Context-dependent roles of alpha-ketoglutarate in brain disorders: molecular mechanisms and translational opportunities

Abstract

Brain disorders, including neurodegenerative, psychiatric and oncologic disorders, represent a major global public health challenge, yet their underlying pathogenic mechanisms remain incompletely understood. Accumulating evidence suggests that mitochondrial dysfunction, oxidative stress, impaired energy metabolism, and neurotransmitter imbalance contribute to the etiology of these disorders. Restoring mitochondrial and metabolic function emerges as a potential therapeutic strategy. α-ketoglutarate (AKG), a key intermediate in the tricarboxylic acid cycle, plays diverse roles in cellular energy metabolism, amino acid biosynthesis, redox regulation and epigenetic control. Preclinical studies indicate that exogenous AKG supplementation or targeted modulation of AKG-related metabolic pathways can influence mitochondrial homeostasis as well as cellular metabolic and epigenetic states. However, the biological effects of AKG appear to be context dependent, varying across disease states and metabolic conditions. This review synthesizes current evidence on the molecular mechanisms through which AKG regulates mitochondrial, metabolic, and epigenetic processes in the nervous system, highlighting its distinct and sometimes divergent roles across neurological conditions. By integrating findings from diverse disease contexts, this review aims to critically assess the therapeutic potential of targeting AKG-related pathways in brain disorders and to outline key challenges and priorities for future translational research.

Keywords

α-Ketoglutarate / brain disorders / TCA cycle / mitochondrial function / energy metabolism

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