Abstract
F1FO-ATP synthase is critical for mitochondrial functions. The deregulation of this enzyme results in dampened mitochondrial oxidative phosphorylation (OXPHOS) and activated mitochondrial permeability transition (mPT), defects which accompany Alzheimer’s disease (AD). However, the molecular mechanisms that connect F1FO-ATP synthase dysfunction and AD remain unclear. Here, we observe selective loss of the oligomycin sensitivity conferring protein (OSCP) subunit of the F1FO-ATP synthase and the physical interaction of OSCP with amyloid beta (Aβ) in the brains of AD individuals and in an AD mouse model. Changes in OSCP levels are more pronounced in neuronal mitochondria. OSCP loss and its interplay with Aβ disrupt F1FO-ATP synthase, leading to reduced ATP production, elevated oxidative stress and activated mPT. The restoration of OSCP ameliorates Aβ-mediated mouse and human neuronal mitochondrial impairments and the resultant synaptic injury. Therefore, mitochondrial F1FO-ATP synthase dysfunction associated with AD progression could potentially be prevented by OSCP stabilization.
Highlights
F1FO-ATP synthase is critical for mitochondrial functions
In a mouse model of Alzheimer’s disease (AD) that overexpresses the human form of amyloid beta (Ab), the loss of oligomycin sensitivity conferring protein (OSCP) is more prominent in synaptic mitochondria
Our results showed a dramatic reduction of OSCP expression in neurons from the temporal lobe of AD individuals (Fig. 1b)
Summary
F1FO-ATP synthase is critical for mitochondrial functions The deregulation of this enzyme results in dampened mitochondrial oxidative phosphorylation (OXPHOS) and activated mitochondrial permeability transition (mPT), defects which accompany Alzheimer’s disease (AD). We observe selective loss of the oligomycin sensitivity conferring protein (OSCP) subunit of the F1FO-ATP synthase and the physical interaction of OSCP with amyloid beta (Ab) in the brains of AD individuals and in an AD mouse model. Impaired mitochondrial OXPHOS efficiency is closely associated with dysfunction of mitochondrial respiratory enzymes, including mitochondrial complex I to IV, as well as the defect of F1FO-ATP synthase. In addition to OSCP loss, we detect a direct physical interaction between OSCP and Ab in the brains from AD cases, as well as in AD mice Such OSCP aberrations disrupt F1FO-ATP synthase stability, leading to severe mitochondrial dysfunction and synaptic injury. Mitochondrial F1FO-ATP synthase dysfunction that results from OSCP aberrations may constitute a primary AD event that can be prevented by OSCP protection, suggesting OSCP as a potential new therapeutic target for AD
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