Kaspar 2021 Sci Adv

From Bioblast
Jump to navigation Jump to search
Publications in the MiPMap
Kaspar S, Oertlin C, Szczepanowska K, Kukat A, Senft K, Lucas C, Brodesser S, Hatzoglou M, Larsson O, Topisirovic I, Trifunovic A (2021) Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR. Sci Adv 7:0971.

» PMID: 34039602 Open Access

Kaspar Sophie, Oertlin Christian, Szczepanowska Karolina, Kukat Alexandra, Senft Katharina, Lucas Christina, Brodesser Susanne, Hatzoglou Maria, Larsson Ola, Topisirovic Ivan, Trifunovic Aleksandra (2021) Sci Adv

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.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).


Bioblast editor: Reiswig R O2k-Network Lab: DE Cologne Trifunovic A


Labels: MiParea: Respiration, nDNA;cell genetics, Genetic knockout;overexpression 


Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k 

2021-08