Abstract
Cell death exists in many different forms. Some are accidental, but most of them have some kind of regulation and are called programmed cell death. Programmed cell death (PCD) is a very diverse and complex mechanism and must be tightly regulated. This study investigated PCD induced by DFNA5, a gene responsible for autosomal dominant hearing loss (HL) and a tumor suppressor gene (TSG) involved in frequent forms of cancer. Mutations in DFNA5 lead to exon 8 skipping and result in HL in several families. Expression of mutant DFNA5, a cDNA construct where exon 8 is deleted, was linked to PCD both in human cell lines and in Saccharomyces cerevisiae. To further investigate the cell death mechanism induced by mutant DFNA5, we performed a microarray study in both models. We used wild-type DFNA5, which does not induce cell death, as a reference. Our data showed that the yeast pathways related to mitochondrial ATP-coupled electron transport chain, oxidative phosphorylation and energy metabolism were up-regulated, while in human cell lines, MAP kinase-related activity was up-regulated. Inhibition of this pathway was able to partially attenuate the resulting cell death induced by mutant DFNA5 in human cell lines. In yeast, the association with mitochondria was demonstrated by up-regulation of several cytochrome c oxidase (COX) genes involved in the cellular oxidative stress production. Both models show a down-regulation of protein sorting- and folding-related mechanisms suggesting an additional role for the endoplasmic reticulum (ER). The exact relationship between ER and mitochondria in DFNA5-induced cell death remains unknown at this moment, but these results suggest a potential link between the two.
Highlights
IntroductionThe role of programmed cell death (PCD) in the pathology of hearing loss (HL) has been well studied and seems to play a prominent role, especially in the development of the vertebrate inner ear and in the morphogenesis of the semicircular canals (Fekete et al, 1997; Nishikori et al, 1999; Leon et al, 2004)
Cell death is a fundamental process of all organisms and inherent to life
We show that the MAPK pathways, namely the induction of the extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), are activated upon mutDFNA5 transfection in human cell lines
Summary
The role of programmed cell death (PCD) in the pathology of hearing loss (HL) has been well studied and seems to play a prominent role, especially in the development of the vertebrate inner ear and in the morphogenesis of the semicircular canals (Fekete et al, 1997; Nishikori et al, 1999; Leon et al, 2004). Several genes related to PCD-induced HL have been identified and many of these are related to the DFNA5 induces programmed cell death mitochondria (Estivill et al, 1998; Jacobs et al, 2005; Ding et al, 2013). Mitochondria are the main producers of cellular ATP due to oxidative phosphorylation. This process generates reactive oxygen species (ROS) (Raha and Robinson, 2000). Enhanced oxidative stress will have detrimental effects on cellular health and plays a major role during aging, mutagenesis, and cell death (Gredilla and Barja, 2005; Maynard et al, 2009; Gredilla et al, 2010)
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