Cyclophilin D and the Mitochondrial Permeability Transition in Kidney Proximal Tubules After Hypoxic and Ischemic Injury

Overview

Journal Am J Physiol Renal Physiol

Publisher American Physiological Society

Specialties Nephrology
Physiology

Date 2011 Apr 15

PMID 21490135

Citations 31

Authors

Jeong Soon Park

Ratna Pasupulati

Thorsten Feldkamp

Nancy F Roeser

Joel M Weinberg

Affiliations

Soon will be listed here.

Abstract

Mitochondrial matrix cyclophilin D (CyPD) is known to promote development of the mitochondrial permeability transition (MPT). Kidney proximal tubule cells are especially prone to deleterious effects of mitochondrial damage because of their dependence on oxidative mitochondrial metabolism for ATP production. To clarify the role of CyPD and the MPT in proximal tubule injury during ischemia-reperfusion (I/R) and hypoxia-reoxygenation (H/R), we assessed freshly isolated tubules and in vivo injury in wild-type (WT) and Ppif(-/-) CyPD-null mice. Isolated mouse tubules developed a sustained, nonesterified fatty acid-mediated energetic deficit after H/R in vitro that could be substantially reversed by delipidated albumin and supplemental citric acid cycle substrates but was not modified by the absence of CyPD. Susceptibility of WT and Ppif(-/-) tubules to the MPT was increased by H/R but was less in normoxic and H/R Ppif(-/-) than WT tubules. Correction of the energetic deficit that developed during H/R strongly increased resistance to the MPT. Ppif(-/-) mice were resistant to I/R injury in vivo spanning a wide range of severity. The data clarify involvement of the MPT in oxygen deprivation-induced tubule cell injury by showing that the MPT does not contribute to the initial bioenergetic deficit produced by H/R but the deficit predisposes to subsequent development of the MPT, which contributes pathogenically to kidney I/R injury in vivo.

Citing Articles

Involvement of necroptosıs and apoptosıs ın protectıve effects of cyclosporın a on ischemıa-reperfusıon injury in rat kıdney.

Ozgen Z, Erdinc M, Kaya M, Aktar F, Ozekinci S, Erdinc L J Mol Histol. 2024; 56(1):30.

PMID: 39630315 DOI: 10.1007/s10735-024-10281-7.

Sustained alterations in proximal tubule gene expression in primary culture associate with HNF4A loss.

Telang A, Ference-Salo J, McElliott M, Chowdhury M, Beamish J Sci Rep. 2024; 14(1):22927.

PMID: 39358473 PMC: 11447228. DOI: 10.1038/s41598-024-73861-3.

Cell death induced by acute renal injury: a perspective on the contributions of accidental and programmed cell death.

Noh M, Padanilam B Am J Physiol Renal Physiol. 2024; 327(1):F4-F20.

PMID: 38660714 PMC: 11390133. DOI: 10.1152/ajprenal.00275.2023.

Comprehensive overview of the role of mitochondrial dysfunction in the pathogenesis of acute kidney ischemia-reperfusion injury: a narrative review.

Kim M, Oh C, Hong C, Jeon J J Yeungnam Med Sci. 2024; 41(2):61-73.

PMID: 38351610 PMC: 11074843. DOI: 10.12701/jyms.2023.01347.

Necroptosis: A Pathogenic Negotiator in Human Diseases.

Chaouhan H, Vinod C, Mahapatra N, Yu S, Wang I, Chen K Int J Mol Sci. 2022; 23(21).

PMID: 36361505 PMC: 9655262. DOI: 10.3390/ijms232112714.

