Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin‐induced diabetic rats

Oliveira, Paulo J.; Seiça, Raquel; Coxito, Pedro; Rolo, Anabela P.; Palmeira, Carlos M.; Santos, Maria S.; Moreno, António J.

doi:10.1016/s0014-5793(03)01233-x

Cited by 76 publications

(69 citation statements)

References 19 publications

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“…Indeed, MPTP opening has been demonstrated in HF induced by myocardial infarction in rats (Javadov et al, 2005) and intracoronary microembolizations in dogs (Sharov et al, 2007), as well as in Ca 2ϩ -induced cardiomyopathy (Nakayama et al, 2007) and diabetic cardiomyopathy (Oliveira et al, 2003). Notably, our studies have demonstrated that the extent of MPTP opening in failing hearts 12 and 18 weeks after coronary artery ligation (Javadov et al, 2005) is lower than that found following acute IR (Griffiths and Halestrap, 1995;Kerr et al, 1999;Javadov et al, 2003).…”

Section: Heart Failurementioning

confidence: 51%

Mitochondrial Permeability Transition Pore Opening as a Promising Therapeutic Target in Cardiac Diseases

Javadov¹,

Karmazyn²,

Escobales³

2009

J Pharmacol Exp Ther

215

166

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In addition to their central role in ATP synthesis, mitochondria play a critical role in cell death. Oxidative stress accompanied by calcium overload, ATP depletion, and elevated phosphate levels induces mitochondrial permeability transition (MPT) with formation of nonspecific MPT pores (MPTP) in the inner mitochondrial membrane. Pore opening results in mitochondrial dysfunction with uncoupled oxidative phosphorylation and ATP hydrolysis, ultimately leading to cell death. For the past 20 years, three proteins have been accepted as key structural components of the MPTP: adenine nucleotide translocase (ANT) in the inner membrane, cyclophilin D (CyP-D) in the matrix, and the voltage-dependent anion channel (VDAC) in the outer membrane. However, most recent studies have questioned the molecular identity of the pores. Genetic studies have eliminated the VDAC as an essential component of MPTP and attributed a regulatory (rather than structural) role to ANT. Currently, the phosphate carrier appears to play a crucial role in MPTP formation. MPTP opening has been examined extensively in cardiac pathological conditions, including ischemia/ reperfusion as well as heart failure. Accordingly, MPTP is accepted as a therapeutic target for both pharmacological and conditional strategies to block pore formation by direct interaction with MPTP components or indirectly by decreasing MPTP inducers. Inhibition of MPTP opening by reduction of CyP-D activity by nonimmunosuppressive analogs of cyclosporine A or sanglifehrin A, as well as attenuation of reactive oxygen species accumulation through mitochondria-targeted antioxidants, is the most promising. This review outlines our current knowledge of the structure and function of the MPTP and describes possible approaches for cardioprotection.Mitochondria play an important role as ATP producers and as regulators of cell death, which make them essential for cell survival. In the heart, mitochondria occupy approximately 30% of cardiomyocyte volume and provide more than 90% ATP necessary for cardiac function. One of the key factors regulating mitochondrial function and ATP synthesis is the mitochondrial Ca 2ϩ concentration. Cardiomyocyte Ca 2ϩ homeostasis is altered under pathological conditions, such as ischemia and heart failure (HF), due to decreased ATP levels resulting from inadequate oxygen consumption. Furthermore, dysfunction of the electron transport chain, particularly during reperfusion, results in increased generation of ROS. Calcium overload and oxidative stress combine with other factors, including high phosphate and low adenine nucleotide concentrations to induce the formation of nonspecific mitochondrial permeability transition pores (MPTP) in the inner mitochondrial membrane (Bernardi et al., 1992;Crompton, 1999;Halestrap et al., 2004). Opening of MPTP causes uncoupling of the mitochondria and swelling of the matrix leading to rupture of the outer mitochondrial membrane and ultimately cell death. In recent years, MPTP openThis work was supported by the Canadian Ins...

