Unravelling the mechanistic basis of age-related mitochondrial membrane reorganizations in the ascomycete Podospora anserina

• Applicant: Professor Dr. Heinz Dieter Osiewacz
• Subject Area: Cell Biology ; Biochemistry
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 283390074

Mitochondria are eukaryotic cell organelles with a number of important functions (e.g ATP generation, biosynthesis of Fe/S clusters). Accordingly, functional impairments lead to degeneration, the development of different diseases and to biological aging. We use the filamentous ascomycete Podospora anserina as a well-established aging model with a strong mitochondrial etiology of aging. During aging of P. anserina gross reorganizations of the mitochondrial DNA and pronounced changes in mitochondrial morphology and ultrastructure occur. In the first period of the DFG-supported project we focused on the role of the mitochondrial F1Fo-ATP-synthase in shaping the ultrastructure of mitochondrial cristae. We experimentally validated a model which relies on earlier electron cryotomography data suggesting that the age-associated dissociation of F1Fo-ATP-synthase dimers, which are essential for the formation of cristae tips, is responsible for the transition of lamellar to vesicular mitochondria during aging. We demonstrated that ATP-synthase subunits e and g are involved in formation of typical cristae. We also showed that deletion of the gene coding for the subunit e induces bulk and mitochondrial autophagy (mitophagy) and thereby potentially compensates impairments caused by the ablation of the two F1Fo-ATP-synthase dimer assembly factors. In a second period of the project we now plan to concentrate on two main topics that will close existing gaps in the network of pathways involved in the biogenesis of mitochondria with most efficient functions. In the first subproject we will put special emphasis on the role of autophagy in strains with mitochondria which are impaired in F1Fo ATP-synthase dimer formation. The second subproject will investigate the role of MICOS (“mitochondrial contact site and cristae organizing system”), a macromolecular protein complex involved in the formation of cristae junctions. During the age-associated changes in mitochondrial ultrastructure MICOS needs to be remodeled. We first will analyze the composition of this complex in P. anserina and generate and analyze strains with modulated abundance (i.e. knockout and overexpression) of the two core subunits PaMIC10 and PaMIC60, respectively. Subsequently, we will experimentally analyze the role of MICOS in age-associated remodeling of the inner mitochondrial membrane. Both subprojects rely on a body of promising data and on experimental prerequisites elaborated in the first funding period. Overall, we will generate advanced new insights into components and mechanisms involved in the dynamic reorganization of mitochondria during aging of biological systems.

• DFG Programme: Research Grants