Effects of Carbonic Anhydrase-Related Protein VIII on Human Cells Harboring A8344G Mitochondrial DNA Mutation

In this study, we show that there is a significant decrease of CA8 (carbonic anhydrase-related protein VIII) in cybrids harboring MERRF A8344G mutation. CA8 deficiency and mutations were found to be associated with a distinctive lifelong gait disorder in wdl (Waddles) mice and novel syndromes characterized by cerebellar ataxia and mental retardation in the human. Our results showed that overexpression of CA8 in MERRF cybrids significantly decreased cell death induced by (STS) staurosporine treatment, suggesting a protective function of CA8 in cells harboring the A8344G mutation of mtDNA.Interestingly, an increase in the formation of LC3-II (microtubule-associated protein 1 light chain 3-II) was found in the cybrids with down-regulated CA8 expression, suggesting that the reduced expression of CA8 leads to autophagy activation. Furthermore, cybrids exhibiting down-regulated CA8 showed increased cytosolic Ca2+ signals and reduced levels of p-Akt (phosphorylated Akt) compared with those in the cybrids with overexpressed CA8, indicating that p-Akt is involved in the protection of cells by CA8. Our findings suggest that CA8 is involved in the autophagic pathway and may have a protective role in cultured cells from MERRF patients. Targeting CA8 and the downstream autophagic pathway might help develop therapeutic agents for treatment of MERRF syndrome in the future.
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Disease Source Type: research