title: Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer's disease.
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.
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Beck
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Guo
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.
authors.forename: Aarron
authors.initials: A
authors.lastname: Phensy
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.|Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Weiqi Road, Jinan, Shandong 250021, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Tandon
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.
authors.forename: Esha
authors.initials: E
authors.lastname: Gauba
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.|Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Weiqi Road, Jinan, Shandong 250021, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Richardson, Texas 75390, USA.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Pascual
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Kroener
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.|Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Weiqi Road, Jinan, Shandong 250021, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Du
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D008565:Membrane Proteins; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases; C020439:oligomycin sensitivity-conferring protein