Modulation by substrates of the protective effect of cyclosporin A on mitochondrial damage

Chávez, Edmundo; Zazueta, Cecilia; Correa, Francisco; Garcı́a, Noemı́; Avilés, César; Robles, Sandra G.; Rodriguez, C.

doi:10.1016/s0024-3205(02)01486-8

Cited by 9 publications

(12 citation statements)

References 30 publications

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“…The PTP in the tubules was highly sensitive to medium ADP and Mg 2ϩ with strong synergism between the two metabolites. Also important in this regard, inhibition of cyclophilin D with CsA did not oppose the MPT in the absence of ADP and Mg 2ϩ , but CsA synergized strongly with ADP, even more strongly with ADPϩMg, and moderately with Mg 2ϩ alone, as described in other systems (14,54,55,57). The effects of ADP to oppose PTP opening are considered to be direct, rather then via its conversion to ATP (37,55), and we confirmed this for the tubules by showing that blocking ATP production by inhibiting the F 1 F O -ATPase and adenylate kinase did not prevent PTP closure by ADP.…”

Section: Discussionmentioning

confidence: 61%

“…ADP and Mg 2ϩ suppress the MPT (14,36,54,55,57), ADP possibly by its interaction with the AAC (34,54) or the voltage-dependent anion carrier, another putative PTP component (63), and Mg 2ϩ by competing with Ca 2ϩ (8). Loss of ADP and Mg 2ϩ from the mitochondrial matrix as the PTP starts to open (32,54,75) will accelerate the process.…”

Section: Discussionmentioning

confidence: 99%

“…1 , and CsA were used in combination for the studies represented in Figs. 1-3 based on extensive prior observations that they act synergistically to modify the MPT (13,14,32,40,54,55,57,75). Moreover, these interactions show tissuespecific differences (54,57).…”

Section: Induction Of the Mpt By Camentioning

confidence: 99%

“…Substrate conditions tested were succinate, glutamateϩmalate, and glutamateϩmalateϩNAD. NAD helps maintain matrix NAD, which can be lost as the PTP opens (1,14,18,54), thereby lowering the efficacy of complex I-dependent substrates. Under all substrate conditions, resistance to development of the MPT indicated by magnitude of Ca 2ϩ reten- had CsAϩMg for 400 s, followed by addition of ADP.…”

Section: Induction Of the Mpt By Camentioning

confidence: 99%

“…Despite this recent progress, regulation of the MPT within the intact cell remains incompletely defined. In particular, the MPT can be strongly suppressed by several endogenous metabolites, including ADP and Mg 2ϩ (13,14,32,32,36,39,40,54,57,75). These metabolites are abundant in cells and should oppose sustained opening of the PTP before catastrophic plasma membrane damage.…”

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confidence: 99%

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Regulation of the mitochondrial permeability transition in kidney proximal tubules and its alteration during hypoxia-reoxygenation

