Low glucose stress decreases cellular NADH and mitochondrial ATP in colonic epithelial cancer cells: Influence of mitochondrial substrates

•Glucose deprivation impairs redox status of cellular pyridine nucleotides.•Glucose stress enhances cytosolic aerobic glycolysis but not mitochondrial activity.•The increase in malic enzyme activity provides pyruvate under low glucose condition.•Cytosolic catabolism of mitochondrial substrates spares glucose for aerobic glycolysis.•Colonic carcinoma cells employ metabolic alterations to alleviate glucose stress.

In this study, we investigated how colonic epithelial cells maintained pyridine nucleotide (NADH/NAD+) redox homeostasis upon acute metabolic variation imposed by glucose deprivation or supplementation with mitochondrial substrates, succinate and malate/glutamate (M/G). Our results showed that low glucose caused cellular NADH/NAD+ redox imbalance that diminished lactate dehydrogenase (LDH) activity and resulted in lower lactate contents. The concurrent activation of malic enzyme (ME) suggested a role for malate in preserving cellular pyruvate that remained unchanged at low glucose. Mitochondrial substrates restored cellular NADH/NAD+ redox homeostasis at low glucose in association with specific compartmental catabolism of mitochondrial substrates. As compared with normal glucose, M/G and low glucose promoted glycolytic ATP production but inhibited mitochondrial-derived ATP generation in association with decreased glucose availability for mitochondrial respiration. At normal glucose, succinate and M/G enhanced mitochondrial respiratory activity, but had minimal impact on mitochondrial-derived ATP production. Collectively, these results are consistent with low glucose-induced NADH/NAD+ redox imbalance in association with decreased aerobic glycolysis that is reversed by supplementation with M/G but not succinate.