BNIP3L/NIX and FUNDC1-mediated mitophagy is required for mitochondrial network remodeling during cardiac progenitor cell differentiation
BNIP3L/NIX and FUNDC1-mediated mitophagy is required for mitochondrial network remodeling during cardiac progenitor cell differentiation
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DOI：
10.1080/15548627.2019.1580095
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发表时间：
2019-02-22
期刊：
影响因子：
13.3
通讯作者：
Gustafsson, Asa B.
中科院分区：
文献类型：
--
作者：
Lampert, Mark A.;Orogo, Amabel M.;Gustafsson, Asa B.
基于细胞的治疗是一种非常有前途的修复和再生受损心脏的策略，以防止进展为心力衰竭。到目前为止，由于缺乏输注细胞的存活和保留，这些治疗方法的成功有限。因此，重要的是增加我们对这些细胞生物学的了解，并利用这些信息来增强它们在受损心脏中的生存和功能。线粒体对祖细胞的功能和存活至关重要。在这里，我们证明了线粒体自噬或有丝分裂吞噬在成人心脏前体细胞(CPC)分化过程中的重要性。我们发现，在CPC分化开始时，很快就会诱导有丝分裂。我们还发现有丝分裂吞噬是由有丝分裂受体介导的，而不是PINK1-PRKN/Parkin通路。BNIP3L/Nix和Fundc1介导的有丝分裂不参与调节祖细胞命运的决定、线粒体的生物发生或重编程。相反，有丝分裂促进了CPC在分化过程中进行适当的线粒体网络重组。在分化过程中取消BNIP3L和FundC1介导的有丝分裂导致持续的线粒体分裂和形成甜甜圈形状的受损线粒体。它还增加了细胞死亡的易感性，并导致心肌梗死后无法存活。最后，衰老与细胞中线粒体DNA(MtDNA)损伤的积累有关，我们发现获得mtDNA突变选择性地扰乱了CPC中分化激活的有丝分裂吞噬程序。这些发现证明了BNIP3L和FundC1介导的有丝分裂作为分化过程中线粒体网络形成的关键调节因子的重要性，以及积累mtDNA突变的后果。
Cell-based therapies represent a very promising strategy to repair and regenerate the injured heart to prevent progression to heart failure. To date, these therapies have had limited success due to a lack of survival and retention of the infused cells. Therefore, it is important to increase our understanding of the biology of these cells and utilize this information to enhance their survival and function in the injured heart. Mitochondria are critical for progenitor cell function and survival. Here, we demonstrate the importance of mitochondrial autophagy, or mitophagy, in the differentiation process in adult cardiac progenitor cells (CPCs). We found that mitophagy was rapidly induced upon initiation of differentiation in CPCs. We also found that mitophagy was mediated by mitophagy receptors, rather than the PINK1-PRKN/PARKIN pathway. Mitophagy mediated by BNIP3L/NIX and FUNDC1 was not involved in regulating progenitor cell fate determination, mitochondrial biogenesis, or reprogramming. Instead, mitophagy facilitated the CPCs to undergo proper mitochondrial network reorganization during differentiation. Abrogating BNIP3L- and FUNDC1-mediated mitophagy during differentiation led to sustained mitochondrial fission and formation of donut-shaped impaired mitochondria. It also resulted in increased susceptibility to cell death and failure to survive the infarcted heart. Finally, aging is associated with accumulation of mitochondrial DNA (mtDNA) damage in cells and we found that acquiring mtDNA mutations selectively disrupted the differentiation-activated mitophagy program in CPCs. These findings demonstrate the importance of BNIP3L- and FUNDC1-mediated mitophagy as a critical regulator of mitochondrial network formation during differentiation, as well as the consequences of accumulating mtDNA mutations.