TARGETING LIPID METABOLISM PRESERVES MOTOR NEURONS AND RESTORES GLUCOSE UTILIZATION IN ALS

When cellular energy homeostasis fails, motor neurons become uniquely vulnerable to degeneration. In amyotrophic lateral sclerosis (ALS), this vulnerability is marked by a pathological shift toward lipid oxidation, accompanied by mitochondrial dysfunction and progressive motor neuron loss. These metabolic alterations highlight energy metabolism as a therapeutic target in ALS. One approach is inhibition of carnitine palmitoyltransferase 1 (CPT1), a central regulator of fatty-acid oxidation, representing a strategy to restore metabolic balance. Here, we investigated whether pharmacological CPT1 inhibition with the novel drug candidate Mitometin could improve disease outcomes in ALS while restoring glucose utilization. We performed a long-term in vivo efficacy study in SOD1 G93A ALS mice, initiating oral Mitometin treatment at symptom onset and continuing until humane endpoint to assess motor performance, disease progression, and survival. In a separate mechanistic study, Mitometin treatment was combined with FDG-PET imaging to assess regional glucose utilization in the brain, spinal cord and skeletal muscle. Chronic Mitometin treatment significantly improved motor performance, preserved body weight, reduced disease severity, and extended survival compared with vehicle-treated SOD1 mice. These benefits were accompanied by increased motor neuron survival and reduced oxidative stress and neuroinflammation. FDG-PET revealed region-specific normalization of glucose metabolism after treatment, with increased glucose uptake in the motor cortex and other brain regions and reduced uptake in skeletal muscle, shifting toward a wild-type metabolic profile. Together, these findings demonstrate that CPT1 inhibition improves functional and survival outcomes in ALS, identifying metabolic dysfunction as a disease-modifying target and positioning Mitometin as a promising therapeutic candidate.