TNF-α-induced mitochondrial oxidative stress and cardiac dysfunction: restoration by superoxide dismutase mimetic Tempol

2007 ◽  
Vol 293 (5) ◽  
pp. H2726-H2737 ◽  
Author(s):  
Nithya Mariappan ◽  
Rajasekaran Namakkal Soorappan ◽  
Masudul Haque ◽  
Srinivas Sriramula ◽  
Joseph Francis
Keyword(s):  
Oxidative Stress ◽  
Cardiac Function ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Adenine Nucleotide ◽  
Redox Homeostasis ◽  
Anion Channel ◽  
Permeability Transition ◽  
Voltage Dependent Anion Channel ◽  
Tnf Α

Mitochondria are indispensable for bioenergetics and for the regulation of physiological/signaling events in cellular life. Although TNF-α-induced oxidative stress and mitochondrial dysfunction are evident in several pathophysiological states, the molecular mechanisms coupled with impaired cardiac function and its potential reversal by drugs such as Tempol or apocyanin have not yet been explored. Here, we hypothesize that TNF-α-induced oxidative stress compromises cardiac function by altering the mitochondrial redox state and the membrane permeability transition pore (MPTP) opening, thereby causing mitochondrial dysfunction. We measured the redox states in the cytosol and mitochondria of the heart to understand the mechanisms related to the MPTP and the antioxidant defense system. Our studies demonstrate that TNF-α-induced oxidative stress alters redox homeostasis by impairing the MPTP proteins adenine nucleotide translocator and voltage-dependent anion channel, thereby resulting in the pore opening, causing uncontrolled transport of substances to alter mitochondrial pH, and subsequently leading to dysfunction of mitochondria and attenuated cardiac function. Interestingly, we show that the supplementation of Tempol along with TNF-α restores mitochondrial and cardiac function.

The mitochondrial permeability transition pore

1999 ◽  
Vol 66 ◽  
pp. 167-179 ◽  
Author(s):  
Martin Crompton ◽  
Sukaina Virji ◽  
Veronica Doyle ◽  
Nicholas Johnson ◽  
John M. Ward
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Anion Channel ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocase ◽  
Voltage Dependent Anion Channel ◽  
Inner Membrane ◽  
Membrane Pore ◽  
Voltage Dependent

This chapter reviews recent advances in the identification of the structural elements of the permeability transition pore. The discovery that cyclosporin A (CsA) inhibits the pore proved instrumental. Various approaches indicate that CsA blocks the pore by binding to cyclophilin (CyP)-D. In particular, covalent labelling of CyP-D in situ by a photoactive CsA derivative has shown that pore ligands have the same effects on the degree to which CsA both blocks the pore and binds to CyP-D. The recognition that CyP-D is a key component has enabled the other constituents to be resolved. Use of a CyP-D fusion protein as affinity matrix has revealed that CyP-D binds very strongly to 1:1 complexes of the voltage-dependent anion channel (from the outer membrane) and adenine nucleotide translocase (inner membrane). Our current model envisages that the pore arises as a complex between these three components at contact sites between the mitochondrial inner and outer membranes. This is in line with recent reconstitutions of pore activity from protein fractions containing these proteins. The strength of interaction between these proteins suggests that it may be a permanent feature rather than assembled only under pathological conditions. Calcium, the key activator of the pore, does not appear to affect pore assembly; rather, an allosteric action allowing pore flicker into an open state is indicated. CsA inhibits pore flicker and lowers the binding affinity for calcium. Whether adenine nucleotide translocase or the voltage-dependent anion channel (via inner membrane insertion) provides the inner membrane pore has not been settled, and data relevant to this issue are also documented.

scholarly journals Purified F-ATP synthase forms a Ca2+-dependent high-conductance channel matching the mitochondrial permeability transition pore

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Andrea Urbani ◽  
Valentina Giorgio ◽  
Andrea Carrer ◽  
Cinzia Franchin ◽  
Giorgio Arrigoni ◽  
...  
Keyword(s):  
Lipid Bilayers ◽  
Atp Synthase ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Adenine Nucleotides ◽  
Permeability Transition Pore ◽  
Anion Channel ◽  
Permeability Transition ◽  
Channel Activity ◽  
Voltage Dependent Anion Channel

