Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule
Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule
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DOI：
10.1080/15548627.2016.1159376
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Rakugi, Hiromi
中科院分区：
文献类型：
--
作者：
Yamamoto, Takeshi;Takabatake, Yoshitsugu;Rakugi, Hiromi
自噬通过对蛋白质和细胞器的质量控制在细胞内稳态中起着至关重要的作用。尽管自噬活性随时间的下降被认为与衰老过程有关，但这个问题仍然存在争议。我们先前证明，自噬维持近端肾小管细胞的动态平衡，并保护肾脏免受损伤。在这里，我们扩展了这项研究，并研究了自噬如何与肾脏老化有关。出乎意料的是，老年肾脏的基础自噬活性高于年轻肾脏；他莫昔芬诱导的近端小管特异性自噬缺陷小鼠的自噬短期停止增加了SQSTM1/p62-和泛素阳性聚集体在老年肾脏中的积累。相比之下，响应代谢应激的自噬通量随着年龄的增长而减弱，正如观察到的那样，表达绿色荧光蛋白(GFP)-微管相关蛋白1轻链3B融合结构的转基因小鼠在年轻小鼠对饥饿的反应中显示出GFP阳性斑点的急剧增加，而在老年小鼠中观察到的略有增加。最后，近端小管特异性自噬缺陷小鼠在24个月龄时表现出显著的肾功能恶化和纤维化，伴随着线粒体功能障碍以及线粒体DNA异常和核DNA损伤，所有这些都是细胞衰老的特征。这些结果表明，依赖于年龄的高基础自噬通过线粒体质量控制在抗肾脏衰老中起着关键作用。此外，对代谢应激反应的自噬通量上调能力的降低可能与年龄相关的肾脏疾病有关。
Autophagy plays an essential role in cellular homeostasis through the quality control of proteins and organelles. Although a time-dependent decline in autophagic activity is believed to be involved in the aging process, the issue remains controversial. We previously demonstrated that autophagy maintains proximal tubular cell homeostasis and protects against kidney injury. Here, we extend that study and examine how autophagy is involved in kidney aging. Unexpectedly, the basal autophagic activity was higher in the aged kidney than that in young kidney; short-term cessation of autophagy in tamoxifen-inducible proximal tubule-specific autophagy-deficient mice increased the accumulation of SQSTM1/p62- and ubiquitin-positive aggregates in the aged kidney. By contrast, autophagic flux in response to metabolic stress was blunted with aging, as demonstrated by the observation that transgenic mice expressing a green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3B fusion construct, showed a drastic increase of GFP-positive puncta in response to starvation in young mice compared to a slight increase observed in aged mice. Finally, proximal tubule-specific autophagy-deficient mice at 24mo of age exhibited a significant deterioration in kidney function and fibrosis concomitant with mitochondrial dysfunction as well as mitochondrial DNA abnormalities and nuclear DNA damage, all of which are hallmark characteristics of cellular senescence. These results suggest that age-dependent high basal autophagy plays a crucial role in counteracting kidney aging through mitochondrial quality control. Furthermore, a reduced capacity for upregulation of autophagic flux in response to metabolic stress may be associated with age-related kidney diseases.