Untersuchung der mechanistischen Grundlagen altersassoziierter Umorganisationen mitochondrialer Membranen bei dem Ascomyceten Podospora anserina
Biochemie
Zusammenfassung der Projektergebnisse
Mitochondrial functional is intimately linked to the ultrastructure. Cristae allow tight packing of the respiratory complexes and thus enable efficiently the formation of the membrane potential required for ATP production. Therefore, it makes sense that different pathways have evolved to control ultrastructure. First, phospholipids with intrinsic conic structure like cardiolipin help in shaping the highly curved cristae membranes. Second, dimers of the F1Fo-ATP-synthase stabilize the cristae ridges. Third, MICOS complex forms the cristae junctions connecting the cristae to the intermembrane space and the outer membrane. We used mutants of all three pathways and found that alterations in any of these pathways differentially affect lifespan. Obviously, F1Fo-ATP-synthase dimerization is crucial for mitochondrial function, its ablation strongly reduces lifespan by inducing excessive mitophagy. None of the other two pathways has such a strong impact on survival. In contrast, ablation of MICOS stimulates beneficial compensatory pathways like phospholipid rewiring or ROS-induced mitohormesis. To understand how to overcome disease- or age-dependent impairments due to ultrastructural changes therefore ultimately requires the understanding of the connection between these different pathways. To this end, the rather “simple” model organism P. anserina turned is a useful tool. We were able to demonstrate that ultrastructural changes do not only result in lifespan reduction as it is shown in the short-lived F1Fo-ATP-synthase dimerization mutants but may also lead to longevity as seen in the MICOS mutants. Moreover, we uncovered independent mechanisms induced by ablation of either of the two MICOS subcomplexes allowing to refine the view on the role of these two subcomplexes.
Projektbezogene Publikationen (Auswahl)
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(2018) Impact of F1Fo-ATP-synthase dimer assembly factors on mitochondrial function and organismic aging. Microbial Cell 5: 198-207
Rampello NG, Stenger M, Westermann B, Osiewacz HD
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(2021) Aging of Podospora anserina leads to alterations of OXPHOS and the induction of non-mitochondrial salvage pathways. Cells 10: 3319
Warnsmann V, Meisterknecht J, Wittig I, Osiewacz HD
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(2021) Impaired F1Fo-ATP-synthase dimerization leads to the induction of cyclophilin D-mediated autophagy-dependent cell death and accelerated aging. Cells 10: 757
Warnsmann V, Marschall LM, Osiewacz HD
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(2022) Disruption of the MICOS complex leads to an aberrant cristae structure and an unexpected, pronounced lifespan extension in Podospora anserina. J Cell Biochem 123: 1306-1326
Warnsmann V, Marschall LM, Meeßen A, Wolters M, Schürmanns L, Basoglu M, Eimer S, Osiewacz HD
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(2022) Lifespan extension of Podospora anserina Mic60-subcomplex mutants depends on cardiolipin remodeling. Int J Mol Sci 23: 4741
Marschall LM, Warnsmann V, Meeßen A, Löser T, Osiewacz HD