Abstract The molecular identity of the mitochondrial megachannel (MMC)/permeability transition pore (PTP), a key effector of cell death, remains controversial. By combining highly purified, fully active bovine F-ATP synthase with preformed liposomes we show that Ca2+ dissipates the H+ gradient generated by ATP hydrolysis. After incorporation of the same preparation into planar lipid bilayers Ca2+ elicits currents matching those of the MMC/PTP. Currents were fully reversible, were stabilized by benzodiazepine 423, a ligand of the OSCP subunit of F-ATP synthase that activates the MMC/PTP, and were inhibited by Mg2+ and adenine nucleotides, which also inhibit the PTP. Channel activity was insensitive to inhibitors of the adenine nucleotide translocase (ANT) and of the voltage-dependent anion channel (VDAC). Native gel-purified oligomers and dimers, but not monomers, gave rise to channel activity. These findings resolve the long-standing mystery of the MMC/PTP and demonstrate that Ca2+ can transform the energy-conserving F-ATP synthase into an energy-dissipating device.

scholarly journals Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system

2011 ◽  
Vol 31 (5) ◽  
pp. 429-437 ◽  
Author(s):  
Jie Cui ◽  
Mei Yu ◽  
Jingwen Niu ◽  
Zhenyu Yue ◽  
Zhiheng Xu
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Neuronal Apoptosis ◽  
Adenine Nucleotide ◽  
Anion Channel ◽  
Permeability Transition ◽  
Underlying Mechanism ◽  
Mutant Form ◽  
Leucine Rich Repeat ◽  
Voltage Dependent Anion Channel

PD (Parkinson's disease) is the most common neurodegenerative movement disorder. Mutations in LRRK2 (leucine-rich repeat kinase 2) gene are linked to the most common inherited and sporadic PD. Overexpression of LRRK2 and its mutants could induce mitochondrial-dependent neuronal apoptosis. However, the underlying mechanism remains elusive. We have identified several novel LRRK2 interacting proteins and showed that LRRK2 can interact with three components of the PTPC (permeability transition pore complex) including ANT (adenine nucleotide translocator), VDAC (voltage-dependent anion channel) and uMtCK [ubiquitous MtCK (mitochondrial creatine kinase)]. Those components have been reported to be involved in the permeability of mitochondrial membrane. We provide evidence that LRRK2 is likely to interact with uMtCK directly and expression of LRRK2 and its mutant form can suppress the processing of the immature form of uMtCK. LRRK2 expression keeps the uMtCK preprotein on the outer mitochondrial membrane instead of entering the mitochondria. In addition, the expression of both wild-type and mutant forms of LRRK2 promotes the interaction between ANT and VDAC, which plays a role in permeabilization transition pore opening. Finally, LRRK2-induced cell death can be suppressed by uMtCK. Our findings imply that LRRK2 can interact directly with uMtCK to block its entry into mitochondria and its subsequent processing, resulting in inhibition of mitochondrial energy channelling. Meanwhile, the decrease of uMtCK in mitochondria results in elevated interaction between ANT and VDAC and leads to neuronal apoptosis. Thus, our study provides the rational for clinical trials using creatine to treat PD and supports the notion of exploiting LRRK2 as a drug target for PD.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

Bcl-2 Family of Proteins: Life-or-Death Switch in Mitochondria

2002 ◽  
Vol 22 (1) ◽  
pp. 47-58 ◽  
Author(s):  
Yoshihide Tsujimoto
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Apoptotic Cell ◽  
Regulatory Protein ◽  
Family Members ◽  
Anion Channel ◽  
Permeability Transition ◽  
Outer Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
Membrane Barrier

An increase in the permeability of outer mitochondrial membrane is central to apoptotic cell death, and results in the release of several apoptogenic factors such as cytochrome c into the cytoplasm to activate downstream destructive programs. The voltage-dependent anion channel (VDAC or mitochondrial porin) plays an essential role in disrupting the mitochondrial membrane barrier and is regulated directly by members of the Bcl-2 family proteins. Anti-apoptotic Bcl-2 family members interact with and close the VDAC, whereas some, but not all, proapoptotic members interact with VDAC to open protein-conducting pore through which apoptogenic factors pass. Although the VDAC is involved directly in breaking the mitochondrial membrane barrier and is a known component of the permeability transition pore complex, VDAC-dependent increase in outer membrane permeability can be independent of the permeability transition event such as mitochondrial swelling followed by rupture of the outer mitochondrial membrane. VDAC interacts not only with Bcl-2 family members but also with proteins such as gelsolin, an actin regulatory protein, and appears to be a convergence point for a variety of cell survival and cell death signals.

