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Cyclophilin D deficiency attenuates mitochondrial F1Fo ATP synthase dysfunction via OSCP in Alzheimer's disease.
Neurobiology of Disease 2019 January
Mitochondrial dysfunction is pivotal in inducing synaptic injury and neuronal stress in Alzheimer's disease (AD). Mitochondrial F1Fo ATP synthase deregulation is a hallmark mitochondrial defect leading to oxidative phosphorylation (OXPHOS) failure in this neurological disorder. Oligomycin sensitivity conferring protein (OSCP) is a crucial F1Fo ATP synthase subunit. Decreased OSCP levels and OSCP interaction with amyloid β (Aβ) constitute key aspects of F1Fo ATP synthase pathology in AD-related conditions. However, the detailed mechanisms promoting such AD-related OSCP changes have not been fully resolved. Here, we have found increased physical interaction of OSCP with Cyclophilin D (CypD) in AD cases as well as in an AD animal model (5xFAD mice). Genetic depletion of CypD mitigates OSCP loss via ubiquitin-dependent OSCP degradation in 5xFAD mice. Moreover, the ablation of CypD also attenuates OSCP/Aβ interaction in AD mice. The relieved OSCP changes by CypD depletion in 5xFAD mice are along with preserved F1Fo ATP synthase function, restored mitochondrial bioenergetics as well as improved mouse cognition. The simplest interpretation of our results is that CypD is a critical mediator that promotes OSCP deficits in AD-related conditions. Therefore, to block the deleterious impact of CypD on OSCP has the potential to be a promising therapeutic strategy to correct mitochondrial dysfunction for AD therapy.
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