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Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR

Discussion in 'Other health news and research' started by darrellpf, May 27, 2021.

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  1. darrellpf

    darrellpf Established Member (Voting Rights)

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    https://advances.sciencemag.org/content/7/22/eabf0971/tab-article-info

    https://doi.org/10.1126/sciadv.abf0971

    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/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.
     
    Peter Trewhitt and Mij like this.

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