Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer’s disease

Simon J. Beck, Lan Guo (), Aarron Phensy, Jing Tian, Lu Wang, Neha Tandon, Esha Gauba, Lin Lu, Juan M. Pascual, Sven Kroener and Heng Du ()
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Simon J. Beck: The University of Texas at Dallas
Lan Guo: The University of Texas at Dallas
Aarron Phensy: School of Behavioral and Brain Sciences, The University of Texas at Dallas
Jing Tian: The University of Texas at Dallas
Lu Wang: The University of Texas at Dallas
Neha Tandon: The University of Texas at Dallas
Esha Gauba: The University of Texas at Dallas
Lin Lu: The University of Texas at Dallas
Juan M. Pascual: The University of Texas Southwestern Medical Center
Sven Kroener: School of Behavioral and Brain Sciences, The University of Texas at Dallas
Heng Du: The University of Texas at Dallas

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11483

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