant in certain diseases, EVs, which suggest the potential to regenerate ATP-deficient mito
thus can be diagnostic and prognostic biomarkers (Lekva, 2023). chondria. Mitochondrial protein-enriched EVs are generally believed to
originate from MDVs, and the presence of mitochondrial proteins may
6. Mitochondrial protein also indicate the mitochondrial fragments (Vasam, 2021). During the
formation of MDVs, sorting nexin (Snx) family proteins play an impor
Multiple studies based on EV proteomics have shown that EVs tant role (Towers, 2021). Lee et al. found that Snx6 and Snx9 are
contain mitochondrial protein components (Vasam, 2021; Camino, required during the formation of MDVs targeted for extracellular release
2022; Quiroz-Baez et al., 2020). Proteins located different mitochondria or lysosomal degradation (Lee and Shin, 2023). Furthermore,
Fig. 2. The biological function of EV-mediated mitochondrial transfer and its application in multiple human diseases. mtDNA, mitochondrial DNA; mtRNA,
mitochondrial RNA; DAMPs, damage-associated molecular patterns. The figure was produced using Figdraw.
7
mitochondrial proteins can activate the immune response and are linked intercellular transfer of invasive behavior by activating Toll-like recep
to the progression of inflammation. Mitochondrial components, such as tor 9 in recipient cells (Rabas, 2021). It also modifies the endosomal
N-formyl peptides, cytochrome C and other mitochondrial proteins are trafficking of pro-invasive receptors in recipient cells, thus promoting
selectively loaded into EVs, which stimulates a strong inflammatory invasiveness. Altered metabolism is a defining characteristic of tumor
response in immune cells (Todkar, 2021). cell (Carles-Fontana et al., 2022). It has been suggested that the transfer
of mitochondria via EVs can contribute to tumor malignancy by
7. Ev-mediated mitochondrial transfer in human diseases inducing metabolic reprogramming (Gharib et al., 2023). This transfer
can lead to malignant characteristics, including elevated levels of oxy
In recent years, advances in detection and analytical technology have gen consumption rates, ATP production, and ROS generation. Besides,
provided numerous pieces of evidence for the existence of mitochondria mitochondrial Lon mediates the loading of oxidized mtDNA into EVs, as
and their components in EVs, and they play an important role in inter well as the secretion of EVs (Cheng, 2020). These EVs are found to
cellular substance exchange and signaling transduction. EV-mediated weaken T-cell immunity and drive the PD-L1-mediated immunoescape
mitochondrial transfer is crucial in the pathogenesis and diagnosis of in the tumor microenvironment. Chemoresistance presents a significant
human pathologies, such as infection, tumorigenesis, metabolic, car challenge in cancer treatment and is crucial for the development of new
diovascular, respiratory, neurological, and musculoskeletal diseases therapies. Chemoresistant breast cancer cells can transfer mitochondria
(Fig. 2). to sensitive cancer cells via EVs, thereby increasing their chemo
resistance. Mechanistically, it has been demonstrated that EVs carrying
7.1. Infection mitochondria contribute to acquired chemoresistance by increasing the
levels of mutated mtDNA in the mtND4 gene, which is responsible for
EVs and their mitochondria components play a crucial role in the tumorigenesis (Abad and Lyakhovich, 2022).
process of bacterial or viral infection. Pathogens activate the EV trans
port mechanism in host cells, promoting the release of mitochondria- 7.3. Metabolic disorder
enriched EVs rich or MDVs to participate in the immune response.
