FIGURE 12.

Proposed model of SIRT3 involvement in promoting mitochondrial dysfunction and brain injury after experimental stroke. Cerebral IR leads by an as yet unidentified mechanism to SIRT3 activation resulting in enhanced deacetylation of mitochondrial ceramide synthases 1, 2, and 6 that increases their activity leading to accumulation of ceramide and mitochondrial dysfunction. Accumulated ceramide inhibits respiratory chain activity at the level of complex III that is accompanied by increased ROS and augmented expression of activated Bax that contributes to MOM permeabilization and brain injury.