Extracellular vesicles (EVs) are naturally secreted as non-cell-autonomous signals involved in regulating immune responses, aging, angiogenesis, and tissue injury and repair within the central nervous system (CNS). Consequently, EVs have emerged as promising therapeutic targets in CNS-related diseases. More recently, a subset of these vesicles has been found to contain mitochondria (mitoEVs), suggesting that vesicles carrying mitochondrial signatures may also function as non-cell-autonomous signals and serve as potential biomarkers for injury or recovery in CNS pathophysiology. In this mini-review, we summarize current findings highlighting the critical roles of EVs and their therapeutic potential as demonstrated in cellular, animal, and human studies related to CNS injury and disease.
LouPLiuSXuX, et al. Extracellular vesicle-based therapeutics for the regeneration of chronic wounds: current knowledge and future perspectives. Acta Biomater2021; 119: 42–56.
2.
ShahRPatelTFreedmanJE.Circulating extracellular vesicles in human disease. N Engl J Med2018; 379(10): 958–966.
3.
WiklanderOPBBrennanMALotvallJ, et al. Advances in therapeutic applications of extracellular vesicles. Sci Transl Med2019; 11(492): eaav8521.
4.
ParkJNakamuraYLiW, et al. Effects of O-GlcNAcylation on functional mitochondrial transfer from astrocytes. J Cereb Blood Flow Metab2021; 41: 1523–1535.
5.
Eun JungJSunGBautista GarridoJ, et al. The mitochondria-derived peptide humanin improves recovery from intracerebral hemorrhage: implication of mitochondria transfer and microglia phenotype change. J Neurosci2020; 40: 2154–2165.
6.
Al Amir DacheZOtandaultA, et al. Blood contains circulating cell-free respiratory competent mitochondria. FASEB J2020; 34(3): 3616–3630.
7.
MiliotisSNicolaldeBOrtegaM, et al. Forms of extracellular mitochondria and their impact in health. Mitochondrion2019; 48: 16–30.
8.
MarleinCRPiddockREMistryJJ, et al. CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma. Cancer Res2019; 79(9): 2285–2297.
9.
LiuKGuoLZhouZ, et al. Mesenchymal stem cells transfer mitochondria into cerebral microvasculature and promote recovery from ischemic stroke. Microvasc Res2019; 123: 74–80.
10.
GaoLZhangZLuJ, et al. Mitochondria are dynamically transferring between human neural cells and alexander disease-associated GFAP mutations impair the astrocytic transfer. Front Cell Neurosci2019; 13: 316.
11.
GaoJQinALiuD, et al. Endoplasmic reticulum mediates mitochondrial transfer within the osteocyte dendritic network. Sci Adv2019; 5(11): eaaw7215.
12.
YaoYFanXLJiangD, et al. Connexin 43-mediated mitochondrial transfer of iPSC-MSCs alleviates asthma inflammation. Stem Cell Rep2018; 11(5): 1120–1135.
13.
SinhaPIslamMNBhattacharyaS, et al. Intercellular mitochondrial transfer: bioenergetic crosstalk between cells. Curr Opin Genet Dev2016; 38: 97–101.
14.
HayakawaKEspositoEWangX, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature2016; 535(7613): 551–555.
15.
IslamMNDasSREminMT, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med2012; 18(5): 759–765.
16.
SpeesJLOlsonSDWhitneyMJ, et al. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci U S A2006; 103(5): 1283–1288.
17.
DavisCHKimKYBushongEA, et al. Transcellular degradation of axonal mitochondria. Proc Natl Acad Sci U S A2014; 111(26): 9633–9638.
18.
BabenkoVASilachevDNZorovaLD, et al. Improving the post-stroke therapeutic potency of mesenchymal multipotent stromal cells by cocultivation with cortical neurons: the role of crosstalk between cells. Stem Cells Transl Med2015; 4(9): 1011–1020.
19.
VelmuruganGVVekariaHJPatelSP, et al. Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging. J Cereb Blood Flow Metab. Epub ahead of print 12 December 2024. DOI: 10.1177/0271678X241306054.
20.
LiuDLiaoPLiH, et al. Regulation of blood-brain barrier integrity by Dmp1-expressing astrocytes through mitochondrial transfer. Sci Adv2024; 10(26): eadk2913.
21.
WangXGerdesHH.Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ2015; 22(7): 1181–1191.
22.
