Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice.
Brain aging is the known strongest risk factor for Alzheimer's disease (AD). In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD, in particular its sporadic form. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increased CypD expression, enhanced CypD/OSCP interaction, and selective loss of OSCP are prominent brain mitochondrial changes in aging mice. Along with these changes, brain mitochondria from the aging mice demonstrated decreased F1FO ATP synthase activity and defective F1FO complex coupling. In contrast, CypD deficient mice exhibited substantially mitigated brain mitochondrial F1FO ATP synthase dysfunction with relatively preserved mitochondrial function during aging. Interestingly, the aging-related OSCP loss was also dramatically attenuated by CypD depletion. Therefore, the simplest interpretation of this study is that CypD promotes F1FO ATP synthase dysfunction and the resultant mitochondrial deficits in aging brains. In addition, in view of CypD and F1FO ATP synthase alterations seen in AD brains, the results further suggest that CypD-mediated F1FO ATP synthase deregulation is a shared mechanism linking mitochondrial deficits in brain aging and AD.
Department of Biological Sciences, The University of Texas, Dallas, Richardson, TX, USA.
Esha
E
Gauba
Department of Biological Sciences, The University of Texas, Dallas, Richardson, TX, USA.
Lan
L
Guo
Department of Biological Sciences, The University of Texas, Dallas, Richardson, TX, USA.|Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
Heng
H
Du
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000375:Aging / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000648:ultrastructure*; D002352:Carrier Proteins / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000494:pharmacology; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D010101:Oxygen Consumption
D002352:Carrier Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D008565:Membrane Proteins; C000631446:PPIF protein, mouse; D018698:Glutamic Acid; D000244:Adenosine Diphosphate; D000251:Adenosine Triphosphatases; C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases; D021983:Cyclophilins; C020439:oligomycin sensitivity-conferring protein
Aging brain; Cyclophilin D; F1FO ATP synthase; mitochondria; oligomycin sensitivity conferring protein