title: F1F0 ATP Synthase-Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline.
abstract: Mitochondrial abnormalities are well known to cause cognitive decline. However, the underlying molecular basis of mitochondria-associated neuronal and synaptic dysfunction in the diabetic brain remains unclear. Here, using a mitochondrial single-channel patch clamp and cyclophilin D (CypD)-deficient mice (Ppif-/-) with streptozotocin-induced diabetes, we observed an increase in the probability of Ca2+-induced mitochondrial permeability transition pore (mPTP) opening in brain mitochondria of diabetic mice, which was further confirmed by mitochondrial swelling and cytochrome c release induced by Ca2+overload. Diabetes-induced elevation of CypD triggers enhancement of F1F0ATP synthase-CypD interaction, which in turn leads to mPTP opening. Indeed, in patients with diabetes, brain cypD protein levels were increased. Notably, blockade of the F1F0ATP synthase-CypD interaction by CypD ablation protected against diabetes-induced mPTP opening, ATP synthesis deficits, oxidative stress, and mitochondria dysfunction. Furthermore, the absence of CypD alleviated deficits in synaptic plasticity, learning, and memory in diabetic mice. Thus, blockade of ATP synthase interaction with CypD provides a promising new target for therapeutic intervention in diabetic encephalopathy.
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Shijun
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Fang
authors.initials: F
authors.lastname: Du
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Long
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Changjia
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ.
authors.forename: Lih-Fen
authors.initials: LF
authors.lastname: Lue
authors.affiliation: Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Walker
authors.affiliation: Nuclear Magnetic Resonance Laboratory, Molecular Structures Group, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Douglas
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS shidu@ku.edu.
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000502:physiology*
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D017382:Reactive Oxygen Species; C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases; D021983:Cyclophilins