Aberrant Decrease of the Endogenous SIRT3 and Increases of Acetylated Proteins in Scrapie-Infected Cell Line SMB-S15 and in the Brains of Experimental Mice.

The linkage between mitochondrial dysfunction and neurodegenerative diseases including prion diseases has been frequently reported. As the major deacetylase in mitochondria, SIRT3 plays a crucial part in regulating the function of many mitochondrial proteins. Although SIRT3 was reported to be linked to several neurodegenerative diseases, it is still unknown if SIRT3 is involved in prion diseases. In this study, we have presented a substantially declined status of mitochondrial SIRT3 in both the levels of cultured cells and an experimental rodent model during scrapie prion replication and infection. Such decreased SIRT3 activity led to a decreased deacetylating activity, resulting in increases of the acetylated forms of some substrates of SIRT3 in cells, such as SOD2 and ATP5β. Declined SOD2 and ATP5β activities subsequently caused an increase of intracellular ROS and a reduction of ATP. Furthermore, we have also proposed evidence that the activity of cellular SIRT3 is partially recovered when abnormal prion propagation in the cultured cells is removed by resveratrol. Those data emphasize a close connection between the prion replication and mitochondrial deacetylation due to SIRT3, thereby partially explaining mitochondrial dysfunction in prion diseases.