Alternatively, EVs derived from pathogens can directly deliver antigens Oxidative stress, insulin resistance (IR) and metabolic disturbance
to participate in the immune and inflammatory response. Many viruses associated with mitochondrial dysfunction are important factors in the
usually exploit cellular organelles, such as mitochondria, to facilitate development of metabolic diseases, such as obesity and diabetes (Chen,
their life cycle. In the case of Zika virus (ZIKV) infection in trophoblast 2022). Restoration of mitochondrial homeostasis is likely to have a
cells, ZIKV promotes the release of EVs. These ZIKV-infected EVs are potential therapeutic effect on metabolic diseases and their complica
enriched in mitochondrial proteins and induce changes in mitochondrial tions. Stem cells have the ability to transfer mitochondria into
dynamics and mitophagy in the host cell (Lee and Shin, 2023). This mitochondria-deficient cells and restore mitochondrial function through
enables ZIKV to evade the innate immune response and facilitate its EVs or gap junction channel-mediated pathways (Yang, 2023). Re
infection. Besides, in HIV patients, particularly in viremic individuals, searchers have discovered that MDVs, which are enriched with func
the level of mtDNA in lEVs and sEVs is significantly increased, indicating tional ATP synthase complex, can fuse with mitochondria of recipient
the incorporation of mtDNA into EVs during HIV infection (Bazié, 2023). cells to produce ATP (Hazan Ben-Menachem, 2023). The transfer of
Peluso et al. found that SARS-CoV-2 and mitochondrial proteins are ATP-producing MDVs may serve as a regulatory mechanism for energy
present in neural-derived exosomes, particularly in patients with supply during metabolic diseases. What’s more, EVs derived from white
neuropsychiatric manifestations (Peluso, 2022). This discovery suggests adipose tissue (WAT) bring the metabolic effects associated with IR and
that mitochondrial proteins in EVs could serve as a biomarker for COVID glucose tolerance (Mastrototaro and Roden, 2021). Injection of EVs
prognostics. Extracellular mitochondria are present in EVs and produce derived from obese WAT into lean mice could lead to IR and inflam
inflammatory mediators, including lysophospholipids, fatty acids, and mation (Ying, 2017). These EVs secreted by adipose tissue contain
mtDNA, which stimulate leukocyte activation and inflammation (Bou mitochondrial brown fat uncoupling protein 1, and other mitochondrial
dreau, 2014). Mitochondria-enriched EVs transfer superoxide dismutase enzymes, which are associated with obesity-related metabolism and
2 to induce the antithrombotic function of neutrophils, thereby thermogenesis activity (Camino, 2022). The opening of the mitochon
ameliorating lipopolysaccharide-induced sepsis (Bao, 2022). Some re drial permeability transition pore under oxidative stress usually leads to
ports also suggest a link between bacterial pathogenesis and mito mtDNA escape into cytosol and partial release of mtDNA via EVs (Pérez-
chondrial function through bacterial outer membrane vesicles (Deo, Treviño et al., 1866). Liu et al. found that the levels of mtDNA are
2020; Tiku, 2021). As mitochondria contain multiple DAMP compo significantly correlated with fasting blood glucose in patients with dia
nents, the process of EV-mediated mitochondria transfer is closely betes mellitus (DM) (Liu, 2016). Intercellular transfer of mtDNA may be
related to inflammation. However, the biological mechanisms involved an important mechanism in the progression of diabetes-related inflam
require further exploration. mation (Chang, 2022). One potential treatment direction for DM is to
intervene in the formation and release of damaged mtDNA or block its
7.2. Tumorigenesis transfer via EVs between cells.
Tumor cells have a more vigorous metabolism and higher energy 7.4. Cardiovascular disease
requirements than normal cells. They also exhibit secretory character
istics and can produce a large number of EVs (Becker, 2016; Marar et al., Myocardial cells are highly energy-consuming and require signifi
2021). Tumor-derived EVs play a crucial role in mediating phenotypic cant levels of ATP and healthy mitochondria. Mitochondria-based
changes in tumor cells. Several studies have shown that the mitochon therapy has shown promising potential in treating myocardial ische
drial components contained in EVs are the dominant factors in tumor mia–reperfusion injury (Dörner, 2021). Cardiac mitochondria pre
occurrence, metastasis, recurrence, and chemoresistance (Abad and conditioning has been suggested to improve the proliferation and repair
Lyakhovich, 2022; Jang, 2019; Bertolini, 2020). Tumor-derived mutant properties of stem cells in ischemic heart disease (Vignais, 2023).
