Dados do Trabalho

Título

INHIBITION OF PROTEIN PHOSPHATASE 2A EXACERBATES ENDOPLASMIC RETICULUM–MITOCHONDRIA APOPTOTIC RESPONSES AND IMPAIRS MEMORY

Fundamentação/Introdução

Endoplasmic reticulum coupling with mitochondria (ER-mitochondria) exerts complimentary functional roles. Abnormal accumulation of unfolded proteins in the ER lumen may trigger ER-mitochondria stress characterized by the up regulation of apoptotic proteins like RNA-dependent protein kinase (PKR)-like ER kinase (PERK), eukaryotic initiation factor-2α (EIF2α) and C/EBP homologous protein (CHOP).The protein phosphatase 2A (PP2A) regulates the dynamic state of EIF2α phosphorylation, serving as homeostatic regulator of ER-mitochondria function. Therefore, when PP2A activity is downregulated it can trigger ER-mitochondria dysfunction. Although increased ROS production sustains ER-mitochondria dysfunction, the bioenergetics mechanisms behind these events are not clear.

Objetivos

In this work we aim to investigate wether brain PP2A inhibition heightens ER-mitochondria dysfunction and cause hierarchical neurochemical abnormalities that drive cells to dysfunction.

Delineamento e Métodos

Male 90 days old CF1 mice were given saline or okadaic acid (OKA, 100ng) and assessed memory fitness by object recognition task, and molecular markers of ER stress coupled with mitochondrial outcomes by western blot, respirometry, hydrogen peroxide production and membrane potential, cell viability. Principal component analysis (PCA) was performed to hierarchize all parameters.

Resultados

We showed that a single i.c.v. infusion of OKA impaired recognition memory, and increased the hippocampal expresion levels of pEIF2αSer51/EIF2α and CHOP, which highlights the importance of PP2A against ER-stress. Concomitant hippocamapal respirometry analysis showed decreased ATP synthesis due to down regulation of the mitochondrial complex V activity, increased proton leak and H2O2 production, markers of mitochondrial dysfunction. Also, apoptotic markers BAX/Bcl2, cytochrome c and cleavedcaspase-3/caspase 3 were increased, whereas cell viability was significantly decreased. PCA showed us that the H2O2 was hierarchized as the highest effector.

Conclusões/Considerações Finais

In summary, decreased PP2A activity upregulated the ER apoptotic signaling mechanistically associated with mitochondrial bioenergetics uncoupling and H2O2 production, implying in ER-mitochondria miscommunication. Also, the PCA analysis highlights H2O2 as an important effector of ER-mitochondrial dysfunction leading to cells death and memory impairment.

Palavras-chave

Protein Phosphatase 2A, Endoplasmic reticulum stress, Mitochondrial dysfunction