As most of the mitochondrial proteome is encoded in the nucleus, mitochondrial functions critically depend on nuclear gene expression and bidirectional mito-nuclear communication. However, mitochondria-to-nucleus communication pathways in mammals are incompletely understood. Here, we identify G-Protein Pathway Suppressor 2 (GPS2) as a mediator of mitochondrial retrograde signaling and a transcriptional activator of nuclear-encoded mitochondrial genes. GPS2-regulated translocation from mitochondria to nucleus is essential for the transcriptional activation of a nuclear stress response to mitochondrial depolarization and for supporting basal mitochondrial biogenesis in differentiating adipocytes and brown adipose tissue (BAT) from mice. In the nucleus, GPS2 recruitment to target gene promoters regulates histone H3K9 demethylation and RNA POL2 activation through inhibition of Ubc13-mediated ubiquitination. These findings, together, reveal an additional layer of regulation of mitochondrial gene transcription, uncover a direct mitochondria-nuclear communication pathway, and indicate that GPS2 retrograde signaling is a key component of the mitochondrial stress response in mammals.

由于大多数线粒体蛋白质组是在细胞核中编码的，因此线粒体的功能关键取决于核基因的表达和双向的线粒体-核通讯。但是，哺乳动物中线粒体与细胞核之间的通讯途径尚不完全清楚。在这里，我们确定G蛋白通路抑制器2（GPS2）作为线粒体逆行信号的介体和核编码线粒体基因的转录激活因子。GPS2调节的从线粒体到核的转运对于激活针对线粒体去极化的核应激反应的转录激活以及支持区分小鼠的脂肪细胞和棕色脂肪组织（BAT）的基础线粒体生物发生至关重要。在原子核中 GPS2募集到目标基因启动子通过抑制Ubc13介导的泛素化来调节组蛋白H3K9去甲基化和RNA POL2激活。这些发现共同揭示了线粒体基因转录调控的另一层，揭示了直接的线粒体-核通讯途径，并表明GPS2逆行信号是哺乳动物线粒体应激反应的关键组成部分。