Investigation of the role of mitochondrial dysfunction and autophagy in manganese neurotoxicity
Project no. 25275 · Status: Kapanmış (Yayın bekleniyor) · 2022
Summary
<p>Manganese (Mn) is an essential trace element that plays a crucial role in maintaining normal cellular function. Chronic environmental and occupational exposure to manganese results in a progressive neurological disorder known as "manganism." Despite recent research aimed at characterizing the risk factors and understanding the pathogenesis of this syndrome, which closely resembles Parkinson's disease, the mechanism of Mn-induced neurodegenerative damage remains unclear. Animal studies have shown that the main region of Mn accumulation in rats is the substantia nigra pars compacta, and the dopaminergic neurons in this region are vulnerable to Mn toxicity. Although the underlying mechanisms are not fully understood, mitochondrial dysfunction and oxidative stress are proposed to be key cellular events in Mn neurotoxicity.</p><p>The aim of our study is to elucidate the cellular mechanisms involved in the development of Mn neurotoxicity, which poses a significant public health concern. For this purpose, Mn toxicity was induced in human neuroblastoma SH-SY5Y cells, and survival, apoptotic cell death, mitochondrial dysfunction, and autophagic processes were investigated in these cells. The results of our study demonstrated that MnCl2 application exhibited an increasingly toxic effect on SH-SY5Y cells in a dose- and time-dependent manner. Experiments conducted to clarify the underlying mechanisms of Mn toxicity showed that MnCl2 application led to an increase in the production of reactive oxygen species (ROS), a decrease in mitochondrial viability, and a dose- and time-dependent increase in caspase-3 activity. When examining the effect of Mn exposure on autophagic activity, it was observed that 4 hours of MnCl2 application had no effect on autophagic processes, while extending the duration to 24 hours significantly stimulated autophagic activity.</p><p>In conclusion, the findings of our study reveal that manganese exposure leads to cell death in neuronal cells through several mechanisms, including the induction of oxidative stress, apoptosis and autophagy, and the impairment of mitochondrial viability, depending on dose and duration.</p>