Universität zu Köln

Narbona Pérez, Álvaro Jesús ORCID: 0000-0002-1517-6610 (2025). Coordination of metabolic homeostasis and innate immunity by the mitochondrial protease OMA1. PhD thesis, Universität zu Köln.

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Abstract

Mitochondrial maintenance and quality control in general, and mitochondrial proteostasis in particular, are of paramount importance for cellular physiology, and their dysfunction can have catastrophic consequences in the context of human disease. Among the effectors of mitochondrial quality control, the mitochondrial protease OMA1 is emerging as a central regulator of cellular adaptation to stress and survival. OMA1 has been described as a stress-activated protease of the inner mitochondrial membrane that regulates fundamental processes like mitochondrial dynamics and cristae morphology through the processing of the dynamin-like GTPase OPA1, and the induction of the mitochondrial integrated stress response through the cleavage of DELE1. Through the regulation of those pathways, OMA1 sits at the interface between apoptosis induction and ferroptosis resistance, highlighted by various mouse models that have shown that the consequences of stress-induced activation of OMA1 are context-specific. However, the factors tilting the balance between OMA1-mediated cell survival and cell death remain to be elucidated. To gain further insight into the pro- and anti-survival roles of OMA1, we followed a systems biology approach. We combined a metabolism-focused CRISPR screen with an in-silico co-expression analysis to identify pathways and metabolic determinants of cell survival decisions by OMA1. The integration of these approaches followed by a multi-omics and biochemical characterization revealed that OMA1 regulates metabolic homeostasis and innate immune signaling, which become relevant under situations of nucleotide scarcity induced by chemotherapy agents. First, OMA1 dictates cell survival upon nuclear DNA damage and p53-dependent apoptosis through the regulation of the metabolic status of the cell. This protective role of OMA1 is independent of OPA1 and DELE1 and is explained by a disturbed glucose metabolism in the absence of OMA1. Second, OMA1 is required for an efficient interferon-stimulated gene response following nucleotide imbalance. This regulatory role of OMA1 occurs through the processing of OPA1 and facilitates nuclear DNA repair. Altogether, these findings provide novel roles of OMA1 for mitochondrial and cellular fitness and shed light on the mechanisms underlying the dichotomic role of OMA1.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Narbona Pérez, Álvaro Jesús anarbonap@gmail.com orcid.org/0000-0002-1517-6610 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-788907
Date:	2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language OMA1 UNSPECIFIED Mitochondria UNSPECIFIED OPA1 UNSPECIFIED Metabolism UNSPECIFIED Interferon UNSPECIFIED Cell death UNSPECIFIED
Date of oral exam:	15 December 2023
Referee:	Name Academic Title Langer, Thomas Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/78890