Minocycline and N-methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition

Theruvath, Tom P.; Zhong, Zhi; Pediaditakis, Peter; Ramshesh, Venkat K.; Currin, Robert T.; Tikunov, Andrey P.; Holmuhamedov, Ekhson; Lemasters, John J.

doi:10.1002/hep.21912

Cited by 100 publications

(126 citation statements)

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“…Accordingly, intravital microscopy has been applied to a wide range of studies of the liver. Intravital microscopy has been almost routinely used to characterize microvascular flow in the liver, [11][12][13] but has also been used to assay hepatocyte cell death [14][15][16][17][18][19][20] apoptosis, 21 inflammatory cell infiltration, 22-24 microvascular permeability, [25][26][27] mitochondrial function, 14,15,[17][18][19]28,29 steatosis, 30,31 tumor angiogenesis 32 and fibrosis. 33 Fluorescent transport substrates cultured cell systems, it is more difficult to achieve in intravital microscopy, especially in the liver, whose proximity to the diaphragm makes it particularly susceptible to respiration-induced motion.…”

Section: Resultsmentioning

confidence: 99%

Quantitative intravital microscopy of hepatic transport

et al. 2012

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Section: Resultsmentioning

confidence: 99%

Quantitative intravital microscopy of hepatic transport

et al. 2012

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“…12 Less inhibition of the ATPase by IF1 can adaptively conserve residual ATP under conditions such as ischemia, in which mitochondrial aerobic metabolism is absent, 12 but can also be deleterious insofar as a low ⌬⌿ m favors opening of the mitochondrial permeability transition pore, which leads to necrosis or apoptosis. 13 The maintenance of ⌬⌿ m in the TALs also indicates persistence of significant glycolytic ATP production in those cells despite omission of glucose from the medium during the period of chemical hypoxia.Additional biochemical questions that could be addressed with this approach come to mind. Would keeping pH 7.4 during chemical hypoxia to limit activation of IF1 allow for better preservation of ⌬⌿ m in the PTs?…”

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confidence: 99%

“…Application and extension to individual mitochondria within cells, quantifying their response to stress and toxins, and use of this knowledge to understand therapies further await future studies. 13,14 Indeed, the future is bright for multiphoton microscopy's advancing our mechanistic understanding to individual cells and organelles with enhanced spatial and temporal resolution and increased imaging depth. …”

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confidence: 99%

“…11 In addition, calcein entry can be used to measure the mitochondrial permeability transition. 13 This has important implications regarding understanding disease pathophysiology and therapy and can be used in vivo. 14,15 Multiphoton microscopy increases the depth of tissue penetration, reduces phototoxicity, and can follow three different fluorescence probes at once.…”

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Illuminating Mitochondrial Function and Dysfunction using Multiphoton Technology

Weinberg¹,

Molitoris²

2009

Journal of the American Society of Nephrology

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Studying differential cell function or dysfunction within the kidney is made difficult by cellular heterogeneity, alterations in regional blood flow, oxygen tension, and interstitial tonicity, resulting in extremely complex anatomic and physiologic arrangements. Creative investigators have developed techniques to reduce this heterogeneity but often with loss or alteration of three-dimensional cellular associations, anatomic and physiologic cell-to-cell interactions, and harsh isolation and experimental conditions. These limitations have made "absolutes" difficult to determine, especially in relation to pathologic processes such as cell type involvement in renal ischemia. In this issue of JASN, Hall et al. 1 use multiphoton microscopy of kidney slices to compare mitochondrial parameters and differential cellular responses to stress. This approach allows them to quantify several key parameters of mitochondrial function and dysfunction in proximal tubular (PT) cells and directly compare different PT segments with each other and with distal tubular (DT) cells of the thick ascending limb (TAL). Because mitochondrial alterations play a central role in normal cell function and in response to injury, the article adds to our previous knowledge about an important area.To understand the significance and limitations of their contribution, one must first understand what is known about differences between PT and TAL cells. Abundant mitochondria in cortical and outer medullary renal epithelial cells are necessary to meet the ATP demands of sodium transport by high-capacity aerobic metabolism. They compose 33% of the volume of proximal convoluted tubular S1 cells, 39% of the cells in the S2 segment, and 22% of the volume of cells in the proximal straight S3 segment; in the medullary and cortical TAL cells, mitochondria account for 30 to 44% of cell volume. 2 Differential tubular cell metabolism is also notable for the absence of aerobic and anaerobic glycolysis in the proximal convoluted tubule (S1), 3,4 which removes an important mechanism for preserving cell ATP and viability during injury. 5 In contrast, DT segments, including the TAL, have well-developed glycolytic pathways. 3,4,6,7 Glycolysis occurs in the S3 segment of the proximal tubule, albeit to a lesser extent than in distal tubules, and contributes to maintaining ATP there when mitochondrial function is impaired. 3,8 Mitochondrial ATP production depends on substrate-supported, electron transport-mediated proton extrusion from the mitochondrial matrix that generates a proton gradient across the inner mitochondrial membrane. In turn, this is used to drive phosphorylation of ADP to ATP by proton movement down the gradient back into the matrix through the inner membrane F 1 F O -ATPase. Electron transport-driven proton extrusion is also responsible for the net potential across the inner membrane (⌬⌿ m ), and ⌬⌿ m in combination with the pH gradient accounts for the net proton electrochemical gradient across the membrane, also called the proton motive force. ⌬⌿ m is the ...

