Additionally, dual overexpression of the oxoglutarate carrier and BCL in CHO cells led to a substantial increase in mitochondrial GSH. Although the increase in mitochondrial GSH was found in CHO cells under overexpression conditions, the coimmunoprecipitation in primary cerebellar granule neurons suggests that the oxoglutarate carrier in concert with BCL may play a role in mitochondrial GSH uptake in neuronal cells; but further study is necessary.Oxidative stress is known to induce apoptosis, and mitochondrial GSH status has become recognized as an important determinant in apoptosis.Furthermore, the sensitization to TNF was recapitulated in control hepatocytes in which approximately of mitochondrial GSH was depleted compared to approximately of cytosolic GSH depletion using hydroxylpentenoate. Ethacrynic acid treated astrocytes were subjected to morpholinosydnonimine and decrease in ATP production, compared to controls. Thus, mitochondrial GSH in astrocytes appears to be vital for defense against oxidantinduced cell death.Apoptosis is key to neurodegenerative disease progression, and there is evidence that mitochondrial GSH may play a key role in regulating apoptosis.To further understand the role of mitochondrial GSH in neurodegenerative diseases, more direct studies involving cell lines and primary cells are needed.If alteration of mitochondrial GSH is established as a key factor in neurodegeneration, then studies seeking inducers of the oxoglutarate carrier andor the dicarboxylate carrier would be valuable.Protein aggregates have been linked to AD, PD, HD and other neurodegenerative diseases. Protein aggregation appears to be caused by an aberrant amount andor modification of particular proteins in the cells.The perturbation due to changes in protein levelmodifications is often caused by dysfunction of protein degradation complexes, leading to abnormal protein turnover, which has been implicated in many neurodegenerative diseases. The protein degradation process removes misfolded, damaged, or otherwise nonfunctional proteins.Degradation can occur through either the ubiquitinproteasome system or by autophagy.Proteins bound for the proteasome are primed with ubiquitin molecules by an ubiquitin ligase targeting system. These proteins are then shuttled to the proteasome where they are broken down catalytically into small peptide fragments.Autophagy is a cellular system that uses the acidic lysosomes to break down proteins during times of starvation and when the ubiquitin proteasome is dysfunctional. Autophagy can also be a mechanism of induced cell death.Dysfunctions in the ubiquitinproteasome system and in autophagy have been implicated in neurodegenerative diseases. Misfolded proteins are hazardous to the cell, and need to be either refolded properly or degraded.Folding of proteins occurs in the lumen of the endoplasmic reticulum, where chaperone molecules assist in configuring nascent polypeptide chains into stable threedimensional structures.Formation of disulfide bonds is critical in folding and maintaining the proper dimensional conformations of many proteins.Accordingly, protein disulfide isomerases catalyze disulfide bond formation and isomerization, facilitating proper pairing of cysteine residues. Unlike most of the cell, the ER has an unusually oxidative environment estimated at a: GSH:GSSG ratio, and protein disulfide isomerase catalysis is enabled by this oxidative environment. Before proteins leave the ER they must pass checkpoints for correct folding or be returned for refolding.Proteins unable to be refolded properly are ubiquitinated and sent to the proteasome for degradation.In general the phenomenon of dysregulated protein folding in the ER is called ER stress that triggers the socalled unfolded protein response that can lead to cell survival or commitment to apoptosis.