TY - JOUR
T1 - Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome
AU - Nakai, Ritsuko
AU - Varnum, Stella
AU - Field, Rachael L.
AU - Shi, Henyun
AU - Giwa, Rocky
AU - Jia, Wentong
AU - Krysa, Samantha J.
AU - Cohen, Eva F.
AU - Borcherding, Nicholas
AU - Saneto, Russell P.
AU - Tsai, Rick C.
AU - Suganuma, Masashi
AU - Ohta, Hisashi
AU - Yokota, Takafumi
AU - Brestoff, Jonathan R.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024/10
Y1 - 2024/10
N2 - 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 Ndufs4−/− 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 Ndufs4−/− 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 Ndufs4−/− mice, whereas mitochondria from Ndufs4−/− mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4−/− mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.
AB - 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 Ndufs4−/− 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 Ndufs4−/− 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 Ndufs4−/− mice, whereas mitochondria from Ndufs4−/− mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4−/− mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.
UR - http://www.scopus.com/inward/record.url?scp=85202921174&partnerID=8YFLogxK
U2 - 10.1038/s42255-024-01125-5
DO - 10.1038/s42255-024-01125-5
M3 - Letter
C2 - 39223312
AN - SCOPUS:85202921174
SN - 2522-5812
VL - 6
SP - 1886
EP - 1896
JO - Nature Metabolism
JF - Nature Metabolism
IS - 10
ER -