The involvement of GSH in the activation of human Sod1 linked to FALS in chronologically aged yeast cells

Abstract

Mutations in Cu, Zn-superoxide dismutase (Sod1) have been associated with familial amyotrophic lateral sclerosis, an age-related disease. Because several studies suggest that oxidative stress plays a central role in neurodegeneration, we aimed to investigate the role of the antioxidant glutathione (GSH) in the activation of human A4V Sod1 during chronological aging. Transformation of wild-type and A4V hSod1 into a gsh null mutant and in its parental strain of Saccharomyces cerevisiae indicated that during aging, the number of viable cells was strongly influenced by A4V hSod1 mainly in cells lacking GSH. Activity of hSod1 increased in response to aging, although the increase observed in A4V hSod1 was almost 60% lower. Activation of hSod1 (A4V and WT) did not occur after aging, in cells lacking GSH, but could still be observed in the absence of Ccs1. Furthermore, no increase in activity could be seen in grx1 and grx2 null mutants, suggesting that glutathionylation is essential for hSod1 activation. The A4V mutation as well as the absence of GSH, reduced hSod1 activity, and increased oxidative damage after aging. In conclusion, our results point to a GSH requirement for hSod1 Ccs1-independent activation as well as for protection of hSod1 during the aging process.

Protein trafficking in the mitochondrial intermembrane space: mechanisms and links to human disease

“…In this case, the co-operation of Mia40 with the MICOS complex was reported to be critical for the efficient targeting of SOD1 in the IMS [103]. Although most studies suggest that CCS1 is critical for the maturation of SOD1, another possibility put forward by Brazil and co-workers is that the glutathione present in the IMS may be critical for the activation of human SOD1 independently of the effect of CCS1 in this process [104,105]. …”

Oxidative folding in the mitochondrial intermembrane space: A regulated process important for cell physiology and disease

“…The import of SOD1 in the IMS relies on the presence of Ccs1 whilst Varabyova et al [59] showed that Mia40 and the MICOS complex regulate the import of the SOD1 mutants that are linked to ALS. Finally, Brazil et al demonstrated that glutathione is essential for the activation of hSOD1 independently of the role of Ccs1 in this process [133], [134].…”

A Review of the Potential Role of Nano-Enabled Drug Delivery Technologies in Amyotrophic Lateral Sclerosis: Lessons Learned from Other Neurodegenerative Disorders

“…Other nanocarrier systems for GSH include nanoparticles coated with hydrophilic polymers such as polyethylene glycol or polysaccharides such as chitosan, pectin, hyaluronic acid, and dextran. However, a recent in vitro study by Brasil et al showed that GSH may be involved in the activation of FALS‐linked mutant SOD1 during chronological aging. GSH therefore may not be a suitable therapeutic agent in ALS.…”