Pluto Bioinformatics

GSE80990: Mitochondrial retrograde signaling in mammals is mediated by the transcriptional cofactor GPS2 via direct mitochondria-to-nucleus translocation [GRO-seq]

Bulk RNA sequencing

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 are incompletely understood. Here, we identify G-Protein Pathway Suppressor 2 (GPS2) as a mediator of mitochondrial retrograde signaling and a key transcriptional activator of nuclear-encoded mitochondrial genes in mammals. GPS2 regulated translocation from mitochondria to nucleus is essential for the transcriptional activation of the nuclear stress response to mitochondrial depolarization and for supporting basal mitochondrial biogenesis in differentiating adipocytes and in brown adipose tissue from mice. In the nucleus, GPS2 recruitment to target gene promoters regulates histone H3K9 demethylation and RNA Polymerase II (POL2) activation through inhibition of Ubc13-mediated ubiquitination. These findings, together, reveal an unexpected layer of regulation of mitochondrial gene transcription, uncover a novel direct mitochondria-nuclear communication pathway and indicate that GPS2 retrograde signaling is a key component of the mitochondrial stress response in mammals. SOURCE: Valentina Perissi (vperissi@bu.edu) - Boston University