Research Article

Redox-Coupled Kinetic Modeling of Dopamine Catabolism in Schizophrenia

Abstract

Dopamine (DA) catabolism generates the reactive aldehyde DOPAL and H2O2 , linking transmitter turnover to redox stress relevant to schizophrenia. Quantify the oxidative cost of DA signaling under variation in MAO/COMT activities and glutathione (GSH) reserves, and identify control points for mitigation. We built a two compartment ODE model (cytosolmitochondria) coupling MAO-driven DOPAL/ H2O2 production to ALDH detoxication and GSH/GPx–GR recycling with NADPH supply. Scenarios included MAO ↑ (+50%), COMT ↓ (-35%, Val158 Met proxy), GSH pool ↓ (-40%), and the combined case; robustness was assessed via Sobol global sensitivity (2,500 sets). Baseline converged to low cytosolic DA ( ≈ 45 nM), DOPAL ss ≈ 5.2 nM, H2O2 ss ≈ 0.22 μM, with 58% of DA catabolism via MAO (oxidative cost 0.58 mol H2O2 per mol DA). MAO↑ elevated DOPAL ss to 11.0 nM and H2O2 ss to 0.29 μM; COMT ↓ increased MAO share to 0.66 with modest oxidant rises; GSH ↓ slowed clearance (H2O2 ss 0.297 μM, DOPAL half-life 5.0 vs 4.0 min). Combined stress yielded the largest burden: DA cyt 30 nM, DOPAL ss 14.0 nM (∼ 2.7× baseline), H2O2 ss 0.35 μM (+58%), oxidative cost 0.74. Mitigations were complementary: ALDH↑(+25%) cut DOPAL AUC 43→25 nM min and DOPAL ss 14.0→8.5 nM, while GSH +30% reduced H2O2 ss 0.35→0.276 μM and trimmed DOPAL ss (∼ 18%); oxidative cost tracked MAO share and remained unchanged by downstream detoxication. Sensitivity ranked MAO Vmax, ALDH Vmax, and GSH pool as dominant drivers; COMT Vmax chiefly governed flux partitioning. Redox coupling brings into play step-wise amplification of aldehyde/peroxide loads under joint MAO↑/COMT↓/GSH↓ conditions. Dual-lever intervention to transcend ALDH upregulation and redress impaired GSH/NADPH provides a logical, complementary control of biochemical risk.