Muller 2013 Exp Neurol
|Muller AP, Haas CB, Camacho-Pereira J, Brochier AW, Gnoatto J, Zimmer ER, de Souza DO, Galina A, Portela LV (2013) Insulin prevents mitochondrial generation of H2O2 in rat brain. Exp Neurol 247:66-72.|
Abstract: The mitochondrial electron transport system (ET-pathway) is a main source of cellular ROS, including hydrogen peroxide (H₂O₂). The production of H₂O₂ also involves the mitochondrial membrane potential (ΔΨm) and oxygen consumption. Impaired insulin signaling causes oxidative neuronal damage and places the brain at risk of neurodegeneration. We evaluated whether insulin signaling cross-talks with ET-pathway components (complexes I and F₀F₁ATP synthase) and ΔΨm to regulate mitochondrial H₂O₂ production, in tissue preparations from rat brain. Insulin (50 to 100 ng/mL) decreased H₂O₂ production in synaptosomal preparations in high Na(+) buffer (polarized state), stimulated by glucose and pyruvate, without affecting the oxygen consumption. In addition, insulin (10 to 100 ng/mL) decreased H₂O₂ production induced by succinate in synaptosomes in high K(+) (depolarized state), whereas wortmannin and LY290042, inhibitors of the PI3K pathway, reversed this effect; heated insulin had no effect. Insulin decreased H₂O₂ production when complexes I and F₀F₁ATP synthase were inhibited by rotenone and oligomycin respectively suggesting a target effect on complex III. Also, insulin prevented the generation of maximum level of ∆Ψm induced by succinate. The PI3K inhibitors and heated insulin maintained the maximum level of ∆Ψm induced by succinate in synaptosomes in a depolarized state. Similarly, insulin decreased ROS production in neuronal cultures. In mitochondrial preparations, insulin neither modulated H2O2 production or oxygen consumption. In conclusion, the normal downstream insulin receptor signaling is necessary to regulate complex III of ET-pathway avoiding the generation of maximal ∆Ψm and increased mitochondrial H2O2 production.
• Keywords: Brain metabolism, H2O2 production, Insulin signaling, Mitochondria
Labels: MiParea: Respiration, mt-Medicine
Organism: Rat Tissue;cell: Nervous system
Coupling state: LEAK, OXPHOS, ET Pathway: N, S HRR: Oxygraph-2k