MITOQUINONE IMPROVES MITOCHONDRIAL FUNCTION BUT DOES NOT PREVENT ROTENONE-INDUCED NEURONAL AND SYNAPTIC DEFICITS

Previous work from our group showed that rotenone exposure (1.325nM, 24h) during in vitro neurodevelopment induces mitochondrial dysfunction and impairs neuronal morphology and synaptic function in primary cortical neurons. Here, we assessed whether mitoquinone (MitoQ), a mitochondria-targeted antioxidant, could prevent or reverse these deficits. Primary cortical neurons from E19 Wistar rat embryos were pre-treated with MitoQ (25nM, 18h) followed by Rot (1.325nM, 24h) at DIV12 (n=3–6). Cell viability, mitochondrial function (membrane potential, calcium homeostasis, superoxide production, and ATP levels), mitochondrial dynamics–related proteins, neuronal morphology (MAP2), and synaptic integrity (PSD95/synaptophysin colocalization) were assessed. Data were expressed as percentage of vehicle control and analyzed by one-way ANOVA with Bonferroni post hoc test. We found that MitoQ 25nM pre-treatment did not changed cellular viability. The MMP and calcium homeostasis was also unaltered. However, we found that MitoQ pre-treatment could restore the mitochondrial superoxide production (MitoQ+Rot:107±7.2%;Rot:83.8±4.7%;p=0.01) and the ATP production (MitoQ+Rot:110.8±10.7nM;Rot:32.03±10.15nM;p=0.0007). We saw that mitochondrial fusion proteins were increased by MitoQ treatment (Opa1:123.9±5.7%p=0.01vs.Veh; Mfn2:126.1±3.2%p=0.01vs.Veh). Interestingly, the dendrites number were reduced in all-treated groups (Rot:18.57±0.87p=0.004; MitoQ:11.17±2.6p=0.0001; MitoQ+Rot:7.5±2.37p=0.0001) in relation to Veh(26.9±1.9). And the dendrites length was also impaired by Rot (30±1.7mmp=0.004) and MitoQ (26.2±5.8mmp=0.03) treatment in comparison to Veh(37.2±1.6mm). The synaptic events were reduced for Rot (0.18±0.01p=0.005), MitoQ (0.16±0.02p=0.0001vs.Veh) and MitoQ+Rot (0.14±0.01p=0.0001vs.Veh). Although MitoQ increased ATP levels and superoxide production, this effect was not sufficient to prevent or reverse the neuronal and synaptic impairments induced by Rot.