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Section: Heart Failurementioning

confidence: 51%

Mitochondrial Permeability Transition Pore Opening as a Promising Therapeutic Target in Cardiac Diseases

Javadov¹,

Karmazyn²,

Escobales³

2009

J Pharmacol Exp Ther

215

166

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“…Mitochondrial dysfunction in type 1 diabetic heart tissue is the result of inhibition of the respiratory chain (33)(34)(35), oxidative stress ( 35,36 ), and decreased resistance to Ca 2+ - ( 37,38 ) and oxidative stressinduced mPTP opening ( 39,40 ).…”

Section: Antibodiesmentioning

confidence: 99%

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov

Riley

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgCompelling epidemiological and clinical data indicate that diabetes mellitus increases the risk for cardiac dysfunction and heart failure independently of other risk factors, such as coronary disease and hypertension. Lipotoxicity is an important contributor to cardiac dysfunction in both type 1 ( 1, 2 ) and type 2 ( 3-6 ) diabetes, which are characterized by excessive accumulation of triacylglycerols, long-chain acyl-CoAs, diacylglycerols, and ceramides in myocardium. Correlation of the increased ceramide level with development of diabetic cardiomyopathy has attracted special attention in recent years because of the well-documented ability of this sphingolipid to regulate a number of cell processes, including cell proliferation, growth arrest, differentiation and apoptosis, and the mediation of responses to stress stimuli .Ceramide is a hub of sphingolipid metabolism ( 7,8 ). The balance between ceramide-producing pathways and pathways that consume it dictates ceramide level in the cell. The de novo ceramide biosynthesis pathway, one of the major ceramide producing pathways, localizes in the endoplasmic reticulum (ER) and starts with the condensation of serine and palmitoyl-CoA producing 3-ketosphingonine, which, in turn, is rapidly converted to dihydrosphingosine. Subsequent acylation of dihydrosphingosine by a set of (dihydro)ceramide synthases (CerSs) gives rise to dihydroceramide. Finally, the removal of two hydrogens from the fatty acid chain of dihydroceramide by desaturase leads to the formation of ceramide. Other possible contributors to elevated ceramide level are: hydrolysis of SM catalyzed by SMases, Abstract Sphingolipids have been implicated as key mediators of cell-stress responses and effectors of mitochondrial function. To investigate potential mechanisms underlying mitochondrial dysfunction, an important contributor to diabetic cardiomyopathy, we examined alterations of cardiac sphingolipid metabolism in a mouse with streptozotocininduced type 1 diabetes. Diabetes increased expression of desaturase 1, (dihydro)ceramide synthase (CerS)2, serine palmitoyl transferase 1, and the rate of ceramide formation by mitochondria-resident CerSs, indicating an activation of ceramide biosynthesis. However, the lack of an increase in mitochondrial ceramide suggests concomitant upregulation of ceramide-metabolizing pathways. Elevated levels of lactosylceramide, one of the initial products in the formation of glycosphingolipids were accompanied with decreased respiration and calcium retention capacity (CRC) in mitochondria from diabetic heart tissue. In baseline mitochondria, lactosylceramide potently suppressed state 3 respiration and decreased CRC, suggesting lactosylceramide as the primary sphingolipid responsible for mitochondrial defects in diabetic hearts. Moreover, knocking down the neutral ceramidase (NCDase) resulted in an increase in lactosylceramide level, suggesting a crosstalk between glucosylceramide synthase-and NCDase-mediated ceramide utiliz...

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“…Several mitochondrial alterations have been described during the progress of diabetes mellitus, including respiratory alterations and altered induction of the MPT (reviewed in (Oliveira, 2005)). Besides the heart (Oliveira, Rolo et al, 2001;Oliveira, Seica et al, 2003;Santos, Palmeira et al, 2003;Bugger & Abel, 2011), alterations of mitochondrial function have been recorded in liver , kidney (Oliveira, Esteves et al, 2004), brain (Moreira, Santos et al, 2004) and testis mitochondria Amaral, Oliveira et al, 2008;Amaral, Mota et al, 2009), which show a multi-organ scope of hyperglycaemia-induced mitochondrial alterations. Oliveira et al demonstrated that streptozotocin (STZ)-induced diabetes results in inhibition of cardiac mitochondrial respiration and increased susceptibility to calcium-induced MPT .…”

Section: Diabetesmentioning

confidence: 99%