Home > Publications Database > Identification of compensatory mechanisms and disease pathways in mitochondrial disease and synucleinopathy > print

001     278574
005     20250923145552.0
024 7 _ |a urn:nbn:de:hbz:5-82889
|2 URN
037 _ _ |a DZNE-2025-00607
041 _ _ |a English
100 1 _ |a Jackson, Joshua
|0 P:(DE-2719)2814190
|b 0
|e First author
245 _ _ |a Identification of compensatory mechanisms and disease pathways in mitochondrial disease and synucleinopathy
260 _ _ |c 2025
300 _ _ |a 97 p.
336 7 _ |a Output Types/Dissertation
|2 DataCite
336 7 _ |a DISSERTATION
|2 ORCID
336 7 _ |a PHDTHESIS
|2 BibTeX
336 7 _ |a Thesis
|0 2
|2 EndNote
336 7 _ |a Dissertation / PhD Thesis
|b phd
|m phd
|0 PUB:(DE-HGF)11
|s 1758632084_10852
|2 PUB:(DE-HGF)
336 7 _ |a doctoralThesis
|2 DRIVER
502 _ _ |a Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn, 2025
|c Rheinische Friedrich-Wilhelms-Universität Bonn
|b Dissertation
|d 2025
|o 2025-05-13
520 _ _ |a 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.
536 _ _ |a 351 - Brain Function (POF4-351)
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|c POF4-351
|f POF IV
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856 4 _ |u https://hdl.handle.net/20.500.11811/13111
856 4 _ |u https://pub.dzne.de/record/278574/files/DZNE-2025-00607_Restricted.pdf
856 4 _ |u https://pub.dzne.de/record/278574/files/DZNE-2025-00607_Restricted.pdf?subformat=pdfa
|x pdfa
909 C O |p VDB
|o oai:pub.dzne.de:278574
910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
|0 I:(DE-588)1065079516
|k DZNE
|b 0
|6 P:(DE-2719)2814190
913 1 _ |a DE-HGF
|b Gesundheit
|l Neurodegenerative Diseases
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|v Brain Function
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920 1 _ |0 I:(DE-2719)1013003
|k AG Bano
|l Aging and Neurodegeneration
|x 0
980 _ _ |a phd
980 _ _ |a VDB
980 _ _ |a I:(DE-2719)1013003
980 _ _ |a UNRESTRICTED

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