Reduced availability of the ALDH cofactor NAD+ by rotenone in a Caenorhabditis elegans model: functional relevance for the metabolism of toxic aldehydes

FERNANDEZ-HUBEID, LUCIA E.; ALBRECHT, PAULA A.; DEZA-PONZIO, ROMINA; VIRGOLINI MB,

Congreso; IX International Meeting of the Latin American Society for Biomedical Research on Alcohol-ism (LASBRA); 2019

LASBRA

The ALDH superfamily is associated with physiological and pathological processes. These enzymes play a key role in toxic aldehydes disposition, not only of those generated by oxidative stress (such as 4-hydroxynonenal) and central and systemic ethanol metabolism (acetaldehyde), but also products of biogenic amines degradation, including DOPAL (3,4-dihidroxyphenylacetaldehyde), dopamine (DA) first metabolite. The mitochondrial ALDH2 isoform is the best described due to its role in ethanol metabolism. Less known is a new body of research suggesting that ALDH2 dysfunction may contribute to a variety of human conditions including aging, neurodegenerative diseases and cancer. In this line, benomyl (a fungicide that directly inhibits ALDH2) and rotenone (a botanical insecticide that prevents NAD+ re oxidation in the mitochondrial complex I) have been associated with the environmental etiology of Parkinson disease. On the basis of these antecedents, in the present study we sought to describe the potential neurotoxicity of the exposure to the indirect ALDH inhibitor rotenone on the model organism Caenorhabditis elegans. Thus, wild type N2 worms were maintained in agar plates in the presence of food (OP50 E. coli) and synchronized to obtain adult animals. They were subsequently exposed to rotenone at 0, 2, 4, 6, 8 and 10 µM concentrations to perform a dose-response curve to evaluate potential lethality of this insecticide. They were also evaluated in their size to determine potential detrimental effects in normal growing conditions. The results demonstrated that the doses selected did not evidence any effect in the worm’s survival, although a reduction in size was observed with the higher doses evaluated. Current experiments are focused on the study of the basal slowing response, a behavior dependent on the DA system integrity, to later determine DA functionality in available DA and ALDH transgenic strains. Overall, we propose the present approach as a useful tool to modulate ALDH functionality, which may have important implications, not only in the field of neurodegenerative diseases but also in the deep understanding of ethanol metabolism as a potential target of the drug addictive effects.