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.