Generic placeholder image

Current Molecular Medicine

Author(s): Kunqiao Hong, Qian Yang, Gen Liu, Hu Qiu and Baoping Yu*

DOI: 10.2174/1566524023666220908112922

DownloadDownload PDF Flyer Cite As
Cyclophilin D Regulates Oxidative Stress and Apoptosis via Mitochondrial Permeability Transition Pore in Acute Acalculous Cholecystitis

Page: [971 - 980] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Objective: Acute acalculous cholecystitis (AAC) is characterized by acute onset, rapid progression, high mortality, and various complications. Cyclophilin D (CypD) regulates the mitochondrial permeability transition pore (MPTP) and is involved in the occurrence of ischemia-reperfusion injury and inflammation; however, the role of CypD in AAC remains unclear.

Methods: Guinea pigs of 300–350 g were randomly divided into three groups, namely the sham group, the common bile duct ligation-24h group (CBDL-24h group), and the CBDL-48h group. Western blot and qRT-PCR were applied to analyze the differential expression of CypD in each group, and transmission electron microscopy was employed to detect changes in mitochondrial structure. Inhibiting the activity of CypD by Cyclosporine A (CsA), we evaluated the difference of mitochondrial utilizing mitochondrial swelling, reactive oxygen species (ROS) detection and mitochondrial membrane potential.

Results: Compared with the sham group, the prolongation of obstruction aggravated gallbladder inflammation and upregulated CypD expression in the CBDL-24h and CBDL-48h groups. The degree of mitochondrial swelling was increased, and the opening of MPTP was prolonged in the CBDL-24h and 48h groups. Decreasing the expression of CypD could repress the opening of MPTP, prevent manipulation of the mitochondrial membrane potential, and ultimately diminish the levels of intracellular ROS and apoptosis.

Conclusion: CypD plays a proinflammatory role in the development of AAC by regulating the opening of MPTP. Inhibiting the activity of CypD could reduce the levels of ROS and apoptosis, rescue the function of mitochondria and finally alleviate AAC. Therefore, CypD might serve as a potential therapeutic target for ACC.

Keywords: Cyclophilin D, mitochondrial permeability transition pore, Cyclosporin A, Acute acalculous cholecystitis, oxidative stress, apoptosis

