Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells^1,2,3. 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 macrophages^4,5,6,7. 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 mutations^8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart^10,11,12, brain^13,14,15 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.

线粒体转移是最近描述的一种现象，其中供体细胞将线粒体递送至受体细胞^1,2,3。线粒体转移的一个可能结果是对邻近细胞的能量支持;例如，外源性健康线粒体可以挽救培养的 ρ⁰ 细胞或 Ndufs4⁻/⁻ 腹膜巨噬细胞^4,5,6,7 中线粒体代谢中的细胞内在缺陷。在自体造血干细胞移植之前将造血干细胞暴露于纯化的线粒体中，可以治疗具有大规模线粒体 DNA 突变的患者的贫血^8,9，线粒体移植被证明可以最大限度地减少对心脏^10,11,12、大脑^13、14、15 和四肢的缺血损伤¹⁶.然而，使用基于线粒体转移的疗法治疗遗传性线粒体疾病的治疗潜力尚不清楚。在这里，我们证明了在与线粒体转移相关的多种治疗范式中，Leigh 综合征 （LS） 的 Ndufs4 ⁻ / ⁻ 小鼠模型的发病率和死亡率有所改善。野生型小鼠骨髓移植与造血细胞衍生的细胞外线粒体释放到循环中以及线粒体转移到多个器官中的宿主细胞有关，可改善小鼠的 LS。此外，施用野生型小鼠的分离线粒体可延长寿命，改善神经功能并增加 Ndufs4 ^{- / -} 小鼠的能量消耗，而 Ndufs4 ^{- / -} 小鼠的线粒体并未改善神经功能。 最后，我们证明将人线粒体跨物种施用到 Ndufs4 ^{− / -} 小鼠也改善了 LS。这些数据表明，可以利用线粒体转移相关方法来治疗线粒体疾病，例如 LS。