Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPRmt Journal Article
| Authors: | Nargund, A. M.; Fiorese, C. J.; Pellegrino, M. W.; Deng, P.; Haynes, C. M. |
| Article Title: | Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPRmt |
| Abstract: | Mitochondrial diseases and aging are associated with defects in the oxidative phosphorylation machinery (OXPHOS), which are the only complexes composed of proteins encoded by separate genomes. To better understand genome coordination and OXPHOS recovery during mitochondrial dysfunction, we examined ATFS-1, a transcription factor that regulates mitochondria-to-nuclear communication during the mitochondrial UPR, via ChIP-sequencing. Surprisingly, in addition to regulating mitochondrial chaperone, OXPHOS complex assembly factor, and glycolysis genes, ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes. Interestingly, atfs-1 was required to limit the accumulation of OXPHOS transcripts during mitochondrial stress, which required accumulation of ATFS-1 in the nucleus and mitochondria. Because balanced ATFS-1 accumulation promoted OXPHOS complex assembly and function, our data suggest that ATFS-1 stimulates respiratory recovery by fine-tuning OXPHOS expression to match the capacity of the suboptimal protein-folding environment instressed mitochondria, while simultaneously increasing proteostasis capacity. •ATFS-1 ChIP-seq indicates the UPRmt includes both proteostasis and metabolism genes•ATFS-1 negatively regulates OXPHOS and TCA cycle mRNAs from the nuclear genome•Mitochondrial ATFS-1 binds mtDNA and limits accumulation of mtDNA-encoded mRNAs•ATFS-1 promotes OXPHOS recovery by matching biogenesis to proteostasis capacity. OXPHOS components are encoded by both the nuclear and mitochondrial genomes. Nargund etal. discover that, during mitochondrial stress, ATFS-1 regulates expression of mitochondrial proteostasis and multiple metabolic genes. By coordinating expression of nuclear and mitochondrial genome-encoded OXPHOS components, ATFS-1 matches OXPHOS complex biogenesis with mitochondrial proteostasis capacity. © 2015 Elsevier Inc. |
| Keywords: | signal transduction; controlled study; promoter region; nonhuman; gene expression; gene expression profiling; animal experiment; animal model; genetic transcription; protein interaction; genome analysis; chromatin immunoprecipitation; dna sequence; lactate dehydrogenase; protein folding; basic leucine zipper transcription factor; mitochondrial protein; cell communication; nuclear localization signal; mitochondrion; glycolysis; oxidative phosphorylation; reduced nicotinamide adenine dinucleotide; bioaccumulation; biogenesis; cell stress; succinate dehydrogenase; chaperone; cytochrome c; citric acid cycle; cytochrome c oxidase; succinate dehydrogenase (ubiquinone); protein homeostasis; unfolded protein response; mitochondrial genome; cell nucleus dna; mitochondrial rna; ubiquinol cytochrome c reductase; proton transporting adenosine triphosphate synthase; activating transcription factor; article; mitochondrial dna replication |
| Journal Title: | Molecular Cell |
| Volume: | 58 |
| Issue: | 1 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2015-04-02 |
| Start Page: | 123 |
| End Page: | 133 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2015.02.008 |
| PROVIDER: | scopus |
| PMCID: | PMC4385436 |
| PUBMED: | 25773600 |
| DOI/URL: | |
| Notes: | Export Date: 4 May 2015 -- Source: Scopus |
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