[1]
Huffman JL, Schenker S. Acute acalculous cholecystitis: A review. Clin Gastroenterol Hepatol 2010; 8(1): 15-22.
[http://dx.doi.org/10.1016/j.cgh.2009.08.034] [PMID: 19747982]
[2]
Poddighe D, Sazonov V. Acute acalculous cholecystitis in children. World J Gastroenterol 2018; 24(43): 4870-9.
[http://dx.doi.org/10.3748/wjg.v24.i43.4870] [PMID: 30487697]
[3]
Barie P S, Eachempati S R. Acute acalculous cholecystitis. Gastroenterol Clin North Am 2010; 39M(2): 343-57.
[http://dx.doi.org/10.1016/j.gtc.2010.02.012]
[4]
McChesney JA, Northup PG, Bickston SJ. Acute acalculous cholecystitis associated with systemic sepsis and visceral arterial hypoperfusion: a case series and review of pathophysiology. Dig Dis Sci 2003; 48(10): 1960-7.
[http://dx.doi.org/10.1023/A:1026118320460] [PMID: 14627341]
[5]
Lin MJ, Chen L, Huang ZP, Qiu H, Yu BP. Neutrophils injure gallbladder interstitial Cajal‐like cells in a guinea pig model of acute cholecystitis. J Cell Physiol 2019; 234(4): 4291-301.
[http://dx.doi.org/10.1002/jcp.27197] [PMID: 30146704]
[6]
Du H, Guo L, Wu X, et al. Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration. Biochim Biophys Acta Mol Basis Dis 2014; 1842(12): 2517-27.
[http://dx.doi.org/10.1016/j.bbadis.2013.03.004] [PMID: 23507145]
[7]
Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P. Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 2005; 280(19): 18558-61.
[http://dx.doi.org/10.1074/jbc.C500089200] [PMID: 15792954]
[8]
Giorgio V, Soriano ME, Basso E, et al. Cyclophilin D in mitochondrial pathophysiology. Biochim Biophys Acta Bioenerg 2010; 1797(6-7): 1113-8.
[http://dx.doi.org/10.1016/j.bbabio.2009.12.006] [PMID: 20026006]
[9]
Ye F, Li X, Liu Y, et al. CypD deficiency confers neuroprotection against mitochondrial abnormality caused by lead in SH-SY5Y cell. Toxicol Lett 2020; 323: 25-34.
[http://dx.doi.org/10.1016/j.toxlet.2019.12.025] [PMID: 31874198]
[10]
Cao S, Sun Y, Wang W, et al. Poly (ADP‐ribose) polymerase inhibition protects against myocardial ischaemia/reperfusion injury via suppressing mitophagy. J Cell Mol Med 2019; 23(10): 6897-906.
[http://dx.doi.org/10.1111/jcmm.14573] [PMID: 31379115]
[11]
Lindblom RSJ, Higgins GC, Nguyen TV, et al. Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D. Clin Sci 2020; 134(2): 239-59.
[http://dx.doi.org/10.1042/CS20190787] [PMID: 31943002]
[12]
Gan X, Zhang L, Liu B, et al. CypD-mPTP axis regulates mitochondrial functions contributing to osteogenic dysfunction of MC3T3-E1 cells in inflammation. J Physiol Biochem 2018; 74(3): 395-402.
[http://dx.doi.org/10.1007/s13105-018-0627-z] [PMID: 29679227]
[13]
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25(4): 402-8.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[14]
Karch J, Bround MJ, Khalil H, et al. Inhibition of mitochondrial permeability transition by deletion of the ANT family and CypD. Sci Adv 2019; 5(8): eaaw4597.
[http://dx.doi.org/10.1126/sciadv.aaw4597] [PMID: 31489369]
[15]
Mohamad N, Gutierrez A, Nunez M, et al. Mitochondrial apoptotic pathways. Biocell 2005; 29(2): 149-61.
[16]
Kimura Y, Takada T, Kawarada Y, et al. Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg 2007; 14(1): 15-26.
[http://dx.doi.org/10.1007/s00534-006-1152-y] [PMID: 17252293]
[17]
Orlando R III, Gleason E, Drezner AD. Acute acalculous cholecystitis in the critically ill patient. Am J Surg 1983; 145(4): 472-6.
[http://dx.doi.org/10.1016/0002-9610(83)90042-9] [PMID: 6188383]
[18]
Cao AM, Eslick GD, Cox MR. Early laparoscopic cholecystectomy is superior to delayed acute cholecystitis: A meta-analysis of case–control studies. Surg Endosc 2016; 30(3): 1172-82.
[http://dx.doi.org/10.1007/s00464-015-4325-4] [PMID: 26139487]
[19]
Mnatsakanyan N, Beutner G, Porter GA, Alavian KN, Jonas EA. Physiological roles of the mitochondrial permeability transition pore. J Bioenerg Biomembr 2017; 49(1): 13-25.
[http://dx.doi.org/10.1007/s10863-016-9652-1] [PMID: 26868013]
[20]
Nighoghossian N, Ovize M, Mewton N, Ong E, Cho TH. Cyclosporine a, a potential therapy of ischemic reperfusion injury. A common history for heart and brain. Cerebrovasc Dis 2016; 42(5-6): 309-18.
[http://dx.doi.org/10.1159/000446850] [PMID: 27245840]
[21]
Wang X, Du H, Shao S, et al. Cyclophilin D deficiency attenuates mitochondrial perturbation and ameliorates hepatic steatosis. Hepatology 2018; 68(1): 62-77.
[http://dx.doi.org/10.1002/hep.29788] [PMID: 29356058]
[22]
Duan Y, Wang H, Mitchell-silbaugh K, et al. Heat shock protein 60 regulates yolk sac erythropoiesis in mice. Cell Death Dis 2019; 10(10): 766.
[http://dx.doi.org/10.1038/s41419-019-2014-2] [PMID: 31601784]
[23]
Perez M J, Ponce D P, Aranguiz A, et al. Mitochondrial permeability transition pore contributes to mitochondrial dysfunction in fibroblasts of patients with sporadic Alzheimer's disease. Redox Biol 2018; 19: 290-300.
[http://dx.doi.org/10.1016/j.redox.2018.09.001]
[24]
Amanakis G, Murphy E, Cyclophilin D. Cyclophilin D: An integrator of mitochondrial function. Front Physiol 2020; 11: 595.
[http://dx.doi.org/10.3389/fphys.2020.00595] [PMID: 32625108]
[25]
Porter GA, Beutner G, Cyclophilin D. Cyclophilin D, somehow a master regulator of mitochondrial function. Biomolecules 2018; 8(4): 176.
[http://dx.doi.org/10.3390/biom8040176] [PMID: 30558250]
[26]
Han JH, Park J, Myung SH, et al. Noxa mitochondrial targeting domain induces necrosis via VDAC2 and mitochondrial catastrophe. Cell Death Dis 2019; 10(7): 519.
[http://dx.doi.org/10.1038/s41419-019-1753-4] [PMID: 31285435]
[27]
Parks RJ, Menazza S, Holmström KM, et al. Cyclophilin D-mediated regulation of the permeability transition pore is altered in mice lacking the mitochondrial calcium uniporter. Cardiovasc Res 2019; 115(2): 385-94.
[http://dx.doi.org/10.1093/cvr/cvy218] [PMID: 30165576]
[28]
Gan I, Jiang J, Lian D, et al. Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection. Am J Transplant 2019; 19(3): 686-98.
[http://dx.doi.org/10.1111/ajt.15112] [PMID: 30203531]
[29]
Elrod JW, Molkentin JD. Physiologic functions of cyclophilin D and the mitochondrial permeability transition pore. Circ J 2013; 77(5): 1111-22.
[http://dx.doi.org/10.1253/circj.CJ-13-0321] [PMID: 23538482]
[30]
Dube H, Selwood D, Malouitre S, Capano M, Simone MI, Crompton M. A mitochondrial-targeted cyclosporin A with high binding affinity for cyclophilin D yields improved cytoprotection of cardiomyocytes. Biochem J 2012; 441(3): 901-7.
[http://dx.doi.org/10.1042/BJ20111301] [PMID: 22035570]
[31]
Estaquier J, Vallette F, Vayssiere JL, Mignotte B. The mitochondrial pathways of apoptosis. Adv Exp Med Biol 2012; 942: 157-83.
[http://dx.doi.org/10.1007/978-94-007-2869-1_7] [PMID: 22399422]
[32]
Wu HY, Huang CH, Lin YH, Wang CC, Jan TR. Cannabidiol induced apoptosis in human monocytes through mitochondrial permeability transition pore-mediated ROS production. Free Radic Biol Med 2018; 124: 311-8.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.06.023] [PMID: 29940353]
[33]
Sun Q, Shen X, Wang P, Ma J, Sha W. Targeting cyclophilin-D by miR-1281 protects human macrophages from Mycobacterium tuberculosis-induced programmed necrosis and apoptosis. Aging 2019; 11(24): 12661-73.
[http://dx.doi.org/10.18632/aging.102593] [PMID: 31884421]