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Our results indicated that Mn could induce mitophagy by enhancing FOXO3 nuclear retention, which might promote mitophagy induced by MnCl.

The mechanism of manganism caused by manganese (Mn), an important environmental risk factor for Parkinson's disease, is still unclear. Recent evidence suggested that autophagy participated in neurodegenerative diseases, in which microRNA played a crucial role. However, roles of microRNA in the aberrant autophagy that occurs in neurodegenerative diseases remains controversial. In nervous system, miRNA-138-5p is highly expressed and plays a key role in regulating memory and axon regeneration. Importantly, we also found that miR-138-5p expression decreased significantly after SH-SY5Y cells exposed to manganese chloride (MnCl 2 ) in previous study. To explore the role of miR-138-5p in Mn-induced autophagy, autophagy associated indicators were detected. And we found that MnCl 2 could induce autophagic dysregulation and inhibit expression of miR-138-5p. While the levels of LC3-II/LC3-I, Beclin1, and p62, the number of autophagosome formation significantly decreased after miR-138-5p over-expression, which demonstrated that miR-138-5p could clearly retard Mn-induced autophagy. In additional, we found there were classical and evolutionarily conserved miR-138-5p binding sites in 3 0 -UTR region of SIRT1, which was inhibited when overexpression of miR-138-5p. Therefore, it was speculated that elevated expression of SIRT1 may be resulted from inhibition of miR-138-5p after cells exposed to MnCl 2 . Finally, we found that SIRT1 inhibitor EX-527 suppressed Mn-induced autophagy as well as miR-138-5p, while the suppression was reversed by SIRT1-specific activator SRT1720. These results indicated that overexpression of miR-138-5p suppressed Mn-induced autophagy by targeting SIRT1. K E Y W O R D S autophagy, manganese, MicroRNA-138-5p, SIRT1

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Methyl tertiary-butyl ether (MTBE), an unleaded gasoline additive, can lead to oxidative stress, thus injuring the nervous system after long-term exposure. SIRT1, a NAD-dependent histone deacetylase, can play a neuroprotective role in brain injury. However, the mechanism is unclear. This present study intended to define the role of SIRT1 during the process of MTBE-induced oxidative stress in mouse hippocampal neurons (HT22 cells). Our data showed that MTBE could directly trigger oxidative stress in HT22 cells by decreasing the activity of superoxide dismutase (SOD) and GSH/T-GSH level while increasing ROS, lipid peroxidation product malondialdehyde (MDA) and GSSG level. Similarly, the expression of SIRT1, an antioxidant, decreased in a dose-dependent manner. To further explore whether SIRT1 plays a key role during the process of oxidative stress, HT22 cells were transfected with siRNA-SIRT1 and preconditioned with the agonist of SIRT1 (SRT1720) for 2 h. The levels of oxidative stress (ROS, SOD, MDA, GSH/GSSG) were detected again after siRNA-SIRT1 HT22 cells and SRT1720 HT22 cells were exposed to MTBE for 6 h. In contrast to the non-pretreated group, levels of oxidative stress were tonic in siRNA-SIRT1 HT22 cells and attenuated in SRT1720 HT22 cells. Our results indicate that MTBE could directly cause oxidative stress in HT-22 cells, and SIRT1 might be an important antioxidant during MTBE-induced oxidative stress.