Methylglyoxal Impairs Mitochondrial Bioenergetics and Microglial Functions

Aging is accompanied by a progressive disruption of brain homeostasis, yet the molecular mechanisms underlying this age-associated deterioration remain poorly understood. Microglia play a critical role in maintaining brain homeostasis by clearing cellular debris and neurotoxic protein aggregates. Here, we investigated the effects of methylglyoxal (MG), a highly reactive endogenous metabolite that accumulates with aging, on microglial functions using the murine microglial cell line BV2. We assessed the effects of MG exposure on multiple aspects of microglial biology in both control and bacterial lipopolysaccharide (LPS)-treated cells, including phagocytic activity, cellular proliferation, cytokine secretion, mitochondrial bioenergetics, mitochondrial membrane potential, and intracellular and mitochondrial reactive oxygen species. We found that MG significantly impaired mitochondrial bioenergetics, leading to reduced cellular energy production, and markedly suppressed multiple essential microglial functions, including phagocytosis. Given the high reactivity of MG with arginine, we also investigated whether arginine depletion contributes to these functional impairments. Arginine depletion recapitulated the impairment of mitochondrial bioenergetics and microglial function induced by MG, demonstrating that arginine availability is a critical determinant of microglial metabolic fitness and immune function. These findings suggest that the age-associated accumulation of MG impairs mitochondrial bioenergetics and microglial functions, thereby potentially accelerating neurodegenerative processes.