Mitochondrion is the energy center of the cell in which different metabolic pathways converge. Cell respiration takes place in this organelle with high production of ATP. Nucleus-mitochondrion communication represents an essential level of cell homeostasis regulation. This crosstalk is strictly related to epigenetic mechanisms, in particular to histone and non-histone proteins acetylation. Budding yeast is a suitable model system to study the interplay between epigenetic and metabolism; in this organism it is possible to analyse fermentative and respiratory pathways varying the carbon source in growth medium. SAGA complex is a transcriptional co-activator with two catalytic domains: the deubiquitination module with DUB Ubp8 and the acetylation domain with HAT Gcn5. In yeast, Gcn5 has a major role in protein acetylation at global and specific lysine; moreover, it is implicated in mitochondrion-nucleus communication. In this work, we found that SAGA complex and its catalytic activities are necessary for cell respiration. Results showed that KAT Gcn5 and DUB Ubp8 are upregulated in respiration at both transcriptional and protein levels. We identify two interactors, the E3 ubiquitin ligase Psh1 and the HDAC Hda1, whose deletion is able to rescue defective respiratory phenotype of strains lacking respectively Ubp8 and Gcn5. We demonstrated that histone residue H3K18 is the preferential target of Hda1 and Gcn5 and its acetylation is needed in respiration. Surprising, we found that Gcn5, Ubp8 and Psh1 localize in both nucleus and mitochondria highlighting a dual role as chromatin modifiers and mitochondrial factors. Moreover, our data showed that Ubp8 expression is regulated by Gcn5, while its cell localization is influenced by Psh1. Finally, results suggest that acetylation is an important mark in respiratory condition