ZhangYYuZJiangD, et al. iPSC-MSCs with high intrinsic MIRO1 and sensitivity to TNF-alpha yield efficacious mitochondrial transfer to rescue anthracycline-induced cardiomyopathy. Stem Cell Reports2016; 7(4): 749–763.
23.
TorralbaDBaixauliFSanchez-MadridF.Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Front Cell Dev Biol2016; 4: 107.
24.
BartGFischerDSamoylenkoA, et al. Characterization of nucleic acids from extracellular vesicle-enriched human sweat. BMC Genomics2021; 22(1): 425.
25.
WangXWeidlingIKoppelS, et al. Detection of mitochondria-pertinent components in exosomes. Mitochondrion2020; 55: 100–110.
26.
HoughKPTrevorJLStrenkowskiJG, et al. Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol2018; 18: 54–64.
27.
WeiZSuWLouH, et al. Trafficking pathway between plasma membrane and mitochondria via clathrin-mediated endocytosis. J Mol Cell Biol2018; 10(6): 539–548.
28.
KitaniTKamiDMatobaS, et al. Internalization of isolated functional mitochondria: involvement of macropinocytosis. J Cell Mol Med2014; 18(8): 1694–1703.
29.
PengTXieYShengH, et al. Mitochondrial-derived vesicles: gatekeepers of mitochondrial response to oxidative stress. Free Radic Biol Med2022; 188: 185–193.
30.
HeynJHeuschkelMAGoettschC.Mitochondrial-derived vesicles-link to extracellular vesicles and implications in cardiovascular disease. Int J Mol Sci2023; 24(3): 2637.
McLellandGLSoubannierVChenCX, et al. Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J2014; 33(4): 282–295.
33.
TodkarKChikhiLDesjardinsV, et al. Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs. Nat Commun2021; 12(1): 1971.
34.
LiBZhaoHWuY, et al. Mitochondrial-derived vesicles protect cardiomyocytes against hypoxic damage. Front Cell Dev Biol2020; 8: 214.
35.
MatheoudDSugiuraABellemare-PelletierA, et al. Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell2016; 166(2): 314–327.
36.
AhmadTMukherjeeSPattnaikB, et al. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J2014; 33(9): 994–1010.
37.
ZhouJZhangLPengJ, et al. Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation. Cell Metab2024; 36(9): 2054–2068.e14.
38.
LevouxJProlaALafusteP, et al. Platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming. Cell Metab2021; 33(2): 283–299 e9.
39.
ZhaoMLiuSWangC, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate mitochondrial damage and inflammation by stabilizing mitochondrial DNA. ACS Nano2021; 15(1): 1519–1538.
40.
PuhmFAfonyushkinTReschU, et al. Mitochondria Are a subset of extracellular vesicles released by activated monocytes and induce Type I IFN and TNF responses in endothelial cells. Circ Res2019; 125(1): 43–52.
41.
KoJHKimHJJeongHJ, et al. Mesenchymal stem and stromal cells harness macrophage-derived amphiregulin to maintain tissue homeostasis. Cell Rep2020; 30(11): 3806–3820.e6.
42.
HayakawaKBruzzeseMChouSH, et al. Extracellular mitochondria for therapy and diagnosis in acute central nervous system injury. JAMA Neurol2018; 75(1): 119–122.
43.
YaoPJErenEGoetzlEJ, et al. Mitochondrial electron transport chain protein abnormalities detected in plasma extracellular vesicles in Alzheimer’s disease. Biomedicines2021; 9(11): 1587.
44.
RajendranLHonshoMZahnTR, et al. Alzheimer’s disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A2006; 103(30): 11172–11177.
45.
Rosas-HernandezHCuevasERaymickJB, et al. Characterization of serum exosomes from a transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res2019; 16(5): 388–395.
46.
EitanEHutchisonERMarosiK, et al. Extracellular vesicle-associated abeta mediates trans-neuronal bioenergetic and Ca(2+)-handling deficits in Alzheimer’s disease models. NPJ Aging Mech Dis2016; 2: 16019-.
47.
ChaDJMengelDMustapicM, et al. miR-212 and miR-132 are downregulated in neurally derived plasma exosomes of Alzheimer’s patients. Front Neurosci2019; 13: 1208.
48.
LiuCGSongJZhangYQ, et al. MicroRNA-193b is a regulator of amyloid precursor protein in the blood and cerebrospinal fluid derived exosomal microRNA-193b is a biomarker of Alzheimer’s disease. Mol Med Rep2014; 10(5): 2395–2400.
49.
