Abstract
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.
Highlights
Arpit Katiyar, Mitsuaki Fujimoto, Ke Tan*, Ai Kurashima, Pratibha Srivastava, Mariko Okada, Ryosuke Takii and Akira Nakai
We show that heat shock transcription factor 1 (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
We treated wild-type and HSF1null mouse embryonic fibroblasts (MEF) cells with 10 lM GTPP, 5 lM CDDO, or 20 lM rotenone for 6 h and found that HSP60, HSP10, and mtHSP70 mRNA levels were increased by 1.2- to 2.0-fold in wild-type cells treated with GTPP
Summary
Arpit Katiyar , Mitsuaki Fujimoto, Ke Tan*, Ai Kurashima, Pratibha Srivastava, Mariko Okada, Ryosuke Takii and Akira Nakai. 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. HSF1 bound constitutively to mitochondrial chaperone gene promoters, and we observed that its occupancy was remarkably enhanced at different levels during the UPRmt. HSF1 supported the maintenance of mitochondrial function under the same conditions. Environmental and metabolic stresses constantly induce protein misfolding and challenge proteostasis capacity To cope with these proteotoxic stresses, cells are equipped with adaptive mechanisms accompanied by changes in gene expression [1]. The HSR is regulated mainly at the transcriptional level by heat shock transcription factor 1 (HSF1) in mammalian cells, and it maintains proteostasis capacity in both the nucleus and cytoplasm [3]. Abbreviations ATF, activating transcription factor; C/EBP, CAAT enhancer-binding protein; CHOP, C/EBP homology protein; HSF1, heat shock transcription factor 1; HSP, heat shock protein; HSR, heat shock response; SSBP1, single-stranded DNA binding protein 1; UPR, unfolded protein response
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