Mitochondrial peroxiredoxin-5 as potential modulator of mitochondria-ER crosstalk in MPP+-induced cell death

摘要

Peroxiredoxin-5 (PRDX5) is an antioxidant enzyme which differs from the other peroxiredoxins with regards to its enzymatic mechanism, its high affinity for organic peroxides and peroxynitrite and its wide subcellular distribution. In particular, the mitochondrial isoform of PRDX5 confers a remarkable cytoprotection toward oxidative stress to mammalian cells. Mitochondrial dysfunction and disruption of Ca2+ homeostasis are implicated in neurodegeneration. Growing evidence supports that endoplasmic reticulum (ER) could operate in tandem with mitochondria to regulate intracellular Ca 2+ fluxes in neurodegenerative processes. Here, we overexpressed mitochondrial PRDX5 in SH-SY5Y cells to dissect the role of this enzyme in 1-methyl-4-phenylpyridinium (MPP)+-induced cell death. Our data show that mitochondria-dependent apoptosis triggered by MPP+, assessed by the measurement of caspase-9 activation and mitochondrial DNA damage, is prevented by mitochondrial PRDX5 overexpression. Moreover, PRDX5 overexpression blocks the increase in intracellular Ca2+, Ca2+-dependent activation of calpains and Bax cleavage. Finally, using Ca2+ channel inhibitors (Nimodipine, Dantrolene and 2-APB), we show that Ca2+ release arises essentially from ER stores through 1,4,5-inositol-trisphosphate receptors (IP3R). Altogether, our results suggest that the MPP + mitochondrial pathway of apoptosis is regulated by mitochondrial PRDX5 in a process that could involve redox modulation of Ca2+ transporters via a crosstalk between mitochondria and ER. PRDX5 protects cells from oxidative stress by reducing peroxides and ONOO- in different subcellular compartments including mitochondria. Here we show that overexpression of mitochondrial PRDX5 prevents MPP+-induced dopaminergic neurodegeneration by inhibiting Ca2+ release from ER through IP3R thereby blocking subsequent apoptotic cascade. Our finding implies that PRDX5 may regulate redox modification of IP3R Ca2+ transporters via a crosstalk between mitochondria and ER.