mtDNAs are the important mediator of metastasis. The researchers Additionally, mitochondria-rich EVs have shown promising potentials in
discovered that pathogenic mtDNA derived from metastatic tumor cells, improving cardiovascular function. Researchers have found that EV-
which enhances metastasis, is transferred to low-metastatic tumor cells mediated mitochondria transfer promotes ATP production and mito
via EVs in the tumor microenvironment (Takenaga et al., 2021). The chondrial biogenesis, which can mitigate doxorubicin injury in car
mtDNA serves as a key EV cargo that is necessary and sufficient for diomyocytes (O’Brien, 2021). Intramyocardial injection of EVs
8
facilitates the transfer of mitochondrial components into injured car stroke (D’Souza, 2021; Hayakawa, 2016; Dave, 2023). The treatment of
diomyocytes, improving cardiac function during myocardial infarction exogenous EVs increases the ATP levels and mitochondrial function of
(Ikeda, 2021). Crewe discovered that EVs secreted by adipocytes contain BECs. It is worth noting that the integrity and functionality of mito
damaged mitochondria (Crewe, 2021). Cardiomyocytes can take up chondria are prerequisites for the protective effect of EVs on the nervous
these EVs via the bloodstream, which triggers a burst of ROS. The system. The transfer of oxidatively damaged astrocytic mitochondria
transfer of mitochondria through EVs serves as a compensatory antiox into neurons usually cause serious neuronal damage and cerebral
idant signal in the heart, protecting cardiomyocytes from ischemic ischemic injury (Gollihue and Norris, 2020). Liu et al. used engineered
stress. Furthermore, the elimination of damaged mitochondria through exosomes to mitigate mitochondrial damage in astrocytes following
EVs could serve as a means of mitochondrial quality control, which is ischemia–reperfusion (Liu, 2022). This ensured the release of healthy
beneficial for maintaining cardiac homeostasis. This is particularly astrocytic mitochondria, which were then transmitted to neurons,
important when lysosomal function is compromised in cardiomyocytes, thereby alleviating mitochondria-mediated neuronal damage. Mito
as EV-mediated mitochondria release can compensate for cellular chondrial dysfunction is also widely recognized as a hallmark of neu
degradation machinery (Liang, 2023). However, some studies suggest rodegeneration, such as Alzheimer’s and Parkinson’s diseases (Yan
that mitochondria present in EVs can induce inflammatory responses in et al., 2013). Delivery of the mitochondrial membrane protein TOM40
endothelial cells. Activated monocytes release mitochondria-enriched via exosomes can protect against oxidative stress in neurodegenerative
MVs to activate type I interferon and tumour necrosis factor signaling, diseases by regulating mitochondrial function (Sayeed and Sugaya,
leading to inflammation during cardiovascular disease (Puhm, 2019). 2022). Additionally, neural stem cells transport functional mitochondria
Therefore, the biological effects of EVs are determined by their maternal via EVs to restore normal mitochondrial dynamics and reduce the levels
cell type. For instance, immune cell-derived EVs are associated with of pro-inflammatory cytokines in neurons (Peruzzotti-Jametti, 2021).
inflammatory responses, while stem cell-derived EVs are more suitable Thus, the transmission of mitochondria through EVs provides a prom
for treatment. ising avenue for developing acellular therapies to restore mitochondrial
dysfunction in degenerative neurological disorders.
7.5. Respiratory disease
7.7. Musculoskeletal disease
EVs are shown to contribute to the development of acute and chronic
inflammation in the respiratory system. Under pathological conditions, Multiple studies have shown that EVs have great potential in the
respiratory cells release EVs that contain mitochondrial components. For treatment of musculoskeletal diseases, such as intervertebral disc
instance, Hough et al. extracted exosomes from bronchoalveolar lavage degeneration, osteoarthritis, tendon injury, and osteoporosis (Liao,
fluid of asthma patients (Hough, 2018). They discovered that exosomes 2023; Yao, 2019; Liao, 2021). The self-healing ability of intervertebral
can transfer a number of mitochondria to receptor T cells and fuse with discs, cartilage, tendons, and other avascular soft tissues is poor. EV-
the mitochondrial network. This process produces reactive oxygen mediated cell-free therapy can promote tissue repair and organ regen
species and activates inflammatory signals in T cells. In addition, the eration. Among them, EVs can mediate mitochondrial transfer between
release of mtDNA into EVs occurred simultaneously with an increase in cells, providing functional mitochondria to augment mitochondrial
the expression of inflammatory markers, such as IL-1β, IL-6, IL-8, and IL- content and function (Thomas, 2022). Mitochondrial transfer can serve
18 (Giordano, 2022). This suggests that mtDNA in plasma EVs could as a signal for osteogenic differentiation. Researchers have found that
serve as a biomarker for chronic pulmonary inflammation. EV-mediated osteoblasts release EVs containing mitochondrial fragments and these
mitochondrial transfer is an important mechanism in stem cell therapy EVs promote the osteogenic differentiation of osteoprogenitor cells upon
for lung injury (Velarde, 2022). Intercellular mitochondrial transfer uptake (Suh, 2023). Mitochondrial dysfunction or inhibition of mito
increases the ATP level of alveolar epithelium, protecting against acute chondrial release via EVs may promote the progression of osteoporosis.