scholarly journals Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis

2004 ◽  
Vol 383 (1) ◽  
pp. 101-109 ◽  
Author(s):  
Yanmin LI ◽  
Nicholas JOHNSON ◽  
Michela CAPANO ◽  
Mina EDWARDS ◽  
Martin CROMPTON
Keyword(s):  
Oxidative Stress ◽  
Cell Injury ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Intact Cells ◽  
Inner Membrane ◽  
Mitochondrial Permeability ◽  
Apoptosis And Necrosis

Cyclophilin-D is a peptidylprolyl cis–trans isomerase of the mitochondrial matrix. It is involved in mitochondrial permeability transition, in which the adenine nucleotide translocase of the inner membrane is transformed from an antiporter to a non-selective pore. The permeability transition has been widely considered as a mechanism in both apoptosis and necrosis. The present study examines the effects of cyclophilin-D on the permeability transition and lethal cell injury, using a neuronal (B50) cell line stably overexpressing cyclophilin-D in mitochondria. Cyclophilin-D overexpression rendered isolated mitochondria far more susceptible to the permeability transition induced by Ca2+ and oxidative stress. Similarly, cyclophilin-D overexpression brought forward the onset of the permeability transition in intact cells subjected to oxidative stress. In addition, in the absence of stress, the mitochondria of cells overexpressing cyclophilin-D maintained a lower inner-membrane potential than those of normal cells. All these effects of cyclophilin-D overexpression were abolished by cyclosporin A. It is concluded that cyclophilin-D promotes the permeability transition in B50 cells. However, cyclophilin-D overexpression had opposite effects on apoptosis and necrosis; whereas NO-induced necrosis was promoted, NO- and staurosporine-induced apoptosis were inhibited. These findings indicate that the permeability transition leads to cell necrosis, but argue against its involvement in apoptosis.

Abstract P237: Exercise Training Prevents Hypercholesterolemia-Induced Cardiac Mitochondrial Dysfunction

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Allison M McGee ◽  
Kyle S McCommis ◽  
M H Laughlin ◽  
Douglas K Bowles ◽  
Christopher P Baines
Keyword(s):  
Oxidative Stress ◽  
Exercise Training ◽  
Manganese Superoxide Dismutase ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Exercise Group ◽  
Ros Generation ◽  
Cyclophilin D ◽  
Negative Effects

Hypercholesterolemia has been suggested to have direct negative effects on myocardial function due to increased reactive oxygen species (ROS) generation and increased myocyte death. Mitochondrial permeability transition (MPT) is a significant mediator of cell death, which is enhanced by ROS generation and attenuated by exercise training. The purpose of this study was to investigate the effect of hypercholesterolemia on the MPT response of cardiac mitochondria. We hypothesized that familial hypercholesterolemic (FH) pigs would have an enhanced MPT response, and that exercise training could reverse this phenotype. FH pigs were obtained from the University of Wisconsin. Control, normolipidemic farm pigs were maintained on standard pig chow. After 4 months on a high-fat diet, the FH pigs were switched to the standard pig chow, and randomized to sedentary or exercise groups. The exercise group underwent a progressive treadmill-based training program for 4 months. At the end of the training protocol the animals were sacrificed and the heart removed. MPT was assessed by mitochondrial swelling in response to Ca2+. Protein nitrotyrosylation, GSH levels, and antioxidant enzyme expression were also examined. FH pigs did show an increased MPT response despite no change in the expression of putative MPT pore components adenine nucleotide translocase (ANT), mitochondrial phosphate carrier (PiC), and cyclophilin-D (CypD). FH also caused increased oxidative stress, depicted by increased protein nitrotyrosylation and decreased GSH levels. This was associated with concomitant decreases in the expression of mitochondrial antioxidant enzymes manganese superoxide dismutase (MnSOD) and thioredoxin-2 (Trx2). However, chronic exercise training was able to normalize the MPT response in FH pigs, reduce oxidative stress, and increase MnSOD expression. We conclude that hypercholesterolemia causes increased oxidative stress and enhances the MPT response in the porcine myocardium, and that exercise training can correct for both the increased oxidative stress and MPT alterations observed with hypercholesterolemia.

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