Therapeutic transplantation of mitochondria and Extracellular Vesicles: Mechanistic insights into mitochondria bioenergetics, redox signaling, and organelle dynamics in preclinical models

Abstract

Mitochondrial and extracellular vesicles (EV) transplantation have emerged as promising therapeutic strategies targeting mitochondrial dysfunction, a central feature of numerous pathologies. This review synthesizes preclinical data on artificial mitochondrial and EV transfer, emphasizing their therapeutic potential and underlying mechanisms. A systematic analysis of 123 animal studies revealed consistent benefits across diverse models, including ischemia-reperfusion injury (IRI), neurological disorders, drug-induced toxicities, and sepsis. Mitochondrial transfer improved organ function, reduced inflammation and apoptosis, and enhanced survival. Mechanistic insights revealed restored bioenergetics, increased oxidative phosphorylation, redox balance through activation of specific pathways, and modulation of mitochondrial dynamics via fusion/fission proteins. Mitochondrial homeostasis was supported through elevated mitophagy and biogenesis, alongside the preservation of mitochondrial-associated membranes. EV demonstrated similar effects, offering a potentially more targeted therapeutic alternative. Although pre-clinical studies have demonstrated safety and feasibility, broader application is limited by variability in isolation methods, lack of mechanistic clarity, and minimal human data. Standardization and mechanistic validation are critical to advance clinical translation. This review underscores the therapeutic promise of mitochondrial and EV transfer while highlighting the need for continued research to refine these interventions and unlock their full potential in regenerative medicine.

Keywords: Artificial mitochondrial transfer; Extracellular vesicles; Microvesicles; Mitochondrial transplantation; Pre-clinical data; Therapeutic; Treatment.

Fig. 1.

Prisma flow diagram.

Fig. 2.

General parameters of mitochondrial and EV transplantation-related studies A. Animal models use for in vivo studies. B. Mitochondrial and EV sources. C. Type of transplantation. D. Administration root of mitochondria and EV. E. Proof of mitochondria and EV isolation. F. Proof of mitochondria and EV transfer. G. Geographical repartition of teams involved in mitochondrial transplantation.

Fig. 3.. Mechanisms of action and clinical outcomes of mitochondrial and extracellular vesicle (EV) transplantation.

Mitochondria and EV can be isolated from various autologous or allogeneic sources, including immune cells, cardiac and neuronal tissues, organs and biological fluids. These mitochondrial therapies have been associated with multiple clinical outcomes such as infarct size reduction, decreased inflammation, rescue of cognitive functions, vascular remodeling, and regeneration of cells and organs. Mechanistically, transplanted mitochondria and EV exert their effects through: (1) enhancement of bioenergetic and redox processes by increasing oxidative phosphorylation (OXPHOS) and ATP production via upregulation of NDUFB8, SDHB, UQCRC, MTCO1, and ATP5A; (2) redox homeostasis maintenance through antioxidant pathways involving Nrf2, SOD, CAT, GSH, MAPK, and FOXO signaling; (3) modulation of mitochondrial dynamics via regulation of fission (Drp1) and fusion (Mfn1, Mfn2, Opa1) processes; and (4) preservation of mitochondrial homeostasis through enhanced mitophagy (increased LC3-II/LC3-I ratio) and mitochondrial biogenesis (upregulation of PGC1α and TFAM). These mechanisms underpin the therapeutic potential of mitochondrial and EV-based interventions across a range of diseases.