Identification of compensatory mechanisms and disease pathways in mitochondrial disease and synucleinopathy

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.<br /> 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.<br /> We sought to explore the compensatory mechanisms that organisms activate in response to the inhibition of OXPHOS using <em>Caenorhabditis elegans</em> 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.<br /> 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.