Mitochondrial permeability transition pore contributes to mitochondrial dysfunction in fibroblasts of patients with sporadic Alzheimer's disease
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In 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
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ReviewPérez M.J.; Quintanilla R.A. (Academic Press Inc., 2017)
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