Genetic regulation of the mitochondrial integrated stress response in humans

Mayer, Eva-Maria Elisabeth (2024): Genetic regulation of the mitochondrial integrated stress response in humans. Dissertation, LMU München: Faculty of Chemistry and Pharmacy

Abstract

Mitochondrial homeostasis is vital for overall cellular fidelity, and its dysfunction is tightly linked to aging and disease. Mitochondrial dysfunction needs to be sensed and signaled to a cytosolic stress response mechanism to be resolved and allow recovery from stress. First, this thesis introduces the topic of mitochondrial stress signaling and discusses which mitochondrial stress response mechanisms in different organisms are activated at increasing stress intensities: from regulation of mitochondrial import processes and stress response mechanisms described in yeast to the mitochondrial unfolded protein response (UPRmt) in C. elegans and the mitochondrial integrated stress response (mtISR) in mammals. Further, we discuss the mitochondrial proteostasis machinery in the individual mitochondrial compartments, focusing on chaperones and proteases. The second chapter entails our study on the OMA1-DELE1-HRI axis, which is triggered in response to various mitochondrial stresses. Herein, the protease OMA1 is activated upon mitochondrial dysfunction and cleaves DELE1, a mitochondrial protein, at steady state. Upon cleavage, a short DELE1 (S-DELE1) fragment translocates to the cytosol and interacts with the eIF2a kinase HRI to activate the downstream integrated stress response (ISR). Chapter three analyzes distinct genetic regulators of mtISR activation in response to proteotoxic stress induced by newly developed mitochondria-targeted drugs. A haploid genetic screen uncovers the g-secretase and the Na+/K+-ATPase as positive regulators of the signaling cascade. We show that the g-secretase cleaves the regulatory factor of the Na+/K+-ATPase, FXYD5. The Na+/K+-ATPase then affects the canonical signaling cascade at the level of OMA1 activation and DELE1 cleavage. Additionally, this chapter analyzes potential mechanisms by which the stress response could be affected in Na+/K+-ATPase defective cells, e.g., changes in cellular energy state. Finally, this chapter uncovers, through an unbiased genetic screen, regulators of steady state ISR induction. Among those are mitochondrial factors of different functional categories that, when lost, induce ISR signaling. The results in this thesis overall contribute to a deeper understanding of mitochondrial stress signaling in humans.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: Mitochondria, Genetic Screen, Haploid, DELE1, HRI, OMA1, Integrated Stress Response, ISR
• Subjects: 500 Natural sciences and mathematics; 500 Natural sciences and mathematics > 540 Chemistry and allied sciences
• Faculties: Faculty of Chemistry and Pharmacy
• Language: English
• Date of oral examination: 15. March 2024
• 1. Referee: Jae, Lucas
• Signature of the printed copy: 0001/UMC 32160