Methylglyoxal in the Brain: From Glycolytic Metabolite to Signalling Molecule

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.

Keywords: behavioural phenotypes; bioenergetics; glyoxalase; homeostasis; methylglyoxal; neurodegenerative; side-product.

Figure 1

Biosynthesis, metabolism, and adduct formation in MGO. MGO biosynthesis: MGO is an unavoidable endogenous coproduct of the metabolism of glucose, threonine acetone, lipids, and proteins. Adduct formation: The incubation of these highly reactive compounds with proteins, lipids, and nucleic acids leads to the rapid formation of AGEs and advanced lipoxidation end-products. MGO metabolism: MGO is converted into S-D-lactoylglutathione in the GSH-dependent GLO1 system and subsequently transformed into D-lactate via GLO Methylglyoxal reductase and aldehyde dehydrogenase convert MGO into hydroxyacetone or pyruvate.

Figure 2

Multiple pathways via which MGO induces oxidative stress, pain, anxiolytic effects, and ageing. The pathways activated by MGO induce oxidative stress, which may play a role in ageing. The formation of AGEs involves nonenzymatic reactions that occur when sugars or dicarbonyl compounds, such as MGO, are reduced. Research has been conducted on the connection between neuropathic pain and the transient receptor potential ankyrin 1 (TRPA1) pathway. MGO mediates the anxiolytic effect via the modulation of GABAergic actions. MGO mediates ERK-, JNK-, and p38-dependent endothelial cell inflammatory responses, which may occur independently of oxidative stress. In addition, BCL2-associated X protein (BAX) accesses mitochondria to induce cytochrome c release, and Bcl-2 inhibits BAX translocation from cytosol to mitochondria during relevant apoptosis. MGO induces the expression of phosphorylated tau protein and increases the expression of protein phosphatase 2A (PP2A) and glycogen synthase kinase-3β (GSK-3β). A reduction in Aβ deposition can eventually improve learning and memory ability. AGE interaction with the receptor for AGEs (RAGE) carries an implication for AD. Glycated Aβ (Aβ-AGE) can aggravate an AD-like pathology via the receptor for the RAGE pathway. MGO increases intracellular calcium in sensory neurons and produces neuropathic pain via the cation TRPA1 channel.

Figure 3

MGO-induced diseases. MGO-induced diseases involve hypertension, pain, anxiety-related behaviour, epigenetic, atherosclerosis, diabetes, ageing, and CNS degeneration.