Mitochondrial and metabolic dysregulation has been linked to aging and multiple human diseases. Therefore, uncovering and understanding novel mechanisms that govern mitochondrial function is important to find treatments for age-related diseases. In this thesis, the impact of sodium butyrate (SB) on mitochondrial and metabolic function as well as lifespan was investigated in Drosophila melanogaster and Caenorhabditis elegans.
SB treatment showed a dose-dependent, rapid, and transient increase in oxygen consumption in whole fly heads. Since SB is a lysine deacetylase inhibitor (KDACi), oxygen consumption increase under SB treatment was hypothesized to be caused by the inhibition of lysine deacetylases. Notably, proteome and acetylome analyses revealed no significant alterations between control and SB treatment. However, mass spectrometry analysis revealed rapid incorporation of 13C4-labeled sodium butyrate into several metabolites involved in mitochondrial pathways. This indicates that the observed phenotype was rather due to a metabolic boost than acetylation changes.
Since alterations in mitochondrial activity seem to be likely affecting longevity, SB was investigated regarding lifespan extension. Here, in line with previous studies, SB showed a dose-dependent effect on worm lifespan. Contrarily, fly lifespan was not affected.
With this in mind, an SB-independent way for mitochondrial activation was assessed in this work. The mitochondrial membrane potential of C. elegans was increased, using a light-activated proton pump, resulting in an extended median lifespan, even if the intervention took part in mid- or late-staged worms.