Peruzzotti-Jametti 2021 PLoS Biol

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Peruzzotti-Jametti L, Bernstock JD, Willis CM, Manferrari G, Rogall R, Fernandez-Vizarra E, Williamson JC, Braga A, van den Bosch A, Leonardi T, Krzak G, Kittel A, Beninca C, Vicario N, Tan S, Bastos C, Bicci I, Iraci N, Smith JA, Peacock B, Muller KH, Lehner PJ, Buzas EI, Faria N, Zeviani M, Frezza C, Brisson A, Matheson NJ, Viscomi C, Pluchino S (2021) Neural stem cells traffic functional mitochondria via extracellular vesicles. PLoS Biol 19:3001166.

» PMID: 33826607 Open Access

Peruzzotti-Jametti Luca, Bernstock Joshua D, Willis Cory M, Manferrari Giulia, Rogall Rebecca, Fernandez-Vizarra Erika, Williamson James C, Braga Alice, van den Bosch Aletta, Leonardi Tommaso, Krzak Grzegorz, Kittel Agnes, Beninca Cristiane, Vicario Nunzio, Tan Sisareuth, Bastos Carlos, Bicci Iacopo, Iraci Nunzio, Smith Jayden A, Peacock Ben, Muller Karin H, Lehner Paul J, Buzas Edit Iren, Faria Nuno, Zeviani Massimo, Frezza Christian, Brisson Alain, Matheson Nicholas J, Viscomi Carlo, Pluchino Stefano (2021) PLoS Biol

Abstract: Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.

Bioblast editor: Reiswig R O2k-Network Lab: IT Padova Viscomi C

Labels: MiParea: Respiration, nDNA;cell genetics  Pathology: Neurodegenerative 

Organism: Mouse  Tissue;cell: Nervous system, Stem cells  Preparation: Permeabilized cells  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: LEAK, OXPHOS  Pathway: N, S, Gp, CIV, ROX  HRR: Oxygraph-2k