Long-chain Ceramide Is a Potent Inhibitor of the Mitochondrial Permeability Transition Pore

Novgorodov, Sergei A.; Gudz, Tatyana I.; Obeid, Lina M.

doi:10.1074/jbc.m801810200

Cited by 38 publications

(28 citation statements)

References 116 publications

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“…While ceramides are generally known to exert growth suppressive and apoptotic functions, C16-ceramide was documented to be antiapoptotic and provide protection against cell death upon ER stress [59]. Similar observations were done in other models attributing anti-apoptotic roles to long chain ceramides [60,61].…”

Section: Dihydrosphingosinesupporting

confidence: 68%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

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Section: Dihydrosphingosinesupporting

confidence: 68%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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“…Although ceramide, among other sphingolipids, is considered to be a major factor regulating respiratory chain activity and mPTP ( 16,17,(19)(20)(21) in type 1 diabetes, the diabetes-induced suppression of respiratory chain activity ( Fig. 10 ) and the decrease in CRC ( Fig.…”

Section: Lactosylceramide Suppresses Mitochondrial Respiration and Dementioning

confidence: 99%

“…Mitochondria contain a variety of sphingolipid species and some of their effects on mitochondrial function are well-documented ( 16 ). For example, ceramide suppresses mitochondrial respiratory chain activity ( 17 ), potentiates insertion of Bax into the outer mitochondrial membrane ( 18 ), and, depending on the conditions, can accelerate or suppress the opening of the mitochondrial permeability transition pore (mPTP) (19)(20)(21) of the inner mitochondrial membrane . Similarly, sphingosine suppresses respiratory chain activity ( 10,22,23 ) and mPTP opening (23)(24)(25).…”

Section: Antibodiesmentioning

confidence: 99%

“…The CRC of mitochondria was monitored using a Ca 2+ -selective electrode (ThermoScientifi c/Orion, Rockford, IL) in a medium containing 250 mM sucrose, 10 mM HEPES, and 2 mM KH 2 PO 4 (pH 7.4) (adjusted with Tris-base) at 25°C, as previously described ( 20,46 ). Mitochondria (0.5 mg/ml) were energized by 10 mM succinate with 1 M rotenone and pulsed with 50 M Ca 2+ every 1.5 min.…”

Section: Crc Of Mitochondriamentioning

confidence: 99%

“…Inner membrane permeabilization was assayed by measurements of the decrease in absorbance of mitochondrial suspension, indicative of mitochondrial swelling, at 520 nm using a Brinkmann PC 910 probe colorimeter and a fi ber optic probe, as we described ( 20 ).…”

Section: Measurement Of Mitochondrial Permeabilizationmentioning

confidence: 99%

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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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Ca2+-dependent nonspecific permeability of the inner membrane of liver mitochondria in the guinea fowl (Numida meleagris)

Vedernikov

Dubinin

Zabiakin

et al. 2015

J Bioenerg Biomembr

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This comparative study presents the results of the induction of Ca(2+)-dependent nonspecific permeability of the inner membrane (pore opening) of rat and guinea fowl liver mitochondria by mechanisms that are both sensitive and insensitive to cyclosporin A (CsA). It was established that energized rat and guinea fowl liver mitochondria incubated with 1 mM of inorganic phosphate (Pi) are capable of swelling upon addition of at least 125 and 875 nmol of CaCl2 per 1 mg protein, respectively. Under these conditions, the Ca(2+) release from the mitochondria of these animals and a drop in Δψ are observed. All of these processes are inhibited by 1 μM of CsA. FCCP, causing organelle de-energization, induces pore opening in rat and guinea fowl liver mitochondria upon addition of 45 и 625 nmol of CaCl2 per 1 mg protein, respectively. These results suggest the existence of a CsA-sensitive mechanism for the induction of Ca(2+)-dependent pores in guinea fowl liver mitochondria, which has been reported in rat liver mitochondria. However, guinea fowl liver mitochondria have a significantly greater resistance to Ca(2+) as a pore inducer compared to rat liver mitochondria. It was found that the addition of α,ω-hexadecanedioic acid (HDA) to rat and guinea fowl liver mitochondria incubated with CsA and loaded with Ca(2+) causes organelle swelling and Ca(2+) release from the matrix. It is assumed that in contrast to the CsA-sensitive pore, the CsA-insensitive pore induced by HDA in the inner membrane of guinea fowl liver mitochondria, as well as in rat liver mitochondria, is lipid in nature.

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Long-chain Ceramide Is a Potent Inhibitor of the Mitochondrial Permeability Transition Pore

Cited by 38 publications

References 116 publications

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Ca2+-dependent nonspecific permeability of the inner membrane of liver mitochondria in the guinea fowl (Numida meleagris)

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