F1F0 ATP Synthase-Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline

Overview

Journal Diabetes

Specialty Endocrinology

Date 2016 Aug 25

PMID 27554467

Citations 30

Authors

Shijun Yan

Fang Du

Long Wu

Zhihua Zhang

Changjia Zhong

Qing Yu

Yongfu Wang

Lih-Fen Lue

Douglas G Walker

Justin T Douglas

Shirley ShiDu Yan

Affiliations

Soon will be listed here.

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 Ca-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 Ca overload. Diabetes-induced elevation of CypD triggers enhancement of FF ATP 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 FF ATP 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.

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References

Taddeo E, Laker R, Breen D, Akhtar Y, Kenwood B, Liao J . Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle. Mol Metab. 2014; 3(2):124-34. PMC: 3953683. DOI: 10.1016/j.molmet.2013.11.003. View

Baines C, Kaiser R, Purcell N, Blair N, Osinska H, Hambleton M . Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature. 2005; 434(7033):658-62. DOI: 10.1038/nature03434. View

Fang D, Wang Y, Zhang Z, Du H, Yan S, Sun Q . Increased neuronal PreP activity reduces Aβ accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model. Hum Mol Genet. 2015; 24(18):5198-210. PMC: 4550821. DOI: 10.1093/hmg/ddv241. View

Kinnally K, Campo M, Tedeschi H . Mitochondrial channel activity studied by patch-clamping mitoplasts. J Bioenerg Biomembr. 1989; 21(4):497-506. DOI: 10.1007/BF00762521. View

Huang C, Chung C, Leu H, Lin L, Chiu C, Hsu C . Diabetes mellitus and the risk of Alzheimer's disease: a nationwide population-based study. PLoS One. 2014; 9(1):e87095. PMC: 3906115. DOI: 10.1371/journal.pone.0087095. View

Huang S, Wang Y, Gan X, Fang D, Zhong C, Wu L . Drp1-mediated mitochondrial abnormalities link to synaptic injury in diabetes model. Diabetes. 2014; 64(5):1728-42. PMC: 4407851. DOI: 10.2337/db14-0758. View

Rasheed M, Tabassum H, Parvez S . Mitochondrial permeability transition pore: a promising target for the treatment of Parkinson's disease. Protoplasma. 2016; 254(1):33-42. DOI: 10.1007/s00709-015-0930-2. View

Kirichok Y, Krapivinsky G, Clapham D . The mitochondrial calcium uniporter is a highly selective ion channel. Nature. 2004; 427(6972):360-4. DOI: 10.1038/nature02246. View

Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D . Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A. 2010; 107(15):7036-41. PMC: 2872449. DOI: 10.1073/pnas.1000645107. View

10.

Folstein M, Folstein S, McHugh P . "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12(3):189-98. DOI: 10.1016/0022-3956(75)90026-6. View

11.

Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H . Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2005; 434(7033):652-8. DOI: 10.1038/nature03317. View

12.

Burdo J, Chen Q, Calcutt N, Schubert D . The pathological interaction between diabetes and presymptomatic Alzheimer's disease. Neurobiol Aging. 2008; 30(12):1910-7. DOI: 10.1016/j.neurobiolaging.2008.02.010. View

13.

Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M . Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci U S A. 2013; 110(15):5887-92. PMC: 3625323. DOI: 10.1073/pnas.1217823110. View

14.

Yan S, Li Z, Li H, Arancio O, Zhang W . Notoginsenoside R1 increases neuronal excitability and ameliorates synaptic and memory dysfunction following amyloid elevation. Sci Rep. 2014; 4:6352. PMC: 4161968. DOI: 10.1038/srep06352. View

15.

Alavian K, Beutner G, Lazrove E, Sacchetti S, Park H, Licznerski P . An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci U S A. 2014; 111(29):10580-5. PMC: 4115574. DOI: 10.1073/pnas.1401591111. View

16.

Feng D, Tang Y, Kwon H, Zong H, Hawkins M, Kitsis R . High-fat diet-induced adipocyte cell death occurs through a cyclophilin D intrinsic signaling pathway independent of adipose tissue inflammation. Diabetes. 2011; 60(8):2134-43. PMC: 3142076. DOI: 10.2337/db10-1411. View

17.

Du H, Guo L, Fang F, Chen D, Sosunov A, McKhann G . Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med. 2008; 14(10):1097-105. PMC: 2789841. DOI: 10.1038/nm.1868. View

18.

Strachan M, Reynolds R, Marioni R, Price J . Cognitive function, dementia and type 2 diabetes mellitus in the elderly. Nat Rev Endocrinol. 2011; 7(2):108-14. DOI: 10.1038/nrendo.2010.228. View

19.

Bernardi P, Rasola A, Forte M, Lippe G . The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology. Physiol Rev. 2015; 95(4):1111-55. PMC: 4600949. DOI: 10.1152/physrev.00001.2015. View

20.

Palma E, Tiepolo T, Angelin A, Sabatelli P, Maraldi N, Basso E . Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice. Hum Mol Genet. 2009; 18(11):2024-31. DOI: 10.1093/hmg/ddp126. View