Mitochondrial stress signalling and its impacts on physiology

Mitochondria are responsible for respiration and energy harvesting across the eukaryotic kingdom. They also take part in other cellular processes like intermediary metabolism. As a result, mitochondrial function directly impacts organismal features such as metabolic homeostasis, fitness and aging. Moreover, mitochondrial dysfunction is involved in numerous pathologies, such as neurodegenerative disease, obesity, diabetes and cancer. Several surveillance pathways constantly monitor mitochondria to ensure their proper function. Among the pathways triggered by stress, the mitochondrial unfolded protein response (UPRmt) aims to restore proteostasis within this organelle. A better understanding of the cellular response to mitochondrial stress would expand our fundamental knowledge of physiological and pathological processes involving mitochondria, leading to potential new therapeutics that target these organelles. This thesis focuses on the mechanistic and physiological characterization of the mitochondrial stress response in several organisms. I used the model organism Caenorhabtis elegans to screen for novel players of the UPRmt and found the poly(A)-binding protein pab-1. Using transcript profiling, we showed that the induction of immune genes is a common consequence of several mitochondrial stressors. We demonstrated that pab-1 regulates the activation of the mitochondrial stress response and innate immunity as well. On top, pab-1 is required for the survival of C. elegans upon bacterial infection. Transcriptomic data from multiple human tissues suggest that the human pab-1 orthologue, PABPC1, has a conserved role in immunity. In mice, I explored the regulation of the mitochondrial stress response using a combination of bioinformatics and in vivo experimental approaches. Combined transcriptomic and proteomic analyses in the BXD mouse genetic reference population revealed a tight co-regulation of the orthologues of the UPRmt under normal physiological conditions. As a complementary approach, we triggered mitochondrial stress pharmacologically in newly born and adult mice. Due to the bacterial ancestry of mitochondria, the effects of the antibiotic doxycycline (dox) are also deleterious to this organelle. We found that dox impairs mitochondrial proteostasis and oxygen consumption in adult mice. However, mitochondrial stress induced by post-natal dox treatment did not cause long-lasting effects on mouse physiology and longevity, which is very distinct from observations in C. elegans. The mammalian gut flora plays an important role in organismal homeostasis. The use of an antibiotic causes perturbations of the microbiota, with repercussions on metabolism, inflammation, and the nervous system. To eliminate these confounding effects, we also treated germ-free mice with dox to characterize the response of the mouse to a so-called “pure” mitochondrial stress. Using multi-omics profiling, we found that organs highly dependent on mitochondria display specific transcriptomic and proteomic signatures following dox treatment. In the kidney, we observed an inhibition of translation and of the mTOR pathway, accompanied by an activation of the ATF4 integrated stress response (ISR). In the liver, dox led to a remodelling of lipid metabolism. In both organs, target transcripts of type I interferon anti-viral response were induced. This thesis demonstrates that the response to mitochondrial stress is a multi-faceted process with conserved aspects acr


Advisor(s):
Auwerx, Johan
Year:
2018
Publisher:
Lausanne, EPFL
Keywords:
Laboratories:
NCEM




 Record created 2018-05-23, last modified 2019-12-05

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