| Parkinson's disease (PD) affects more than 5 million worldwide. It has become increasingly apparent that there are several abnormalities in both mitochondria and the protein turnover system in PD. Several of these abnormalities are related to the proteins responsible for mitochondrial fission and fusion. Mitochondria are dynamic organelles undergoing perpetual changes in size and shape and this flux is a delicate balance between fission and fusion. The main protein responsible for mitochondria! fission is Drpl and the proteins responsible for mitochondria! fusion are Mfnl (mitofusin 1) and Mfn2 (mitofusin 2). In the most common form of familial PD, parkin, an E3 ubiquitinligase, is mutated. Parkin targets Dpl, MfnI, and Mfn2 for degradation through both the ubiquitin proteasome system and mitochondrial specific autophagy (mitophagy). Here we investigated the role that deubiquitination plays in the expression of these parkin targets and found that Drp 1 expression may be stabilized by deubiquitinase function. In addition, we prove that autophagy is the main turnover mechanism for Drpl in cell lines and primary rat neurons. This was determined by blocking autophagy with several chemical inhibitors and by genetic ablation of ATG7, a key protein responsible for autophagic initiation. Drpl overexpression contributes to the neuronal pathology in both Parkinson's and Alzheimer's disease. We show that inducing neuronal-specific autophagy with two FDA-approved compounds reliably lowers Drp 1 levels, suggesting autophagie induction may be beneficial in both PD and AD.;In addition to this work, we investigated the role of antiviral compounds on mitochondria) function. Studies have demonstrated the mitochondrial toxicity of several of antiretrovirals in liver cells and fibroblasts. We demonstrate that efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, which has been linked with neuropsychiatrie toxicity, decreased ATP production in both neuronal cell lines and primary rat neurons. These changes in ATP production coincide with increased autophagy, mitochondrial fragmentation, and mitochondria) depolarization. Further, we demonstrate EFV induced mitophagy with a tandem fluorescent outer mitochondria) membrane protein. EFV is able to acutely induce autophagy and mitochondrial morphological changes in neurons; we hypothesize that these effects are involved in the mechanism leading to CNS toxicity seen with clinical EFV use. |
