GCN5-like Protein 1 (GCN5L1) Controls Mitochondrial Content through Coordinated Regulation of Mitochondrial Biogenesis and Mitophagy
GCN5-like Protein 1 (GCN5L1) Controls Mitochondrial Content through Coordinated Regulation of Mitochondrial Biogenesis and Mitophagy
复制标题
DOI：
10.1074/jbc.m113.521641
复制
发表时间：
2014-01-31
影响因子：
4.8
通讯作者：
Sack, Michael N.
中科院分区：
文献类型：
--
作者：
Scott, Iain;Webster, Bradley R.;Sack, Michael N.
背景：线粒体生物发生和自噬之间的平衡控制着细胞线粒体的含量。结果：线粒体去乙酰化诱导的有丝分裂引起TFEB和PGC-1的同时和相互依赖的上调，以维持细胞线粒体的含量。结论：线粒体含量受GCN5L1调控下的线粒体和溶酶体生物发生程序的协调调节。意义：反向调节相互依赖的程序以一种营养感知、乙酰化依赖的方式维持线粒体内容/内稳。细胞线粒体内容受细胞器生物发生和降解的竞争过程控制。建议严格调控这些程序，以确保细胞维持足够的细胞器，以满足其生物合成、能量和其他动态平衡的要求。我们最近报道了GCN5L1，一个可能的营养感知调节因子，通过自噬控制线粒体的去除。在这里，我们发现GCN5L1的基因缺失对转录因子EB(TFEB)的表达和活性有直接的正向影响，TFEB是自噬的主要调节因子。令人惊讶的是，TFEB介导的自噬途径的诱导并没有减少细胞线粒体的含量，因为它的活性被线粒体生物发生转录共激活因子PPAR辅助激活因子1(PGC-1)的诱导所抵消。同时诱导TFEB和PGC-1通路导致GCN5L1(-/-)细胞线粒体周转率增加。最后，我们发现，TFEB或PGC-1的基因敲除会导致另一基因表达的相应下降，这表明这些蛋白在营养感知信号的调节下，既协调又相反地维持细胞线粒体的含量。
Background: The balance between mitochondrial biogenesis and autophagy controls cellular mitochondrial content. Results: Mitochondrial deacetylation-induced mitophagy evokes concurrent and interdependent up-regulation of TFEB and PGC-1 to sustain cellular mitochondrial content. Conclusion: Mitochondrial content is coordinately regulated by the mitochondrial and lysosome biogenesis programs under GCN5L1 control. Significance: Counter-regulatory interdependent programs function to sustain mitochondrial content/homeostasis in a nutrient-sensing, acetylation-dependent manner.Cellular mitochondrial content is governed by the competing processes of organelle biogenesis and degradation. It is proposed that these programs are tightly regulated to ensure that the cell maintains sufficient organelles to meet its biosynthetic, energetic, and other homeostatic requirements. We recently reported that GCN5L1, a putative nutrient-sensing regulator, controls mitochondrial removal by autophagy. Here we show that genetic deletion of GCN5L1 has a direct positive effect on the expression and activity of Transcriptional Factor EB (TFEB), which acts as a master regulator of autophagy. Surprisingly, the induction of TFEB-mediated autophagy pathways does not diminish cellular mitochondrial content, as its activity is countered by induction of the mitochondrial biogenesis transcriptional co-activator PPAR coactivator 1 (PGC-1). Concurrent induction of the TFEB and PGC-1 pathways results in an increased mitochondrial turnover rate in GCN5L1(-/-) cells. Finally, we show that genetic knockdown of either TFEB or PGC-1 leads to a corresponding decrease in the expression of the other gene, indicating that these proteins act coordinately, and in opposition, to maintain cellular mitochondrial content in response to the modulation of nutrient-sensing signatures.