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Involvement of mitochondria in endoplasmic reticulum stress‐induced apoptotic cell death pathway triggered by the prion peptide PrP 106–126
Author(s) -
Ferreiro Elisabete,
Costa Rui,
Marques Sueli,
Cardoso Sandra Morais,
Oliveira Catarina R.,
Pereira Cláudia M. F.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.05048.x
Subject(s) - endoplasmic reticulum , unfolded protein response , apoptosis , microbiology and biotechnology , mitochondrion , programmed cell death , cytochrome c , biology , ryanodine receptor , cell culture , poly adp ribose polymerase , caspase , biochemistry , polymerase , dna , genetics
Abstract Prion disorders are progressive neurodegenerative diseases characterized by extensive neuronal loss and by the accumulation of the pathogenic form of prion protein, designated PrP Sc . Recently, we have shown that PrP 106–126 induces endoplasmic reticulum (ER) stress, leading to mitochondrial cytochrome c release, caspase 3 activation and apoptotic death. In order to further clarify the role of mitochondria in ER stress‐mediated apoptotic pathway triggered by the PrP peptide, we investigated the effects of PrP 106–126 on the Ntera2 human teratocarcinoma cell line that had been depleted of their mitochondrial DNA, termed NT2 ρ0 cells, characterized by the absence of functional mitochondria, as well as on the parental NT2 ρ+ cells. In this study, we show that PrP 106–126 induces ER stress in both cell lines, given that ER Ca 2+ content is low, glucose‐regulated protein 78 levels are increased and caspase 4 is activated. Furthermore, in parental NT2 ρ+ cells, PrP 106–126 ‐activated caspase 9 and 3, induced poly (ADP‐ribose) polymerase cleavage and increased the number of apoptotic cells. Dantrolene was shown to protect NT2 ρ+ from PrP 106–126 ‐induced cell death, demonstrating the involvement of Ca 2+ release through ER ryanodine receptors. However, in PrP 106–126 ‐treated NT2 ρ0 cells, apoptosis was not able to proceed. These results demonstrate that functional mitochondria are required for cell death as a result of ER stress triggered by the PrP peptide, and further elucidate the molecular mechanisms involved in the neuronal loss that occurs in prion disorders.