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“…One proposed mechanism is modulation of the mitochondrial permeability transition (mPT), a Ca 2ϩ -dependent pathogenic event leading to necrotic and/or apoptotic cell death. [1][2][3][4][5] A recent study in HEPATOLOGY by Theruvath et al, 6 investigating storage/ reperfusion injury following rat liver transplantation, concluded that minocycline prevented mPT and mitigated liver injury by decreasing mitochondrial Ca 2ϩ uptake without affecting mitochondrial respiration. Further, the authors argue that it could be consistent with clinical practice to (pre)treat stored livers and graft recipients with minocycline.…”

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Minocycline sensitizes rodent and human liver mitochondria to the permeability transition: Implications for toxicity in liver transplantation

et al. 2009

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The antibiotic minocycline exerts cytoprotection in animal disease models. One proposed mechanism is modulation of the mitochondrial permeability transition (mPT), a Ca 2ϩ -dependent pathogenic event leading to necrotic and/or apoptotic cell death. [1][2][3][4][5] A recent study in HEPATOLOGY by Theruvath et al., 6 investigating storage/ reperfusion injury following rat liver transplantation, concluded that minocycline prevented mPT and mitigated liver injury by decreasing mitochondrial Ca 2ϩ uptake without affecting mitochondrial respiration. Further, the authors argue that it could be consistent with clinical practice to (pre)treat stored livers and graft recipients with minocycline. The driving force for mitochondrial Ca 2ϩ transport is the mitochondrial membrane potential and the amount of Ca 2ϩ retained is dependent on the proton gradient and the matrix pH. 7 Respiratory inhibition will decrease Ca 2ϩ retention capacity and sensitize mitochondria toward mPT. 5,7 Further, endogenous inhibitors of mPT such as adenine nucleotides and Mg 2ϩ will influence the amount of Ca 2ϩ sequestered prior to mPT. In Theruvath et al., the effect of minocyline on mPT was determined in two classical assays, both using bolus additions of calcium chloride: (1) the swelling assay and (2) the Ca 2ϩ retention capacity assay. In both assays, the endpoint is Ca 2ϩ overload and induction of mPT. The authors found that minocycline prevented Ca 2ϩ -induced swelling and decreased Ca 2ϩ retention and interpreted this as a specific inhibitory effect on Ca 2ϩ uptake. They excluded respiratory inhibition as the explanation to their findings by determining the respiration of mitochondria exposed to minocycline with and without Ca 2ϩ addition. However, the buffer used in the respiration assay was different from the one used in the Ca 2ϩ bolus assays, with high Mg 2ϩ concentration (Mg 2ϩ is a known endogenous inhibitor of mPT) and with the presence of the potent pharmacological mPT inhibitor cyclosporin A during Ca 2ϩ addition. We argue that minocycline at moderate to high dosing, similar to what we have shown in brain mitochondria, prevents Ca 2ϩ -uptake and mPT-induced swelling by respiratory inhibition. 1,5 Further, depending on the buffer system used, the decreased Ca 2ϩ retention can be explained by minocycline-induced increase of mPT sensitivity related to (1) inhibited respiration 1,5 and (2) chelating of Mg 2ϩ , 8 or (3) direct activation of mPT (even during concurrent cyclosporin A treatment) by adding Ca 2ϩ or in Ca 2ϩ loaded mitochondria, as recently shown by Kupsch et al. 8 To stringently evaluate effects of minocycline during the process of Ca 2ϩ uptake, retention, and mPT, mitochondrial oxygen consumption can be monitored during a continuous Ca 2ϩ infusion (Fig. 1A,B). This assay provides information of the bioenergetic demand on mitochondria caused by Ca 2ϩ uptake as well as the respiratory inhibition triggered by mitochondrial Ca 2ϩ overload and mPT. 5,7 Alternatively, the effect of minocycline on isolated mitochondria can be di...

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Minocycline and N-methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition

Cited by 100 publications

References 40 publications

Quantitative intravital microscopy of hepatic transport

Quantitative intravital microscopy of hepatic transport

Illuminating Mitochondrial Function and Dysfunction using Multiphoton Technology

Minocycline sensitizes rodent and human liver mitochondria to the permeability transition: Implications for toxicity in liver transplantation

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