Drosophila melanogaster larval development is characterised by considerable growth, which requires the rapid conversion of nutrients into biomass. Lactate dehydrogenase (LDH) is crucial for this process because it helps to maintain redox balance within cells by regenerating NAD+ from NADH, which is essential for maintaining high levels of glucose metabolism. Now, Hongde Li, Jason Tennessen and colleagues investigate the role of LDH during Drosophila larval development. They confirm that Ldh mutants indeed exhibit an abnormal NAD+/NADH redox balance, although their growth rate remains unaffected. Instead, the authors notice increased levels of glycerol-3-phosphate (G3P), which is synthesised by G3P dehydrogenase (GPDH1) through a mechanism that also regenerates NAD+. This suggests that flies compensate for the absence of LDH function by upregulating GPDH1 activity. Indeed, unlike either single mutant, Gpdh1; Ldh double mutants exhibit severe growth defects and decreased glycolytic flux, thus revealing a mechanism that cooperatively regulates redox balance during larval growth. Collectively, these results illustrate the remarkable metabolic flexibility of Drosophila larval development. These findings are also relevant to cancer therapy, as LDH inhibition has been proposed to interfere with tumour growth, but may instead be counteracted by cancer cells employing alternative metabolic pathways for growth.
