Dual roles of mitochondrial fusion gene FZO1 in yeast age asymmetry and in longevity mediated by a novel ATG32-dependent retrograde response
Dual roles of mitochondrial fusion gene FZO1 in yeast age asymmetry and in longevity mediated by a novel ATG32-dependent retrograde response
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DOI：
10.1007/s10522-018-9779-z
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发表时间：
2019-02-01
期刊：
影响因子：
4.5
通讯作者：
Jazwinski, S. Michal
中科院分区：
文献类型：
--
作者：
Jiang, James C.;Stumpferl, Stefan W.;Jazwinski, S. Michal
酿酒酵母的复制寿命模拟了干细胞的老化。在每次细胞分裂期间，母细胞和子细胞之间的年龄不对称性建立，使得子细胞保留自我更新的能力，而这种能力在母亲中减弱。全功能线粒体与子细胞的分离是这种年龄不对称的一种机制。在这项研究中，我们研究了线粒体动力学在这种现象中的作用。线粒体动力学包括分裂和融合的过程。在测试的三个融合基因和三个裂变基因中，我们发现只有FZO 1是将全功能线粒体分离到子细胞和维持年龄不对称所必需的，这表现在尽管其在母亲中恶化，但女儿的完整复制寿命的潜力中。线粒体的质量由其周转决定，我们还发现FZO 1的缺失减少了线粒体自噬。线粒体功能障碍引起代偿性逆行反应，延长复制寿命。通常，触发这种反应的功能障碍包括能量产生。通过FZO 1的缺失破坏线粒体动力学也激活逆行反应以延长复制寿命。我们称这种新的途径为线粒体动力学相关的逆行反应（MDARR），因为它在启动它的线粒体近端的信号是不同的。此外，MDARR接合线粒体表面上的线粒体自噬受体Atg 32，我们认为这是由于Atg 32-Atg 11-Dnm 1复合物在线粒体表面的积累，而Fzo 1活性的情况下。MDARR可以通过经典的“逆行反应”操作来掩盖。
The replicative lifespan of the yeast Saccharomyces cerevisiae models the aging of stem cells. Age asymmetry between the mother and daughter cells is established during each cell division, such that the daughter retains the capacity for self-renewal while this ability is diminished in the mother. The segregation of fully-functional mitochondria to daughter cells is one mechanism that underlies this age asymmetry. In this study, we have examined the role of mitochondrial dynamics in this phenomenon. Mitochondrial dynamics involve the processes of fission and fusion. Out of the three fusion and three fission genes tested, we have found that only FZO1 is required for the segregation of fully-functional mitochondria to daughter cells and in the maintenance of age asymmetry as manifested in the potential of daughters for a full replicative lifespan despite its deterioration in their mothers. The quality of mitochondria is determined by their turnover, and we have also discovered that deletion of FZO1 reduces mitophagy. Mitochondrial dysfunction elicits a compensatory retrograde response that extends replicative lifespan. Typically, the dysfunction that triggers this response encompasses energy production. The disruption of mitochondrial dynamics by deletion of FZO1 also activates the retrograde response to extend replicative lifespan. We call this novel pathway the mitochondrial dynamics-associated retrograde response (MDARR) because it is distinct in the signal proximal to the mitochondrion that initiates it. Furthermore, the MDARR engages the mitophagy receptor Atg32 on the mitochondrial surface, and we propose that this is due to the accumulation of Atg32-Atg11-Dnm1 complexes on the mitochondrion in the absence of Fzo1 activity. MDARR can be masked by the operation of the classic' retrograde response.