GPS2 regulates mitochondria biogenesis via mitochondrial retrograde signaling and chromatin remodeling of nuclear-encoded mitochondrial genes

Abstract

2 SummaryAs 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. Together, these findings reveal an unexpected layer of regulation of mitochondrial gene transcription as they uncover a novel mitochondrianuclear communication pathway.

Subcellular origin of mitochondrial DNA deletions in human skeletal muscle

“…We found that Hsp60 and TFAM levels were similar, however GPS2 was elevated in perinuclear regions, consistent with its role as nuclear transcription factor28. In patient muscle, compared to perinuclear COX-positive areas, Hsp60 (2.2-fold), GPS2 (1.2-fold), and TFAM (1.5-fold) levels were all higher in COX-deficient niches.…”

“…Our data in human skeletal muscle suggests a role for the UPR mt and possibly implicates other factors such as GPS2, which transcriptionally activates mitochondrial biogenesis in response to mitochondrial stress or depolarization32. Beclin1 labelling suggests no change in mitophagy in small foci.…”

“…Both the UPR mt and GPS2 retrograde signaling pathways have been shown to be upstream of mitochondrial biogenesis12, 28. Accordingly, mitochondrial TFAM was also increased in 70% of foci, relative to COX-positive regions.…”

“…We analyzed the mitochondrial biogenesis marker TFAM, UPR mt marker Hsp60, retrograde signaling factor GPS228 and mitophagy marker Beclin1 (Fig 5A). COX-deficient foci were compared to equivalent COX-positive regions of the same fibers, representing the early stage respiratory chain deficiency (Fig 5B) and fully COX-deficient fibers compared to COX-positive fibers representing the late-stage of respiratory chain deficiency (Fig 5C).…”

Mitochondria ensure immune surveillance by retro-communication with the nucleus

“…In light of the absent homology of the RTG genes in higher eukaryotes, mitochondrial communication with the nucleus is evidently far more complex, especially in mammals that deploy different executors for various mitochondrial stressors. Those identified, to date, encompass transcription factors (e.g., GPS2, CHOP, SHREB, ATF4, and NF-kB; Jazwinski, 2014;Cardamone et al, 2018) that rapidly accumulate in the nucleus in response to stress.…”