Feldkamp

Park

Pasupulati

et al. 2009

American Journal of Physiology-Renal Physiology

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Feldkamp T, Park JS, Pasupulati R, Amora D, Roeser NF, Venkatachalam MA, Weinberg JM. Regulation of the mitochondrial permeability transition in kidney proximal tubules and its alteration during hypoxia/reoxygenation. Am J Physiol Renal Physiol 297: F1632-F1646, 2009. First published September 9, 2009 doi:10.1152/ajprenal.00422.2009.-Development of the mitochondrial permeability transition (MPT) can importantly contribute to lethal cell injury from both necrosis and apoptosis, but its role varies considerably with both the type of cell and type of injury, and it can be strongly opposed by the normally abundant endogenous metabolites ADP and Mg 2ϩ . To better characterize the MPT in kidney proximal tubule cells and assess its contribution to injury to them, we have refined and validated approaches to follow the process in whole kidney proximal tubules and studied its regulation in normoxic tubules and after hypoxia-reoxygenation (H/R). Physiological levels of ADP and Mg 2ϩ greatly decreased sensitivity to the MPT. Inhibition of cyclophilin D by cyclosporine A (CsA) effectively opposed the MPT only in the presence of ADP and/or Mg 2ϩ . Nonesterified fatty acids (NEFA) had a large role in the decreased resistance to the MPT seen after H/R irrespective of the available substrate or the presence of ADP, Mg 2ϩ , or CsA, but removal of NEFA was less effective at restoring normal resistance to the MPT in the presence of electron transport complex I-dependent substrates than with succinate. The data indicate that the NEFA accumulation that occurs during both hypoxia in vitro and ischemic acute kidney injury in vivo is a critical sensitizing factor for the MPT that overcomes the antagonistic effect of endogenous metabolites and cyclophilin D inhibition, particularly in the presence of complex I-dependent substrates, which predominate in vivo.acute kidney injury; membrane potential; mitochondria A VARIETY OF INSULTS can produce a sustained increase of the permeability of the inner mitochondrial membrane that prevents it from maintaining the transmembrane ion gradients necessary for energy conservation. The process, now most commonly called the mitochondrial permeability transition (MPT), is characterized by loss of inorganic and small organic matrix solutes and mitochondrial swelling. Considerable evidence supports the concept that the MPT results from reversible opening of an ϳ3-nm-diameter pore with a size exclusion limit of ϳ1,500 Da that is frequently termed the permeability transition pore (PTP) (5,7,32,34,36,39,40,48,69,75,82). There also is evidence for more selective substates of the MPT (10,13,40,46,51) and for its transient opening under physiological conditions (42,70). In isolated mitochondria, the development of the PTP is regulated by matrix divalent cations, mitochondrial membrane potential (⌬⌿ m ), matrix pH, ADP, and NAD(P)H redox state (5,32,34,36,39,48,82). Opening of the pore can be prevented and reversed by cyclosporine A (CsA), via inhibition by CsA of the binding of mitochondrial matrix cyclophilin...

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Induction Of the Mpt By Camentioning

confidence: 99%

Section: Induction Of the Mpt By Camentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Regulation of the mitochondrial permeability transition in kidney proximal tubules and its alteration during hypoxia-reoxygenation

Feldkamp

Park

Pasupulati

et al. 2009

American Journal of Physiology-Renal Physiology

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Titration of lysine residues on adenine nucleotide translocase by fluorescamine induces permeability transition

Buelna‐Chontal

Pavón

Correa

et al. 2013

Cell Biology International

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Chemical modification of primary amino groups of mitochondrial membrane proteins by the fluorescent probe fluorescamine induces non-specific membrane permeabilisation. Titration of the lysine ϵ-amino group promoted efflux of accumulated Ca(2+), collapse of transmembrane potential and mitochondrial swelling. Ca(2+) release was inhibited by cyclosporin A. Considering the latter, we assumed that fluorescamine induces permeability transition. Carboxyatractyloside also inhibited the reaction. Using a polyclonal antibody for adenine nucleotide translocase, Western blot analysis showed that the carrier appeared labelled with the fluorescent probe. The results point out the importance of the ϵ-amino group of lysine residues, located in the adenine nucleotide carrier, on the modulation of membrane permeability, since its blockage suffices to promote opening of the non-specific nanopore.

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Blood lymphocyte blastogenesis in patients with thyroid dysfunction: ex vivo response to mitogen activation and cyclosporin A

et al. 2010

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Lymphocytes from hypothyroid patients exhibited reduced response to PHA and lower sensitivity to CsA compared with control, which could be attributed to their reduced activation capability coexisting with hypothyroidism. In hyperthyroxinaemic samples, the actions of high CsA concentrations were mostly targeted toward activated lymphoblasts. Considering the cellular targets that thyroid hormones and CsA may share, the therapeutic implications of their cross-talk need careful consideration.

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Modulation by substrates of the protective effect of cyclosporin A on mitochondrial damage

Cited by 9 publications

References 30 publications

Regulation of the mitochondrial permeability transition in kidney proximal tubules and its alteration during hypoxia-reoxygenation

Regulation of the mitochondrial permeability transition in kidney proximal tubules and its alteration during hypoxia-reoxygenation

Titration of lysine residues on adenine nucleotide translocase by fluorescamine induces permeability transition

Blood lymphocyte blastogenesis in patients with thyroid dysfunction: ex vivo response to mitogen activation and cyclosporin A

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