Nrf1 and Nrf2 Knockdown Effect in Anxiety-related Behavior and Mitochondrial Function

 Nuclear factor, erythroid-derived 2, -like2 (Nrf2) and Nuclear erythroid 2-related factor 1 (Nrf1) stand as two important regulators of antioxidant defense system.

Small interfering RNA (siRNA) targeting Nrf1 and Nrf2 (Nrf1&2) was injected in dorsal third ventricle of adult male albino Wistar rats. Anxiety-related behaviors and protein level of mitochondrial biogenesis, apoptotic marker factors and also electron transport chain (ETC), Citrate synthase (CS) and Malate dehydrogenase (MDH) enzymes activity in three brain regions: hippocampus, prefrontal cortex, and amygdala were evaluated.

Nrf1&2-silenced rats induced anxiety-like behaviors compared to the control group. The level of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) protein increased in those three regions. Although Nrf1&2-silencing decreased MDH activity in hippocampus and prefrontal cortex, the activity of CS was increased in all three mentioned areas. However, Nrf1&2 silencing had no effect in complex I and II-III activity, but complex IV activity was increased, particularly in amygdala. Furthermore, Bax/Bcl2 ratio and cleavage of caspase-3 was increased in all mentioned areas of the brain in Nrf1&2-silenced group.

In conclusion, the presented data evaluated the complexity of mitochondrial functions and Nrf1 and Nrf2 in rat’s brain and points to mitochondrial crucial role in oxidative stress, energy metabolism, and behavior.