Mitochondria are the power plants of our cells. Defects in mitochondrial functions, especially the response to stress, lead to diseases like neurodegenerative diseases or myocardial disorders. Understanding the mitochondrial stress response in mammals remains a pivotal gap in knowledge. Over the last years it became increasingly clear that unlike in model organisms like C. elegans, mammalian mitochondrial unfolded protein response (UPRmt)may not be the primary nor prominent response to mitochondrial respiratory dysfunction. Experiments with patient-derived cell lines and cells treated with mitochondrial toxins exhibit transcriptional reprogramming mimicking the integrated stress response arm of the “classical” cellular unfolded protein response, which is centered on the activating transcription factor 4 (ATF4). However, many questions on the regulation of the mitochondrial stress response remains enigmatic, in particular fine tuning of the transcriptional regulation.
Trifunovic and her team with Sophie Kaspar in the lead now uncovered an unexpected intricate interplay between three transcription factors that regulate the mitochondrial stress response: CHOP, C/EBPβ, and ATF4. By analyzing a large amount of multiomics data and verification in animal models this finding disputes a long-standing paradigm viewing CHOP as a main transcriptional activator of mitochondrial unfolded protein response. The researchers present that CHOP interacts with the inhibitory isoform of C/EBPβ and thereby attenuated prolonged integrated stress response through regulation of ATF4 activity.
The results highlight the role of CHOP as a rheostat that attenuates prolonged integrated stress response, prevents unfavorable modification of metabolism, and postpones the onset of mitochondrial cardiomyopathy.
These results represent another piece of the puzzle for understanding these largely unknown mechanisms that play a central role in determining the extent of tissue specific defect arising from the respiratory chain deficiency, but also highlight the importance of temporal changes in integrated stress response and progression of disease in vivo.
“We have just started uncovering the complexity of how mitochondria signal their discomfort and stress. Our results suggest that some of these responses might be potential drug targets in myriad of pathological states, including aging, when mitochondria do not function properly,” said Trifunovic
For this study Trifunovic cooperated with Scientists from McGill University (Montreal, Canada), Karolinska Institute (Sweden) and Case Western Reserve University (Cleveland, Ohio, USA), all of which are have strong background in the regulation of integrated stress response in different pathophysiological conditions.
Original Publication:
Kaspar S, Oertlin C, Szczepanowska K, Kukat A, Senft K, Lucas C, Brodesser S, Hatzoglou M, Larsson O, Topisirovic I, Trifunovic A. Adaptation to mitochondrial stress requires
CHOP-directed tuning of ISR. Sci Adv. 2021
https://advances.sciencemag.org/content/7/22/eabf0971