Endoplasmic reticulum and mitochondria interplay mediates apoptotic cell death: relevance to Parkinson's disease.
Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta. Many cellular mechanisms are thought to be involved in the death of these specific neurons in PD, including oxidative stress, changes of intracellular calcium homeostasis, and mitochondrial dysfunction. Since recent studies have revealed that also endoplasmic reticulum (ER) stress in conjunction with abnormal protein degradation can contribute to the PD pathophysiology, we investigated here the molecular mechanisms underlying the interplay between ER and mitochondria and its relevance in the control of neuronal cell death in PD. We observed that MPP+ induced changes in the mitochondrial function, affecting mitochondrial membrane potential and electron transport chain function. Likewise, it was also evident the unfolded protein response activation by an overexpression of GRP78 protein. Moreover, stress stimuli caused the release of Ca2+ from the ER that consistently induced mitochondrial Ca2+ uptake, with a rise of mitochondrial matrix free Ca2+. Besides, Ca2+ release inhibition prevented MPP+ mediated mitochondria-dependent caspases activation. Our findings show that ER and mitochondria are in a close communication, establishing a dynamic ER-Ca2+-mitochondria interconnection that can play a prominent role in the neuronal cell death induction under particular stressful circumstances of PD pathology.
Centro de Neurociências e Biologia Celular, Faculdade de Medicina, Universidade de Coimbra, 3004-504 Coimbra, Portugal.
Daniela Moniz
DM
Arduíno
A Raquel
AR
Esteves
Sandra M
SM
Cardoso
Catarina R
CR
Oliveira
D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D002118:Calcium