Atf5 As A Regulator Of A Mammalian Mitochondrial Unfolded Protein Response

Abstract

Mitochondrial dysfunction is pervasive in human pathologies such as neurodegeneration, diabetes, cancer and pathogen infections as well as during normal aging. Cells sense and respond to mitochondrial stress or dysfunction by activating a protective transcriptional program known as the mitochondrial unfolded protein response (UPRmt), which includes genes that promote mitochondrial protein homeostasis and the regeneration of metabolically defective organelles (Nargund, Pellegrino et al. 2012, Nargund, Fiorese et al. 2015). Work in C. elegans has shown that the UPRmt is regulated by the transcription factor ATFS-1, which is regulated by organelle partitioning. Normally, ATFS-1 accumulates within mitochondria, but during respiratory chain dysfunction, high levels of ROS or mitochondrial protein folding stress, a percentage of ATFS-1 accumulates in the cytosol and traffics to the nucleus where it activates the UPRmt (Nargund, Pellegrino et al. 2012). While similar transcriptional responses have been described in mammals (Zhao, Wang et al. 2002, Wu, Williams et al. 2014), how the UPRmt is regulated remains unclear. Here, we describe a mammalian transcription factor, ATF5, which is regulated similarly to ATFS-1 and induces a similar transcriptional response. ATF5 expression can rescue UPRmt signaling in atfs-1-deficient worms requiring the same UPRmt promoter element identified in C. elegans. Furthermore, mammalian cells require ATF5 to maintain mitochondrial activity during mitochondrial stress and to promote organelle recovery. Combined, these data suggest that regulation of the UPRmt is conserved from worms to mammals.