Mitochondrial permeability transition during hypothermic to normothermic reperfusion in rat liver demonstrated by the protective effect of cyclosporin A

The purpose of this study was to test the hypothesis that mitochondrial permeability transition might be implicated in mitochondrial and intact organ dysfunctions associated with damage induced by reperfusion after cold ischaemia. Energetic metabolism was assessed continuously by 31P-NMR on a model system of isolated perfused rat liver; mitochondria were extracted from the livers and studied by using top-down control analysis. During the temperature transition from hypothermic to normothermic perfusion (from 4 to 37 °C) the ATP content of the perfused organ fell rapidly, and top-down metabolic control analysis of damaged mitochondria revealed a specific control pattern characterized by a dysfunction of the phosphorylation subsystem leading to a decreased response to cellular ATP demand. Both dysfunctions were fully prevented by cyclosporin A, a specific inhibitor of the mitochondrial transition pore (MTP). These results strongly suggest the involvement of the opening of MTP in vivo during the transition to normothermia on rat liver mitochondrial function and organ energetics.

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Trehalose loading through the mitochondrial permeability transition pore enhances desiccation tolerance in rat liver mitochondria

Biochimica et Biophysica Acta (BBA) - Biomembranes ◽

10.1016/j.bbamem.2005.09.012 ◽

2005 ◽

Vol 1717 (1) ◽

pp. 21-26 ◽

Cited By ~ 19

Author(s):

Xiang-Hong Liu ◽

Alptekin Aksan ◽

Michael A. Menze ◽

Steven C. Hand ◽

Mehmet Toner

Keyword(s):

Rat Liver ◽

Desiccation Tolerance ◽

Mitochondrial Permeability Transition Pore ◽

Mitochondrial Permeability Transition ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Liver Mitochondria ◽

Rat Liver Mitochondria ◽

Mitochondrial Permeability

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Ca2+-induced Reactive Oxygen Species Production Promotes CytochromecRelease from Rat Liver Mitochondria via Mitochondrial Permeability Transition (MPT)-dependent and MPT-independent Mechanisms

Journal of Biological Chemistry ◽

10.1074/jbc.m407500200 ◽

2004 ◽

Vol 279 (51) ◽

pp. 53103-53108 ◽

Cited By ~ 115

Author(s):

Giuseppe Petrosillo ◽

Francesca M. Ruggiero ◽

Marilva Pistolese ◽

Giuseppe Paradies

Keyword(s):

Reactive Oxygen Species ◽

Rat Liver ◽

Reactive Oxygen Species Production ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Liver Mitochondria ◽

Rat Liver Mitochondria ◽

Oxygen Species ◽

Mitochondrial Permeability ◽

Species Production

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Toxicity of Evodiae fructus on Rat Liver Mitochondria: The Role of Oxidative Stress and Mitochondrial Permeability Transition

Molecules ◽

10.3390/molecules191221168 ◽

2014 ◽

Vol 19 (12) ◽

pp. 21168-21182 ◽

Cited By ~ 21

Author(s):

Qingyan Cai ◽

Jingjing Wei ◽

Wei Zhao ◽

Si Shi ◽

Yu Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Rat Liver ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Liver Mitochondria ◽

Rat Liver Mitochondria ◽

Mitochondrial Permeability

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Enhanced resistance to Ca2+-induced mitochondrial permeability transition in the long-lived red-footed tortoise Chelonoidis carbonaria

Journal of Experimental Biology ◽

10.1242/jeb.243532 ◽

2021 ◽

Author(s):

Marina R. Sartori ◽

Claudia D.C. Navarro ◽

Roger F. Castilho ◽

Anibal E. Vercesi

Keyword(s):

Rat Liver ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Liver Mitochondria ◽

System Capacity ◽

Rat Liver Mitochondria ◽

Cyclophilin D ◽

Retention Capacity ◽

Mitochondrial Permeability ◽

Enhanced Resistance

The interaction between supraphysiological cytosolic Ca2+ levels and mitochondrial redox imbalance mediates the mitochondrial permeability transition (MPT). MPT is involved in cell death, diseases, and aging. This study compared the liver mitochondrial Ca2+ retention capacity and oxygen consumption in the long-lived red-footed tortoise (Chelonoidis carbonaria) to the rat as a reference standard. Mitochondrial Ca2+ retention capacity, a quantitative measure of MPT sensitivity, was remarkably higher in tortoises than rats. This difference was minimized in the presence of the MPT inhibitors, ADP and cyclosporine A. However, the Ca2+ retention capacities of tortoise and rat liver mitochondria were similar when both MPT inhibitors were present simultaneously. NADH-linked phosphorylating respiration rates of tortoise liver mitochondria represented only 30% of the maximal electron transport system capacity, indicating a limitation imposed by the phosphorylation system. These results suggested underlying differences in putative MPT structural components (e.g. ATP synthase, adenine nucleotide translocase (ANT), and cyclophilin D) between tortoises and rats. Indeed, in tortoise mitochondria, titrations of inhibitors of the oxidative phosphorylation components revealed a higher limitation of ANT. Furthermore, cyclophilin D activity was approximately 70% lower in tortoises than in rats. Investigation of critical properties of mitochondrial redox control that affect MPT demonstrated that tortoise and rat liver mitochondria exhibited similar rates of H2O2 release and glutathione redox status. Overall, our findings suggest that constraints imposed by ANT and cyclophilin D, putative components or regulators of the MPT pore, are associated with the enhanced resistance to Ca2+-induced MPT in tortoises.

