Figure 11.

Scheme depicting the mechanism underlying DA-, and Rot-induced N27-A dopaminergic neuron death. A. DA treatment to cultured N27-A dopaminergic neurons induces cell death by increasing Parkin translocation into mitochondria, where it promotes ubiquitination of Mitofilin and its degradation. Loss of Mitofilin in the IMM causes mitochondrial structural damage and dysfunction that is responsible for the reduction of membrane potential as well as an increase in ROS production and mitochondrial calpain activity. Together, the resulted deleterious mitochondrial effects provoke cleavage and release of AIF into the cytosol, where its nuclear translocation, facilitated by PARP, ultimately initiates DNA condensation and fragmentation that subsequently leads to cell death. B. Rot increases cell death by upregulating cytosolic Parkin, which in part translocates into mitochondria where it interacts with Mitofilin to increase mitochondrial structural damage and dysfunction. Damage in mitochondria, associated with ubiquitination of outer membrane proteins by Parkin promote an excessive eliminated by mitophagy that reduces the pool of mitochondria causing cell death.