Methylglyoxal in the Brain: From Glycolytic Metabolite to Signalling Molecule

HIGHLIGHTS: ●. MGO may be essential for glycometabolism and bioenergetics in homeostasis and neural development; ●. MGO may be an essential molecule in the regulation of neural homeostasis (redox homeostasis, lipid metabolism homeostasis, energy homeostasis, protein steady-state, epigenetic mechanisms, and neurotransmitters); ●. Glycolysis is a source of protein homeostasis destruction. MGO formation as a by-product of glycolysis drives damage to the proteome. ABSTRACT: Advances in molecular biology technology have piqued tremendous interest in glycometabolism and bioenergetics in homeostasis and neural development linked to ageing and age-related diseases. Methylglyoxal (MGO) is a by-product of glycolysis, and it can covalently modify proteins, nucleic acids, and lipids, leading to cell growth inhibition and, eventually, cell death. MGO can alter intracellular calcium homeostasis, which is a major cell-permeant precursor to advanced glycation end-products (AGEs). As side-products or signalling molecules, MGO is involved in several pathologies, including neurodevelopmental disorders, ageing, and neurodegenerative diseases. In this review, we demonstrate that MGO (the metabolic side-product of glycolysis), the GLO system, and their analogous relationship with behavioural phenotypes, epigenetics, ageing, pain, and CNS degeneration. Furthermore, we summarise several therapeutic approaches that target MGO and the glyoxalase (GLO) system in neurodegenerative diseases.