Villar-VesgaJHenao-RestrepoJVoshartDC, et al. Differential profile of systemic extracellular vesicles from sporadic and familial Alzheimer’s disease leads to neuroglial and endothelial cell degeneration. Front Aging Neurosci2020; 12: 587989.
50.
KimKMMengQPerezdeAchaO, et al. Mitochondrial RNA in Alzheimer’s disease circulating extracellular vesicles. Front Cell Dev Biol2020; 8: 581882.
ThurairajahKBriggsGDBaloghZJ.The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies. Eur J Trauma Emerg Surg2018; 44(3): 325–334.
53.
Cervera-CarlesLAlcoleaDEstangaA, et al. Cerebrospinal fluid mitochondrial DNA in the Alzheimer’s disease continuum. Neurobiol Aging2017; 53: 192.e1–192.e4.
54.
PengYZhengDZhangX, et al. Cell-free mitochondrial DNA in the CSF: A potential prognostic biomarker of anti-NMDAR encephalitis. Front Immunol2019; 10: 103.
55.
PiccaABeliRCalvaniR, et al. Older adults with physical frailty and sarcopenia show increased levels of circulating small extracellular vesicles with a specific mitochondrial signature. Cells2020; 9(4): 973.
56.
PiccaAGuerraFCalvaniR, et al. Mitochondrial signatures in circulating extracellular vesicles of older adults with Parkinson’s disease: results from the EXosomes in PArkiNson’s Disease (EXPAND) Study. J Clin Med2020; 9(2): 504.
57.
ShippeyLECampbellSGHillAF, et al. Propagation of Parkinson’s disease by extracellular vesicle production and secretion. Biochem Soc Trans2022; 50(5): 1303–1314.
58.
ChangCLangHGengN, et al. Exosomes of BV-2 cells induced by alpha-synuclein: important mediator of neurodegeneration in PD. Neurosci Lett2013; 548: 190–195.
59.
KongSMChanBKParkJS, et al. Parkinson’s disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes alpha-Synuclein externalization via exosomes. Hum Mol Genet2014; 23(11): 2816–2833.
60.
Dos SantosMCTBarreto-SanzMACorreiaBRS, et al. miRNA-based signatures in cerebrospinal fluid as potential diagnostic tools for early stage Parkinson’s disease. Oncotarget2018; 9(25): 17455–17465.
61.
GuiYLiuHZhangL, et al. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget2015; 6(35): 37043–37053.
62.
WangQHanCLWangKL, et al. Integrated analysis of exosomal lncRNA and mRNA expression profiles reveals the involvement of lnc-MKRN2-42:1 in the pathogenesis of Parkinson’s disease. CNS Neurosci Ther2020; 26(5): 527–537.
63.
LazoSNoren HootenNGreenJ, et al. Mitochondrial DNA in extracellular vesicles declines with age. Aging Cell2021; 20(1): e13283.
64.
ChenXLuoYZhuQ, et al. Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism. Nat Aging2024; 4(6): 814–838.
65.
Mendez-GarciaAGarcia-MendozaMAZarate-PeraltaCP, et al. Mitochondrial microRNAs (mitomiRs) as emerging biomarkers and therapeutic targets for chronic human diseases. Front Genet2025; 16: 1555563.
66.
KerrNGarcia-ContrerasMAbbassiS, et al. Inflammasome proteins in serum and serum-derived extracellular vesicles as biomarkers of stroke. Front Mol Neurosci2018; 11: 309.
67.
JiQJiYPengJ, et al. Increased brain-specific MiR-9 and MiR-124 in the serum exosomes of acute ischemic stroke patients. PLoS One2016; 11(9): e0163645.
68.
ChouSHLanJEspositoE, et al. Extracellular mitochondria in cerebrospinal fluid and neurological recovery after subarachnoid hemorrhage. Stroke2017; 48(8): 2231–2237.
69.
YounDHKimBJKimY, et al. Extracellular mitochondrial dysfunction in cerebrospinal fluid of patients with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neurocrit Care2020; 33(2): 422–428.
70.
MarcattiMSaadaJOkerekeI, et al. Quantification of circulating cell free mitochondrial DNA in extracellular vesicles with PicoGreen in liquid biopsies: fast assessment of disease/trauma severity. Cells2021; 10(4): 819.
71.
GoetzlEJWolkowitzOMSrihariVH, et al. Abnormal levels of mitochondrial proteins in plasma neuronal extracellular vesicles in major depressive disorder. Mol Psychiatry2021; 26(12): 7355–7362.
