Department of Molecular and Cellular Biology, Davis University of California, Davis, CA, USA.
EMBO J. 2011 Jun 1;30(11):2101-14. doi: 10.1038/emboj.2011.104. Epub 2011 Apr 5.
Autophagy is a conserved degradative process that is crucial for cellular homeostasis and cellular quality control via the selective removal of subcellular structures such as mitochondria. We demonstrate that a regulatory link exists between mitochondrial function and autophagy in Saccharomyces cerevisiae. During amino-acid starvation, the autophagic response consists of two independent regulatory arms-autophagy gene induction and autophagic flux-and our analysis indicates that mitochondrial respiratory deficiency severely compromises both. We show that the evolutionarily conserved protein kinases Atg1, target of rapamycin kinase complex I, and protein kinase A (PKA) regulate autophagic flux, whereas autophagy gene induction depends solely on PKA. Within this regulatory network, mitochondrial respiratory deficiency suppresses autophagic flux, autophagy gene induction, and recruitment of the Atg1-Atg13 kinase complex to the pre-autophagosomal structure by stimulating PKA activity. Our findings indicate an interrelation of two common risk factors-mitochondrial dysfunction and autophagy inhibition-for ageing, cancerogenesis, and neurodegeneration.
自噬是一种保守的降解过程，对于细胞内环境稳定和细胞质量控制至关重要，它通过选择性去除线粒体等亚细胞结构来实现。我们证明了酿酒酵母中线粒体功能和自噬之间存在调节联系。在氨基酸饥饿时，自噬反应由两个独立的调节臂组成——自噬基因诱导和自噬流——我们的分析表明，线粒体呼吸缺陷严重损害了这两者。我们表明，进化上保守的蛋白激酶 Atg1、雷帕霉素激酶复合物 I 的靶标和蛋白激酶 A（PKA）调节自噬流，而自噬基因诱导仅依赖于 PKA。在这个调节网络中，线粒体呼吸缺陷通过刺激 PKA 活性来抑制自噬流、自噬基因诱导以及 Atg1-Atg13 激酶复合物向前自噬体结构的募集。我们的发现表明，两种常见的风险因素——线粒体功能障碍和自噬抑制——与衰老、癌症发生和神经退行性变有关。