lung injury (Islam, 2012). Researchers also found that exosomes can On the other hand, skeletal muscles are capable of producing high levels
transfer mitochondrial components to alveolar macrophages, elevating of EVs. According to Estrada et al., at least 5 % of circulating EVs
the level of mtDNA, mitochondrial membrane potential and ATP gen originate from skeletal muscle fibers (Estrada, 2022). During exercise,
eration (Xia, 2022). This restores the metabolic homeostasis of airway muscle cells release EVs that are rich in peptides and nucleic acids,
macrophages and ameliorates lung inflammation. Previous studies have which are referred to as ’exerkines’ (Safdar et al., 2016). Circulating EVs
demonstrated that stem cells can suppress the secretion of proin contain various mitochondrial components and are implicated in
flammatory cytokines, enhance phagocytic capacity, and promote the various systemic diseases (Picca, 2023). What’s more, EV-mediated
M2 macrophage phenotype in human macrophages (Morrison, 2017). mitochondria transfer is involved in the progression of musculoskel
The therapeutic effects of stem cells are shown to be mediated by etal inflammation. Kim et al. discovered that oxidative stressors cause
paracrine mechanisms, particularly EVs. The paracrine effects include the release of mtRNAs into the cytosol and extracellular space, which in
the transfer of mitochondria and are critically dependent on the turn triggers the activation of the innate immune system in osteoarthritis
enhancement of oxidative phosphorylation and ATP level in macro (Kim, 2022). Inhibition of exosome release or removal of cytosolic
phages (Morrison, 2017; Jackson, 2016). mtRNAs can protect chondrocytes from mitochondrial stress. Chronic
low-grade inflammation is a characteristic of physical frailty and sar
7.6. Neurological disease copenia. A functional link exists between muscular mitochondrial
dysfunction and systemic inflammation, possibly mediated by the
Mitochondrial dysfunction is commonly acknowledged as a hallmark release of MDVs into the circulation (Marzetti, 2019). The release of
of ischemic stroke and is known to cause pathological changes during MDVs also serves as the way of mitochondrial clearance, leading to the
ischemia and reperfusion (He et al., 2020; Yang et al., 2018). Mito loss of skeletal muscle mitochondrial content and respiratory capacity
chondria play a crucial role in promoting neural survival and recovery during sarcopenia (Leermakers, 2020).
after ischemic stroke. Ischemic stroke always results in the death of
brain endothelial cells (BECs) and damage to the integrity of the 8. Concluding remarks
blood–brain barrier. Mitochondrial dysfunction induced by ischemia in
BECs leads to the generation of excessive ROS, a reduction in ATP levels, Extensive research has been conducted on EVs in the past decade,
and ultimately BEC death (Shanmughapriya et al., 2020). Several with a focus on the mechanisms of EV biogenesis, transport, content
studies have suggested that mitochondria-containing EVs could reduce sorting, release, and cellular uptake. EVs play a crucial role in both
brain infarct sizes in animal models and protect BECs against ischemic cellular physiological activities and pathological processes of diseases.
9
Engineered EVs have also been extensively designed and applied in functions, and medical applications. Enriching our understanding of EV
various cells and disease models based on their biological characteristics content will help us conduct more in-depth EV research.
and functions (Sharma and Mukhopadhyay, 2024; Nieland et al., 2023;
Zhang, 2021). With the increasing research on the proteome, tran CRediT authorship contribution statement
scriptome, and lipidome of EVs, the understanding of EV contents is
gradually deepening. Evidence suggests that EVs contain essential Zhiwei Liao: Writing – review & editing, Writing – original draft,
components, including mitochondria and their fragments. These intact Funding acquisition, Data curation, Conceptualization. Bide Tong:
mitochondria possess complete functionality and can fuse with the Formal analysis, Data curation, Conceptualization. Wencan Ke: Inves
mitochondrial network of recipient cells. The addition of exogenous tigation, Data curation. Cao Yang: Writing – review & editing. Xinghuo
mitochondria can enhance cellular energy production, which is partic Wu: Writing – review & editing, Supervision. Ming Lei: Writing – re
ularly important for energy-deficient cells or tissues. Mitochondrial view & editing, Supervision, Funding acquisition.
transport via EVs may also serve as a crucial self-regulatory mechanism
under stress. During the progression of pathological diseases, intracel Acknowledgments
lular mitochondrial fragments or components such as mtDNA and
mtRNA can affect surrounding cells through paracrine pathways. Due to This work was supported by the National Natural Science Foundation
the disruption of mitochondrial integrity, various proteins and nucleic of China (82302763) and the Surface Project of Technical Innovation
acids as DAMPs may escape into the cytoplasm that induce inflamma Special Project of Hubei Province (2021CFB591).
tion. It has been confirmed that EV-mediated transfer of mitochondrial-
related DAMPs is involved in the progression of various inflammatory References
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Mitochondrion 78 (2024) 101935

Contents lists available at ScienceDirect

Extracellular vesicles as carriers for mitochondria: Biological functions and

1. Introduction phospholipid compositions. They contain various enzymes, structural

5. Transfer of mitochondrial component in EVs 5.3. mtDNA

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