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Mitochondrial permeability transition pore contributes to mitochondrial dysfunction in fibroblasts of patients with sporadic Alzheimer's disease

dc.contributor.authorPérez M.J.
dc.contributor.authorPonce D.P.
dc.contributor.authorAranguiz A.
dc.contributor.authorBehrens M.I.
dc.contributor.authorQuintanilla R.A.
dc.date.accessioned2020-09-02T22:26:02Z
dc.date.available2020-09-02T22:26:02Z
dc.date.issued2018
dc.identifier10.1016/j.redox.2018.09.001
dc.identifier.citation19, , 290-300
dc.identifier.issn22132317
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5869
dc.descriptionIn the last few decades, many reports have suggested that mitochondrial function impairment is a hallmark of Alzheimer's disease (AD). Although AD is a neurodegenerative disorder, mitochondrial damage is also present in patients’ peripheral tissues, suggesting a target to develop new biomarkers. Our previous findings indicate that AD fibroblasts show specific defects in mitochondrial dynamics and bioenergetics, which affects the generation of adenosine triphosphate (ATP). Therefore, we explored the possible mechanisms involved in this mitochondrial failure. We found that compared with normal fibroblasts, AD fibroblasts had mitochondrial calcium dysregulation. Further, AD fibroblasts showed a persistent activation of the non-specific mitochondrial calcium channel, the mitochondrial permeability transition pore (mPTP). Moreover, the pharmacological blockage of mPTP with Cyclosporine A (CsA) prevented the increase of mitochondrial superoxide levels, and significantly improved mitochondrial and cytosolic calcium dysregulation in AD fibroblasts. Finally, despite the failure of CsA to improve ATP levels, the inhibition of mitochondrial calcium uptake by the mitochondrial calcium uniporter increased ATP production in AD fibroblasts, indicating that these two mechanisms may contribute to mitochondrial failure in AD fibroblasts. These findings suggest that peripheral cells present similar signs of mitochondrial dysfunction observed in the brain of AD patients. Therefore, our work creates possibilities of new targets to study for early diagnosis of the AD. © 2018 The Authors
dc.language.isoen
dc.publisherElsevier B.V.
dc.subjectAlzheimer´s disease
dc.subjectCalcium homeostasis
dc.subjectFibroblasts
dc.subjectMitochondria
dc.subjectmPTP
dc.subjectadenosine triphosphate
dc.subjectcalcium
dc.subjectcalcium channel
dc.subjectcyclosporine
dc.subjectmitochondrial permeability transition pore
dc.subjectsuperoxide
dc.subjectadenosine triphosphate
dc.subjectcalcium
dc.subjectcarrier protein
dc.subjectmitochondrial permeability transition pore
dc.subjectaged
dc.subjectAlzheimer disease
dc.subjectArticle
dc.subjectbiosynthesis
dc.subjectcalcium cell level
dc.subjectcalcium homeostasis
dc.subjectcalcium transport
dc.subjectclinical article
dc.subjectcontrolled study
dc.subjectcytosol
dc.subjectdisease course
dc.subjectdisorders of mitochondrial functions
dc.subjecthuman
dc.subjecthuman cell
dc.subjectpathophysiology
dc.subjectpriority journal
dc.subjectprotein function
dc.subjectskin fibroblast
dc.subjectvery elderly
dc.subjectAlzheimer disease
dc.subjectfemale
dc.subjectfibroblast
dc.subjectmale
dc.subjectmetabolism
dc.subjectmitochondrial membrane potential
dc.subjectmitochondrion
dc.subjectpathology
dc.subjectAdenosine Triphosphate
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectAlzheimer Disease
dc.subjectCalcium
dc.subjectFemale
dc.subjectFibroblasts
dc.subjectHumans
dc.subjectMale
dc.subjectMembrane Potential, Mitochondrial
dc.subjectMitochondria
dc.subjectMitochondrial Membrane Transport Proteins
dc.titleMitochondrial permeability transition pore contributes to mitochondrial dysfunction in fibroblasts of patients with sporadic Alzheimer's disease
dc.typeArticle


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