Mitochondria-targeted reactive species scavenger JP4-039 protects against disturbances of redox homeostasis, mitochondrial quality control, and glucose metabolism in brains of glutaryl-CoA dehydrogenase-deficient mice: A potential new therapeutic strategy for glutaric acidemia type 1.
de Britto Renata, Moura Alvorcem Leonardo de, Marcuzzo Manuela Bianchin, Ribeiro Rafael T, Soares Carolina, Vizuete Adriana Fernanda K, Bobermin Larissa D, Venturin Gianina Teribele, Greggio Samuel, Zimmer Eduardo R, Quincozes-Santos André, de Souza Diogo Onofre, Gonçalves Carlos-Alberto, Wipf Peter, Vockley Jerry, Seminotti Bianca, Wajner Moacir, Leipnitz Guilhian
Abstract
Glutaric aciduria type 1 (GA1) is a cerebral organic aciduria caused by deficient activity of glutaryl-CoA dehydrogenase (GCDH). Patients present with acute striatal degeneration and develop progressive cortical leukodystrophy whose pathophysiology is only partially known. As treatment for GA1 is limited, we evaluated the impact of JP4-039, a mitochondria-targeted reactive oxygen species (ROS) and electron scavenger, on redox homeostasis, mitochondrial quality control, and glucose metabolism in the cortical and striatal brain tissues of GCDH-deficient (Gcdh-/-) mice. Both tissues exhibited increases in lipid peroxidation, ROS levels, and the activities of superoxide dismutase, catalase, and glutathione S-transferase. Furthermore, glutathione reductase activity was increased, and glutathione peroxidase was reduced in the striatum, while Nrf2 mRNA levels were elevated in the cortex. Notably, most of these altered endpoints of redox homeostasis were prevented by treatment with JP4-039. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression was reduced in the cortex of Gcdh-/- mice, whereas voltage-dependent anion channel (VDAC) and dynamin-related protein 1 (DRP1) expression were increased in the striatum, signaling a disturbance of mitochondrial quality control. JP4-039 mitigated the DRP1 change. The cerebral cortex displayed reduced glucose metabolism, increased lactate levels, and elevated activities of hexokinase, pyruvate kinase, and lactate dehydrogenase (LDH), which JP4-039 mitigated. GLUT3 expression was reduced in the cerebral cortex, but JP4-039 did not change this effect. Our data suggest that redox imbalance and dysregulated mitochondrial quality control and of the glycolytic pathway contribute to the pathophysiology of GA1, and that JP4-039 may offer therapeutic benefit.
Key Findings
- GCDH-deficient mice exhibited increased lipid peroxidation, ROS levels, and altered antioxidant enzyme activities in brain tissues.
- Nrf2 mRNA levels were elevated in the cortex, indicating an oxidative stress response.
- JP4-039 treatment prevented most redox homeostasis alterations, mitigated mitochondrial quality control disturbances, and improved glucose metabolism abnormalities.
Clinical Significance
JP4-039, a mitochondria-targeted ROS scavenger, shows potential as a therapeutic agent to restore redox balance, mitochondrial function, and glucose metabolism in glutaric acidemia type 1, addressing key pathological mechanisms of the disease.
Citation
de Britto Renata, Moura Alvorcem Leonardo de, Marcuzzo Manuela Bianchinet al.. Mitochondria-targeted reactive species scavenger JP4-039 protects against disturbances of redox homeostasis, mitochondrial quality control, and glucose metabolism in brains of glutaryl-CoA dehydrogenase-deficient mice: A potential new therapeutic strategy for glutaric acidemia type 1. Biochemical pharmacology. 2026-Jul-24.