HSF1 is required for induction of mitochondrial chaperones during the mitochondrial unfolded protein response

• Published in: FEBS open bio 2020-06, Vol.10 (6), p.1135-1148
• Main Authors: Katiyar, Arpit, Fujimoto, Mitsuaki, Tan, Ke, Kurashima, Ai, Srivastava, Pratibha, Okada, Mariko, Takii, Ryosuke, Nakai, Akira
• Format: Article
• Language: English
• Subjects: Adenoviruses; Animals; Chaperones; Cloning; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Electron transfer; Embryo fibroblasts; Fibroblasts; Gene expression; Gene Knockdown Techniques; Heat; heat shock protein; Heat Shock Transcription Factors - genetics; Heat Shock Transcription Factors - metabolism; HEK293 Cells; HeLa Cells; HSF1; HSF1 protein; Hsp60 protein; Humans; Kinases; Mammalian cells; Mammals; Membrane Potential, Mitochondrial - genetics; Mice; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular Chaperones - genetics; Phosphorylation; Promoter Regions, Genetic - genetics; Protein folding; Proteinase; Proteins; proteostasis; proteotoxic stress; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA Interference; SSBP1; Transcription activation; Transcription factors; Unfolded Protein Response - genetics
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12863

The mitochondrial unfolded protein response (UPRmt) is characterized by the transcriptional induction of mitochondrial chaperone and protease genes in response to impaired mitochondrial proteostasis and is regulated by ATF5 and CHOP in mammalian cells. However, the detailed mechanisms underlying the UPRmt are currently unclear. Here, we show that HSF1 is required for activation of mitochondrial chaperone genes, including HSP60, HSP10, and mtHSP70, in mouse embryonic fibroblasts during inhibition of matrix chaperone TRAP1, protease Lon, or electron transfer complex 1 activity. HSF1 bound constitutively to mitochondrial chaperone gene promoters, and we observed that its occupancy was remarkably enhanced at different levels during the UPRmt. Furthermore, HSF1 supported the maintenance of mitochondrial function under the same conditions. These results demonstrate that HSF1 is required for induction of mitochondrial chaperones during the UPRmt, and thus, it may be one of the guardians of mitochondrial function under conditions of impaired mitochondrial proteostasis. The mitochondrial unfolded protein response (UPRmt) is characterized by the transcriptional induction of mitochondrial chaperone and protease genes in response to impaired mitochondrial proteostasis. Here, we show that heat shock transcription factor (HSF1) is required for activation of mitochondrial chaperone genes and supports the maintenance of mitochondrial function in mouse cells during the UPRmt.