72.
TsilioniITheoharidesTC.Extracellular vesicles are increased in the serum of children with autism spectrum disorder, contain mitochondrial DNA, and stimulate human microglia to secrete IL-1beta. J Neuroinflammation2018; 15(1): 239.
73.
KhadimallahIJenniRCabungcalJH, et al. Mitochondrial, exosomal miR137-COX6A2 and gamma synchrony as biomarkers of parvalbumin interneurons, psychopathology, and neurocognition in schizophrenia. Mol Psychiatry2022; 27(2): 1192–1204.
74.
del ZoppoGJ. Inflammation and the neurovascular unit in the setting of focal cerebral ischemia. Neuroscience2009; 158(3): 972–982.
75.
HawkinsBTDavisTP.The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev2005; 57(2): 173–185.
76.
IadecolaC.Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci2004; 5: 347–360.
77.
LoEHBroderickJPMoskowitzMA.tPA and proteolysis in the neurovascular unit. Stroke2004; 35(2): 354–356.
78.
ZacchignaSLambrechtsDCarmelietP.Neurovascular signalling defects in neurodegeneration. Nat Rev Neurosci2008; 9(3): 169–181.
79.
ZlokovicBV.The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron2008; 57(2): 178–201.
80.
McCullyJDLevitskySDel NidoPJ, et al. Mitochondrial transplantation for therapeutic use. Clin Transl Med2016; 5(1): 16.
81.
ShinBSaeedMYEschJJ, et al. A novel biological strategy for myocardial protection by intracoronary delivery of mitochondria: safety and efficacy. JACC Basic Transl Sci2019; 4(8): 871–888.
ParkerWDJrParksJK.Cytochrome c oxidase in Alzheimer’s disease brain: purification and characterization. Neurology1995; 45(3 Pt 1): 482–486.
84.
PohlandMPellowskaMAsseburgH, et al. MH84 improves mitochondrial dysfunction in a mouse model of early Alzheimer’s disease. Alzheimers Res Ther2018; 10(1): 18.
85.
NitzanKBenhamronSValitskyM, et al. Mitochondrial transfer ameliorates cognitive deficits, neuronal loss, and gliosis in Alzheimer’s disease mice. J Alzheimers Dis2019; 72(2): 587–604.
86.
MaHJiangTTangW, et al. Transplantation of platelet-derived mitochondria alleviates cognitive impairment and mitochondrial dysfunction in db/db mice. Clin Sci (Lond)2020; 134(16): 2161–2175.
87.
LosurdoMPedrazzoliMD’AgostinoC, et al. Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer’s disease. Stem Cells Transl Med2020; 9(9): 1068–1084.
88.
YangDDengZZhouH, et al. Exosome-mediated dual drug delivery of curcumin and methylene blue for enhanced cognitive function and mechanistic elucidation in Alzheimer’s disease therapy. Front Cell Dev Biol2025; 13: 1562565.
89.
LillCM.Genetics of Parkinson’s disease. Mol Cell Probes2016; 30(6): 386–396.
90.
MoonHEPaekSH.Mitochondrial dysfunction in Parkinson’s disease. Exp Neurobiol2015; 24(2): 103–116.
91.
BealMFOakesDShoulsonI, et al. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol2014; 71(5): 543–552.
92.
KieburtzKTilleyBCElmJJ, et al. Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial. JAMA2015; 313(6): 584–593.
93.
ShiXZhaoMFuC, et al. Intravenous administration of mitochondria for treating experimental Parkinson’s disease. Mitochondrion2017; 34: 91–100.
94.
ChangJCWuSLLiuKH, et al. Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson’s disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine-induced neurotoxicity. Transl Res2016; 170: 40–56.e3.
95.
ChangJCChaoYCChangHS, et al. Intranasal delivery of mitochondria for treatment of Parkinson’s disease model rats lesioned with 6-hydroxydopamine. Sci Rep2021; 11(1): 10597.
96.
SulJHShinSKimHK, et al. Dopamine-conjugated extracellular vesicles induce autophagy in Parkinson’s disease. J Extracell Vesicles2024; 13(12): e70018.
97.
HaneyMJKlyachkoNLZhaoY, et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release2015; 207: 18–30.
98.
IzcoMBlesaJSchleefM, et al. Systemic exosomal delivery of shRNA minicircles prevents parkinsonian pathology. Mol Ther2019; 27(12): 2111–2122.
99.
