Universität zu Köln

Pazurek-Weber, Lilli Amal ORCID: 0000-0002-9779-6361 (2026). Role of proteolytic processing of Opa1 in mitochondrial quality control and stress response. PhD thesis, Universität zu Köln.

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Abstract

Mitochondrial plasticity enables mitochondria to adapt to changing cellular demands through continuous remodeling of their morphology, proteome and function. This dynamic equilibrium is maintained by constant fusion and fission processes of the organelle. Proteins driving the mitochondrial dynamics are Drp1 and Mfn1/2 on the outer membrane (OM) and Opa1 on the inner membrane (IM). Mitochondrial plasticity is further controlled by the IM proteases Yme1l and Oma1, which influence mitochondrial signaling through substrate cleavage. While Yme1l performs constitutive housekeeping cleavage of the fusion-active l-Opa1 into soluble s-Opa1 at the S2 site, Oma1 acts as a stress-responsive protease and recognizes the S1 cleavage site in Opa1. Here, we showed that the expression of only one Opa1 isoform (isoform variant 1) is sufficient for embryonic and adult development in mice. Yme1l-mediated Opa1 cleavage is dispensable in basal conditions and upon metabolic and thermal stress. Additional suppression of Oma1-dependent processing through the modification of four amino acids in the S1 region of Opa1 also shows no phenotype until adult age. Nevertheless, we found evidence of unhealthy aging due to a lack of the Opa1 isoforms and processing in old age. These mild effects appear to be tissue-specific and vary in severity. By an additional introduction of an OXPHOS deficiency model, we identified the necessity of Opa1 processing by Oma1 for maintaining the balance of biogenesis and mitophagy in order to execute an adequate stress response. Mice lacking Opa1 processing fail to undergo compensatory cardiac hypertrophy upon Cox10-/-, resulting in a shortened lifespan. Fibroblasts derived from these Opa1 mutants show decreased OXPHOS complexes, impaired respiration and reduced mtDNA maintenance. The imbalance of l- to s-Opa1 alters mitochondrial distribution within the cell, accompanied by a disruption of mitochondria-endoplasmic reticulum (ER) contact sites. The lack of Oma1-dependent Opa1 cleavage is associated with a delayed response upon H2O2 treatment and a reduced interferon-stimulated gene response (ISG response) under basal and nucleotide imbalance conditions. Proteomic analysis identified the interactome of s-Opa1 with OM proteins involved in fission, mitophagy, and cytoskeletal dynamics, providing an explanation for the disrupted mitophagy observed in Opa1-uncleavable hearts. In addition, we linked s-Opa1 to mitochondrial translation by identifying a promising interaction partner, Fam210a, which might explain the disrupted mitochondrial biogenesis in vivo. Together, our finding uncover a central role of Oma1-dependent Opa1 processing in coordinating mitochondrial architecture with stress adaptation, energy maintenance and in mitochondrial quality control.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Pazurek-Weber, Lilli Amal lilli.paz@web.de https://orcid.org/0000-0002-9779-6361 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-802326
Date:	12 January 2026
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Natural sciences and mathematics Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Mitochondria, OPA1, OMA1, mitochondrial dynamics, cardiac hypertrophy English
Date of oral exam:	9 March 2026
Referee:	Name Academic Title Trifunovic, Aleksandra Prof Dr Riemer, Jan Prof Dr
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80232