| First Author | Kaspar S | Year | 2021 |
| Journal | Sci Adv | Volume | 7 |
| Issue | 22 | PubMed ID | 34039602 |
| Mgi Jnum | J:314226 | Mgi Id | MGI:6813085 |
| Doi | 10.1126/sciadv.abf0971 | Citation | Kaspar S, et al. (2021) Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR. Sci Adv 7(22) |
| abstractText | In response to disturbed mitochondrial gene expression and protein synthesis, an adaptive transcriptional response sharing a signature of the integrated stress response (ISR) is activated. We report an intricate interplay between three transcription factors regulating the mitochondrial stress response: CHOP, C/EBPbeta, and ATF4. We show that CHOP acts as a rheostat that attenuates prolonged ISR, prevents unfavorable metabolic alterations, and postpones the onset of mitochondrial cardiomyopathy. Upon mitochondrial dysfunction, CHOP interaction with C/EBPbeta is needed to adjust ATF4 levels, thus preventing overactivation of the ATF4-regulated transcriptional program. Failure of this interaction switches ISR from an acute to a chronic state, leading to early respiratory chain deficiency, energy crisis, and premature death. Therefore, contrary to its previously proposed role as a transcriptional activator of mitochondrial unfolded protein response, our results highlight a role of CHOP in the fine-tuning of mitochondrial ISR in mammals. |
