Synthesis and metabolism of methylglyoxal, S-D-lactoylglutathione and D-lactate in cancer and Alzheimer's disease. Exploring the crossroad of eternal youth and premature aging

Both cancer and Alzheimer's disease (AD) are emerging as metabolic diseases in which aberrant/dysregulated glucose metabolism and bioenergetics occur, and play a key role in disease progression. Interestingly, an enhancement of glucose uptake, glycolysis and pentose phosphate pathway occurs in both cancer cells and amyloid-beta-resistant neurons in the early phase of AD. However, this metabolic shift has its adverse effects. One of them is the increase in methylglyoxal production, a physiological cytotoxic by-product of glucose catabolism. Methylglyoxal is mainly detoxified via cytosolic glyoxalase route comprising glyoxalase 1 and glyoxalase 2 with the production of S-D-lactoylglutathione and D-lactate as intermediate and end-product, respectively. Due to the existence of mitochondrial carriers and intramitochondrial glyoxalase 2 and D-lactate dehydrogenase, the transport and metabolism of both S-D-lactoylglutathione and D-lactate in mitochondria can contribute to methylglyoxal elimination, cellular antioxidant power and energy production. In this review, it is supposed that the different ability of cancer cells and AD neurons to metabolize methylglyoxal, S-D-lactoylglutathione and D-lactate scores cell fate, therefore being at the very crossroad of the eternal youth of cancer and the premature death of AD neurons. Understanding of these processes would help to elaborate novel metabolism-based therapies for cancer and AD treatment.