VoslerPSGrahamSHWechslerLR, et al. Mitochondrial targets for stroke: focusing basic science research toward development of clinically translatable therapeutics. Stroke2009; 40(9): 3149–3155.
100.
LoEH.A new penumbra: transitioning from injury into repair after stroke. Nat Med2008; 14(5): 497–500.
RussoENguyenHLippertT, et al. Mitochondrial targeting as a novel therapy for stroke. Brain Circ2018; 4(3): 84–94.
103.
BaekSHNohARKimKA, et al. Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage. Stroke2014; 45(8): 2438–2443.
104.
HuangPJKuoCCLeeHC, et al. Transferring xenogenic mitochondria provides neural protection against ischemic stress in ischemic rat brains. Cell Transplant2016; 25(5): 913–927.
105.
ZhangZMaZYanC, et al. Muscle-derived autologous mitochondrial transplantation: A novel strategy for treating cerebral ischemic injury. Behav Brain Res2019; 356: 322–331.
106.
NakamuraYLoEHHayakawaK.Placental mitochondria therapy for cerebral ischemia-reperfusion injury in mice. Stroke2020; 51: 3142–3146.
107.
RenDZhengPZouS, et al. GJA1-20K enhances mitochondria transfer from astrocytes to neurons via Cx43-TnTs after traumatic brain injury. Cell Mol Neurobiol2022; 42(6): 1887–1895.
ZhangBGaoYLiQ, et al. Effects of brain-derived mitochondria on the function of neuron and vascular endothelial cell after traumatic brain injury. World Neurosurg2020; 138: e1–e9.
110.
ZhaoJQuDXiZ, et al. Mitochondria transplantation protects traumatic brain injury via promoting neuronal survival and astrocytic BDNF. Transl Res2021; 235: 102–114.
111.
GollihueJLPatelSPEldahanKC, et al. Effects of mitochondrial transplantation on bioenergetics, cellular incorporation, and functional recovery after spinal cord injury. J Neurotrauma2018; 35(15): 1800–1818.
112.
LiHWangCHeT, et al. Mitochondrial transfer from bone marrow mesenchymal stem cells to motor neurons in spinal cord injury rats via gap junction. Theranostics2019; 9(7): 2017–2035.
113.
KuoCCSuHLChangTL, et al. Prevention of axonal degeneration by perineurium injection of mitochondria in a sciatic nerve crush injury model. Neurosurgery2017; 80(3): 475–488.
114.
ParkJHLoEHHayakawaK.Endoplasmic reticulum interaction supports energy production and redox homeostasis in mitochondria released from astrocytes. Transl Stroke Res2021; 12: 1045–1054.
115.
ParkJHTanakaMNakanoT, et al. O-GlcNAcylation is essential for therapeutic mitochondrial transplantation. Commun Med (Lond)2023; 3(1): 169.
116.
BrestoffJRSinghKKAquilanoK, et al. Recommendations for mitochondria transfer and transplantation nomenclature and characterization. Nat Metab2025; 7(1): 53–67.
117.
VekariaHJKalimonOJPrajapatiP, et al. An efficient and high-throughput method for the evaluation of mitochondrial dysfunction in frozen brain samples after traumatic brain injury. Front Mol Biosci2024; 11: 1378536.
118.
YaoPJMunkRGorospeM, et al. Analysis of mitochondrial respiration and ATP synthase in frozen brain tissues. Heliyon2023; 9(3): e13888.
119.
MadsenPMPintoMPatelS, et al. Mitochondrial DNA double-strand breaks in oligodendrocytes cause demyelination, axonal injury, and CNS inflammation. J Neurosci2017; 37(42): 10185–10199.
120.
Anne StetlerRLeakRKGaoY, et al. The dynamics of the mitochondrial organelle as a potential therapeutic target. J Cereb Blood Flow Metab2013; 33(1): 22–32.
121.
SimonRMellerRYangT, et al. Enhancing base excision repair of mitochondrial DNA to reduce ischemic injury following reperfusion. Transl Stroke Res2019; 10(6): 664–671.
122.
VekariaHJTalley WattsLLinAL, et al. Targeting mitochondrial dysfunction in CNS injury using Methylene Blue; still a magic bullet?Neurochem Int2017; 109: 117–125.
123.
SheDTJoDGArumugamTV.Emerging roles of sirtuins in ischemic stroke. Transl Stroke Res. Epub ahead of print 27 June 2017. DOI: 10.1007/s12975-017-0544-4.
