Open AccessAdaptation to mitochondrial stress requires CHOP-directed tuning of ISR
Author(s) -
Sophie Kaspar,
Christian Oertlin,
Karolina Szczepanowska,
Alexandra Kukat,
Katharina Senft,
Christina Lucas,
Susanne Brodesser,
Maria Hatzoglou,
Ola Larsson,
Ivan Topisirović,
Aleksandra Trifunović
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abf0971
Subject(s) - chop , adaptation (eye) , cardiomyopathy , mitochondrion , stress (linguistics) , biology , bioinformatics , medicine , microbiology and biotechnology , neuroscience , endoplasmic reticulum , heart failure , linguistics , philosophy
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/EBPβ, 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/EBPβ 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.