Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR.
Sci Adv
; 7(22)2021 05.
Article
en En
| MEDLINE
| ID: mdl-34039602
ABSTRACT
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/EBPß, 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/EBPß 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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Sci Adv
Año:
2021
Tipo del documento:
Article
País de afiliación:
Alemania