References

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

Mokhova E, Khailova L . Involvement of mitochondrial inner membrane anion carriers in the uncoupling effect of fatty acids. Biochemistry (Mosc). 2005; 70(2):159-63. DOI: 10.1007/s10541-005-0096-1. View

Bernardi P, Rasola A . Calcium and cell death: the mitochondrial connection. Subcell Biochem. 2008; 45:481-506. DOI: 10.1007/978-1-4020-6191-2_18. View

Muller F, Liu Y, Abdul-Ghani M, Lustgarten M, Bhattacharya A, Jang Y . High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I- and complex II-linked substrates. Biochem J. 2007; 409(2):491-9. DOI: 10.1042/BJ20071162. View

Schinzel A, Takeuchi O, Huang Z, Fisher J, Zhou Z, Rubens J . Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A. 2005; 102(34):12005-10. PMC: 1189333. DOI: 10.1073/pnas.0505294102. View

Feldkamp T, Kribben A, Roeser N, Ostrowski T, Weinberg J . Alleviation of fatty acid and hypoxia-reoxygenation-induced proximal tubule deenergization by ADP/ATP carrier inhibition and glutamate. Am J Physiol Renal Physiol. 2007; 292(5):F1606-16. DOI: 10.1152/ajprenal.00476.2006. View

Novgorodov S, Gudz T, Brierley G, Pfeiffer D . Magnesium ion modulates the sensitivity of the mitochondrial permeability transition pore to cyclosporin A and ADP. Arch Biochem Biophys. 1994; 311(2):219-28. DOI: 10.1006/abbi.1994.1230. View

Giorgio V, Bisetto E, Soriano M, Dabbeni-Sala F, Basso E, Petronilli V . Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex. J Biol Chem. 2009; 284(49):33982-8. PMC: 2797168. DOI: 10.1074/jbc.M109.020115. View

Di Lisa F, Menabo R, Canton M, Barile M, Bernardi P . Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J Biol Chem. 2000; 276(4):2571-5. DOI: 10.1074/jbc.M006825200. View

10.

Leung A, Varanyuwatana P, Halestrap A . The mitochondrial phosphate carrier interacts with cyclophilin D and may play a key role in the permeability transition. J Biol Chem. 2008; 283(39):26312-23. PMC: 3258905. DOI: 10.1074/jbc.M805235200. View

11.

Hackenbrock C, Rehn T, Weinbach E, Lemasters J . Oxidative phosphorylation and ultrastructural transformation in mitochondria in the intact ascites tumor cell. J Cell Biol. 1971; 51(1):123-37. PMC: 2108254. DOI: 10.1083/jcb.51.1.123. View

12.

Zhu T, Au-Yeung K, Siow Y, Wang G, O K . Cyclosporine A protects against apoptosis in ischaemic/reperfused rat kidneys. Clin Exp Pharmacol Physiol. 2002; 29(9):852-4. DOI: 10.1046/j.1440-1681.2002.03736.x. View

13.

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

14.

Rasola A, Sciacovelli M, Pantic B, Bernardi P . Signal transduction to the permeability transition pore. FEBS Lett. 2010; 584(10):1989-96. PMC: 2866765. DOI: 10.1016/j.febslet.2010.02.022. View

15.

Weinberg J, Roeser N, Davis J, Schultz S, Nissim I . Relationships between intracellular amino acid levels and protection against injury to isolated proximal tubules. Am J Physiol. 1991; 260(3 Pt 2):F410-9. DOI: 10.1152/ajprenal.1991.260.3.F410. View

16.

Wang Z, Havasi A, Gall J, Bonegio R, Li Z, Mao H . GSK3beta promotes apoptosis after renal ischemic injury. J Am Soc Nephrol. 2010; 21(2):284-94. PMC: 2834548. DOI: 10.1681/ASN.2009080828. View

17.

Arnold P, Van Putten V, Lumlertgul D, BURKE T, Schrier R . Adenine nucleotide metabolism and mitochondrial Ca2+ transport following renal ischemia. Am J Physiol. 1986; 250(2 Pt 2):F357-63. DOI: 10.1152/ajprenal.1986.250.2.F357. View

18.

Hunter D, Haworth R . The Ca2+-induced membrane transition in mitochondria. III. Transitional Ca2+ release. Arch Biochem Biophys. 1979; 195(2):468-77. DOI: 10.1016/0003-9861(79)90373-4. View

19.

CARLE B . Autofluorescence in the identification of myocardial infarcts. Hum Pathol. 1981; 12(7):643-6. DOI: 10.1016/s0046-8177(81)80049-4. 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