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Generation of the mitochondrial permeability transition does not involve inhibition of lysophospholipid acylation. Acyl-coenzyme A:1-acyllysophospholipid acyltransferase activity is not found in rat liver mitochondria.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)54765-7 ◽

1991 ◽

Vol 266 (31) ◽

pp. 20700-20708

Author(s):

K.M. Broekemeier ◽

P.C. Schmid ◽

M.E. Dempsey ◽

D.R. Pfeiffer

Keyword(s):

Rat Liver ◽

Coenzyme A ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Liver Mitochondria ◽

Rat Liver Mitochondria ◽

Acyltransferase Activity ◽

Mitochondrial Permeability ◽

Acyl Coenzyme A

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The Effects of PK11195 and Protoporphyrin IX Can Modulate Chronic Alcohol Intoxication in Rat Liver Mitochondria under the Opening of the Mitochondrial Permeability Transition Pore

Cells ◽

10.3390/cells9081774 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1774

Author(s):

Yulia Baburina ◽

Irina Odinokova ◽

Olga Krestinina

Keyword(s):

Rat Liver ◽

Mitochondrial Permeability Transition Pore ◽

Mitochondrial Permeability Transition ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Alcohol Exposure ◽

Liver Mitochondria ◽

Rat Liver Mitochondria ◽

Chronic Alcohol ◽

Mitochondrial Permeability

Decades of active research have shown that mitochondrial dysfunction, the associated oxidative stress, impaired anti-stress defense mechanisms, and the activation of the proapoptotic signaling pathways underlie pathological changes in organs and tissues. Pathologies caused by alcohol primarily affect the liver. Alcohol abuse is the cause of many liver diseases, such as steatosis, alcoholic steatohepatitis, fibrosis, cirrhosis, and, potentially, hepatocellular cancer. In this study, the effect of chronic alcohol exposure on rat liver mitochondria was investigated. We observed an ethanol-induced increase in sensitivity to calcium, changes in the level of protein kinase Akt and GSK-3β phosphorylation, an induction of the mitochondrial permeability transition pore (mPTP), and strong alterations in the expression of mPTP regulators. Moreover, we also showed an enhanced effect of PK11195 and PPIX, on the parameters of the mPTP opening in rat liver mitochondria (RLM) isolated from ethanol-treated rats compared to the RLM from control rats. We suggest that the results of this study could help elucidate the mechanisms of chronic ethanol action on the mitochondria and contribute to the development of new therapeutic strategies for treating the effects of ethanol-related diseases.

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Fractions of Adenopus breviflorus Extract Modulate Calcium-induced Mitochondrial Permeability Transition Pore Opening in Rat Liver

Annals of Science and Technology ◽

10.2478/ast-2018-0011 ◽

2018 ◽

Vol 3 (1) ◽

pp. 21-27

Author(s):

Tolulope A. Oyedeji ◽

Chibuzor I. Akobi ◽

Daniel O. Onireti ◽

Olufunso O. Olorunsogo

Keyword(s):

Rat Liver ◽

Mitochondrial Permeability Transition Pore ◽

Mitochondrial Permeability Transition ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Rat Liver Mitochondria ◽

Mitochondrial Atpase ◽

Dependent Manner ◽

Mitochondrial Permeability ◽

Pore Opening

AbstractMitochondrial dysfunction (MD) and impaired apoptotic pathways cause irreversible opening of the Mitochondrial Permeability Transition (MPT) pore, resulting in several pathological conditions e.g. cancer, ageing and neurodegenerative diseases. Many bioactive compounds from plants have been identified as modulators of the MPT pore which makes them possible drugs for the management of MD associated diseases. Adenopus breviflorus (A.breviflorus) is a tropical medicinal plant used in folkore medicine as an abortifacient and in treating gonorrhoea. In this study, the effects of ethylacetate and methanol fractions of A.breviflorus were assessed on rat liver MPT pore and Mitochondrial ATPase (mATPase). The fruit of A.breviflorus was extracted with water to obtain the aqueous Extract (AEAB), which was fractionated using vacuum liquid chromatography (VLC) to obtain ethylacetate and methanol fractions of A.breviflorus (EFAB, and MFAB). The extent of MPT pore opening and mATPase by EFAB and MFAB were assayed spectrophotometrically. The results obtained showed that EFAB and MFAB have no significant inductive effect on the MPT pore in the absence of Ca2+. However, in the presence of Ca2+, EFAB inhibited calcium-induced MPT pore opening in a non-concentration dependent manner. Maximum inhibition of MPT pore opening was 57.1% at 50 μg/ml. Interestingly, MFAB potentiated calcium ion effect by opening the pore further. Specifically, MFAB opened the MPT pore by 11, 10, 17 and 9% at 50, 150, 250 and 350 μg/ml, respectively. Furthermore, EFAB and MFAB inhibited mATPase activity in rat liver mitochondria at 62.5, 187.5, 312.5 and 437.5 μg/ml by 2.6, 18.8, 37.3, 52.6% and 41.8, 6.8, 24.3, 8.4%, respectively. The ethylacetate and methanol fractions of Adenopus breviflorus possess potential phytochemicals that can modulate opening of the mitochondrial permeability transition pore and inhibit mitochondrial ATPase activity in rat liver. These fractions may find use in drug development against diseases where excessive apoptosis takes place.

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