Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome

Authors
Nakai, Ritsuko, Varnum, Stella, Field, Rachael L., Shi, Henyun, Giwa, Rocky, Jia, Wentong, Krysa, Samantha J., Cohen, Eva F., Borcherding, Nicholas, Saneto, Russell P., Tsai, Rick C., Suganuma, Masashi, Ohta, Hisashi, Yokota, Takafumi, Brestoff, Jonathan R.


Lab

Journal
Nature Metabolism

Abstract
Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1-3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4to/to peritoneal macrophages4-7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10-12, brain13-15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4to/to mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4to/to mice, whereas mitochondria from Ndufs4to/to mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4to/to mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS. Administration of exogenous mitochondria from mice or humans, or stimulation of mitochondria transfer from haematopoietic cells through bone marrow transplant from wild-type mice, is shown to improve morbidity and mortality in a mouse model of the mitochondrial disease Leigh syndrome.

Keywords/Topics
mitochondria;transfer-based;therapies;reduce;morbidity;mortality;leigh;syndrome;transfer;recently

BIOSEB Instruments Used:
Bioseb CIS Software (BIO-CIS2),Grip strength test (BIO-GS4)

Source :

https://www.nature.com/articles/s42255-024-01125-5

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