Modulation of the alternative oxidase activity by regulation of the mitochondrial glycerol-3-phosphate dehydrogenase levels

Abstract

Genetic, metabolic or physiological disorders that affect the mitochondrial respiratory chain cause depletion of cellular ATP levels and excessive formation of reactive oxygen species (ROS). The xenotopic expression of the mitochondrial alternative oxidase (AOX) has been considered a possible therapy to prevent excess ROS formation by the respiratory chain in pathological conditions, with restablishment of oxygen consumption in patients' mitochondria. Despite the countless promising results, the functioning of AOX in animal cells is still poorly understood. Our preliminary results using Drosophila melanogaster indicate that AOX interacts functionally with the mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), uncoupling mitochondria. This interaction is beneficial in individuals exposed to intense cold, but it is harmful when they are cultured in a low-nutrient diet. The aim of this project is to characterize strains of D. melanogaster with varying expression levels of mGPDH and verify how the co-expression of AOX affects development when the flies are submitted to different nutritional conditions. We hypothesize that the harmful phenotype caused by the mGPDH-AOX interaction will be intensified when mGPDH is overexpressed, or it will be attenuated/abolished when mGPDH is depleted. Considering the important role that mGPDH has in different tissues, we hope to contribute to the predictability of the effectiveness of future treatments using AOX as a therapeutic enzyme.