TBK1 Deficiency Disrupts Microglial Metabolic Reprogramming, Promoting Glycolyt…

TBK1 loss-of-function mutations in ALS disrupt microglial metabolic homeostasis by impairing mTOR-dependent metabolic checkpoint signaling and mitochondrial quality control. Under normal conditions, TBK1 phosphorylates ULK1 and AMPK to coordinate autophagy-mediated mitochondrial turnover with oxidative metabolism, enabling microglia to maintain anti-inflammatory M2 polarization. In ALS patients with TBK1 mutations, defective mitophagy leads to accumulation of damaged mitochondria and compensatory upregulation of glycolysis through HIF-1α stabilization. This metabolic shift toward aerobic glycolysis (Warburg-like metabolism) fundamentally reprograms microglial transcriptional landscapes, favoring pro-inflammatory M1 polarization and sustained SASP production. The metabolic dysfunction creates a feed-forward loop where impaired oxidative phosphorylation increases ROS production from dysfunctional mitochondria, further activating HIF-1α and perpetuating glycolytic dependence. Additionally, TBK1 deficiency disrupts the pentose phosphate pathway through altered glucose-6-phosphate dehydrogenase regulation, reducing NADPH availability for antioxidant defense and exacerbating oxidative stress. This metabolic crisis transforms microglia into persistently activated, SASP-secreting cells that release IL-1β, TNF-α, and complement factors, creating a neurotoxic environment that accelerates motor neuron degeneration. The hypothesis predicts that metabolic rescue through mitochondrial biogenesis enhancers, glycolysis inhibitors, or direct mitochondrial transplantation could restore microglial homeostasis and slow ALS progression, offering therapeutic targets distinct from traditional anti-inflammatory approaches.