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ABSTRACT
Introduction
Ischemic stroke-induced mitochondrial dysfunction in brain endothelial cells (BECs) leads to breakdown of the blood–brain barrier (BBB) causing long-term neurological dysfunction. Restoration of mitochondrial function in injured BECs is a promising therapeutic strategy to alleviate stroke-induced damage. Mounting evidence demonstrate that selected subsets of cell-derived extracellular vehicles (EVs), such as exosomes (EXOs) and microvesicles (MVs), contain functional mitochondrial components. Therefore, development of BEC-derived mitochondria-containing EVs for delivery to the BBB will (1) alleviate mitochondrial dysfunction and limit long-term neurological dysfunction in ischemic stroke and (2) provide an alternative therapeutic option for treating numerous other diseases associated with mitochondrial dysfunction.
Area covered
This review will discuss (1) how EV subsets package different types of mitochondrial components during their biogenesis, (2) mechanisms of EV internalization and functional mitochondrial responses in the recipient cells, and (3) EV biodistribution and pharmacokinetics – key factors involved in the development of mitochondria-containing EVs as a novel BBB-targeted stroke therapy.
Expert opinion
Mitochondria-containing MVs have demonstrated therapeutic benefits in ischemic stroke and other pathologies associated with mitochondrial dysfunction. Delivery of MV mitochondria to the BBB is expected to protect the BBB integrity and neurovascular unit post-stroke. MV mitochondria quality control, characterization, mechanistic understanding of its effects in vivo, safety and efficacy in different preclinical models, large-scale production, and establishment of regulatory guidelines are foreseeable milestones to harness the clinical potential of MV mitochondria delivery.
Article highlights
Ischemic stroke causes mitochondrial dysfunction and tight junction breakdown in brain endothelial cells that leads to long-term neurological damage post-stroke.
Cell-derived extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles (MVs), package mitochondrial content during their biogenesis.
EXOs contain mtDNA and mitochondrial proteins whereas MVs contain functional mitochondria.
EV-mediated transfer of mitochondrial components to recipient cells increases cellular bioenergetics, survival, mtDNA copy number, and modulates anti-inflammatory responses.
Mitochondria-containing EVs show therapeutic benefits in various pathological conditions associated with mitochondrial dysfunction, including ischemic stroke.
Key abbreviations
| ATP | = | Adenosine triphosphate |
| BBB | = | Blood-brain barrier |
| BEC | = | Brain endothelial cells |
| CSF | = | Cerebrospinal fluid |
| DAMPs | = | Damage-associated molecular patterns |
| ESCRT | = | Endosomal-sorting complex essential for transport |
| EVs | = | Extracellular vesicles |
| EXOs | = | Exosomes |
| IN | = | Intranasal |
| IV | = | Intravenous |
| MCAO | = | Middle cerebral artery occlusion |
| MDV | = | Mitochondria-derived vesicles |
| MSCs | = | Mesenchymal stem cells |
| mtDNA | = | mitochondrial DNA |
| MVs | = | Microvesicles |
| MVB | = | Multivesicular bodies |
| OGD | = | Oxygen-glucose deprivation |
| PEG | = | Poly(ethylene glycol) |
| ROS | = | Reactive oxygen species |
| TEM | = | Transmission electron microscopy |
| TJ | = | Tight junction |
Declaration of interest
DS Manickam is a named inventor on a provisional patent application disclosing mitochondria-enriched EVs discussed here. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.