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| Home > Publications Database > Identification of compensatory mechanisms and disease pathways in mitochondrial disease and synucleinopathy |
| Home > Publications Database > Identification of compensatory mechanisms and disease pathways in mitochondrial disease and synucleinopathy |
| Dissertation / PhD Thesis | DZNE-2025-00607 |
2025
Please use a persistent id in citations: urn:nbn:de:hbz:5-82889
Abstract: Mitochondria play vital roles in a variety of processes such as cellular metabolism, intracellular signalling and cell death. Defects in mitochondria can lead to inherited metabolic disorders and neurodegenerative diseases. There is often a poor genotype-to-phenotype correlation in mitochondrial diseases, with distinct mutations that lead to a wide variety of clinical manifestations, age of onset and disease severity. This heterogeneity of symptoms, in combination with a relatively low frequency in the population, makes the development of novel treatments particularly challenging.In invertebrates and some mouse models of mitochondrial diseases, inhibition of the mitochondrial oxidative phosphorylation (OXPHOS) can lead to a paradoxical lifespan extension through the engagement of compensatory mechanisms. As an explanation of this phenomena, the “mitochondrial threshold effect theory” states that mitochondrial dysfunction below a certain threshold promotes stress resilience and metabolic rewiring, leading to enhanced longevity. However, if damage exceeds a certain threshold, animals develop disease. In a human context, a better understanding of the “mitochondrial threshold effect” may explain some of the molecular signatures and variable disease traits observed in patients. We sought to explore the compensatory mechanisms that organisms activate in response to the inhibition of OXPHOS using Caenorhabditis elegans as a genetically tractable model, in combination with mouse and human cells. Our goals were to investigate the underlying molecular mechanisms that contribute to mitochondrial dysfunction and neurodegenerative processes.By performing a cross-species analysis, we identified VPS-39/VPS39 and SPL-1/SGPL1 to be part of the molecular mechanisms that compensate for mitochondrial dysfunction. In the context of neurodegenerative processes, we found that the actin nucleation promoting factor WSP-1/N-WASP is a disease modifier that contributes to mitochondrial dysfunction and proteotoxicity. Together, these results build on our growing understanding of the mechanisms that counteract mitochondrial dysfunction and pathogenic processes.
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