|
| Status |
Public on Jun 28, 2016 |
| Title |
Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The mitochondrial matrix is unique in that it must integrate folding and assembly of proteins derived from nuclear and mitochondrial genomes. In C. elegans, the mitochondrial unfolded protein response (UPRmt) senses matrix protein misfolding and induces a program of nuclear gene expression, including mitochondrial chaperonins, to promote mitochondrial proteostasis. While misfolded mitochondrial matrix-localized ornithine trans-carbamylase (OTC) induces chaperonin expression, our understanding of mammalian UPRmt is rudimentary, reflecting a lack of acute triggers for UPRmt activation. This limitation has prevented analysis of the cellular responses to matrix protein misfolding and the effects of UPRmt on mitochondrial translation to control protein folding loads. Here, we combine pharmacological inhibitors of matrix-localized HSP90/TRAP1 or LON protease, which promote chaperonin expression, with global transcriptional and proteomic analysis to reveal an extensive and acute response of human cells to UPRmt. This response involved widespread induction of nuclear genes, including matrix-localized proteins involved in folding, pre-RNA processing and translation. Functional studies revealed rapid but reversible translation inhibition in mitochondria occurring concurrently with defects in pre-RNA processing due to transcriptional repression and LON-dependent turnover of the mitochondrial pre-RNA processing nuclease MRPP3. This study reveals that acute mitochondrial protein folding stress activates both increased chaperone availability within the matrix and reduced matrix-localized protein synthesis through translational inhibition, and provides a framework for further dissection of mammalian UPRmt.
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| |
|
| Overall design |
triplicate experiment of 3 conditions (untreated, GTPP treatment, CDDO treatment)
|
| |
|
| Contributor(s) |
Münch C, Harper JW |
| Citation(s) |
27350246 |
| Submission date |
Nov 20, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Christian Munch |
| E-mail(s) |
christian_munch@hms.harvard.edu
|
| Organization name |
Harvard Medical School
|
| Department |
Cell Biology
|
| Street address |
240 Longwood Avenue
|
| City |
Boston |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (9)
|
|
| This SubSeries is part of SuperSeries: |
| GSE75411 |
Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation |
|
| Relations |
| BioProject |
PRJNA302895 |
| SRA |
SRP066487 |
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