Elucidating the Molecular Pathologies in Mouse Models for Mitochondrial Diseases

by Angela Boshnakovska
Doctoral thesis
Date of Examination:2024-06-06
Date of issue:2025-06-04
Advisor:Prof. Dr. Peter Rehling
Referee:Prof. Dr. Dörthe Katschinski
Referee:Prof. Dr. Stephan E. Lehnart
Referee:Prof. Dr. Ralph Kehlenbach
Referee:PD Dr. Antje Ebert
Referee:Dr. Dieter Klopfenstein
Persistent Address: http://dx.doi.org/10.53846/goediss-11300

 

 

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Abstract

English

The field of exploring mitochondrial diseases has gained much attention and notoriety in recent years. Individual mutations in proteins involved in mitochondrial structure and function are rare. However, when taken as a whole, the prevalence of mitochondrial disease is estimated at approximately 1 in 5000 cases. We investigate the intricate connection between mitochondrial dysfunction and cellular dynamics guiding disease progression by looking at four distinct mouse models. We show how gene mutations in nuclear-encoded mitochondrial proteins can disrupt mitochondrial energetics, ultimately leading to various pathologies. Mitochondria are responsible for most energy production in the eukaryotic cell through the OXPHOS system. The proper assembly and function of the OXPHOS complexes are fundamental for cellular health. We have described four mouse models here, each harboring a unique genetic defect and affecting mitochondrial health. The first model, a TAZG197V mouse, mimics Barth Syndrome pathology, a condition caused by a mutation in the Taz gene. This mutation disrupts cardiolipin remodeling, which in turn impairs mitochondrial inner membrane organization and consequently affects the structure and function of the OXPHOS complexes. These mice exhibit heart dysfunction and a reduced capacity for fatty acid oxidation in the heart. In both mouse hearts and patient-derived iPSCs harboring the TAZG197V mutation, a metabolic switch from OXPHOS-based ATP production to glycolysis is observed. This increase in glycolytic ATP inactivates AMPK, leading to altered metabolic signaling. However, treating mutant cells with an AMPK activator restores fatty acid-dependent OXPHOS and protects mice from cardiac dysfunction. The second, a SMIM20-/- mouse model, lacks a protein (SMIM20), involved in complex IV assembly, the final enzyme in the OXPHOS chain. These knockout mice develop a cardiac phenotype as a result of complex IV deficiency and metabolic alterations that favor glycolysis over fatty acid oxidation. This finding points towards a novel tissue- specific consequence of complex IV dysfunction. The COX14M19I and COA3Y72C mouse models harbor patient mutations, which affect COX1 module assembly, leading to a complex IV deficiency. COX14M19I mice display a broader range of tissue-specific pathologies, with severe liver inflammation as a hallmark. This inflammatory response is triggered by the release of mitochondrial RNA into the cytosol as a result of increased ROS. The COA3Y72C mice exhibit a similar but milder inflammatory phenotype. Our analysis of these mouse models reveals how distinct genetic defects in nuclear- encoded mitochondrial proteins can manifest as diverse disease pathologies. These findings shed valuable light on the mechanisms underlying mitochondrial diseases, paving the way for potential therapeutic development.
Keywords: Mitochondria; cardiomyopathies; Mouse models; Biochemistry
Schlagwörter: Mitochondria; cardiomyopathies; Mouse models; Biochemistry
 
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