Malate-aspartate shuttle mediates the intracellular ATP levels, antioxidation capacity and survival of differentiated PC12 cells.

NAD(+) and NADH play pivotal roles in numerous redox reactions in cells. While increasing evidence has indicated important roles of NAD(+) in cell survival and cellular functions, there has been distinct deficiency in the studies regarding the biological functions of NADH. NADH shuttles mediate the transfer of the reducing equivalents of the cytosolic NADH into mitochondria. Cumulating evidence has suggested that malate-aspartate shuttle (MAS), one of the two types of NADH shuttles, plays significant roles in multiple biological processes such as glutamate synthesis in neurons. Because there has been no information regarding the roles of NADH shuttle in the energy metabolism, antioxidation capacity, and survival of any type of neural cells, in this study we used differentiated PC12 cells as a cellular model to investigate the roles of MAS in the energy metabolism, antioxidation capacity and survival of cells. We found that MAS inhibition led to a significant decrease in the levels of GSH - a major antioxidation molecule in cells, suggesting an important role of MAS in maintaining the antioxidation capacity of cells. Our study has also suggested that MAS could play critical roles in maintaining the intracellular ATP levels of the cells. Moreover, MAS inhibition was shown to significantly decrease the survival of differentiated PC12 cells. Collectively, our study has provided first evidence suggesting important roles of NADH shuttles in maintaining antioxidation capacity of cells. Our study has also suggested important roles of MAS in maintaining the intracellular ATP levels and survival of differentiated PC12 cells.