ROS-HIF1α-driven glycolytic reprogramming sustains ATP production in Huntington's disease

Huntington's disease (HD) is a progressive neurodegenerative disorder in which mitochondrial dysfunction and impaired energy metabolism contribute to disease pathogenesis. Surprisingly, we find that ATP levels are not diminished but instead elevated in the striatum of R6/2 HD mice despite impaired TCA cycle intermediates and mitochondrial deficits. Integrative metabolomics, gene expression profiling, and pharmacological perturbation reveal that increased reactive oxygen species stabilize hypoxia-inducible factor-1α (HIF1α), driving enhanced glucose uptake and glycolytic flux. In vivo dynamic glucose-enhanced (DGE) MRI further supports altered glucose handling in the living R6/2 brain. Inhibition of either glycolysis or HIF1α abolishes ATP elevation, suggesting that HIF1α-dependent glycolysis compensates for mitochondrial impairment. Single-nucleus RNA sequencing further uncovers coordinated metabolic reprogramming across neuronal and glial populations. These findings reveal an oxidative stress-triggered metabolic switch that sustains ATP production in HD, redefining bioenergetic adaptation in neurodegenerative diseases.