Role of sphingomyelinase in mitochondrial ceramide accumulation during reperfusion

Abstract

Ceramide accumulation in mitochondria has been associated with reperfusion damage, but the underlying mechanisms are not clearly elucidated. In this work we investigate the role of sphingomyelinases in mitochondrial ceramide accumulation, its effect on reactive oxygen species production, as well as on mitochondrial function by using the sphingomyelinase inhibitor, tricyclodecan-9-yl-xanthogenate (D609). Correlation between neutral sphingomyelinase (nSMase) activity and changes in ceramide content were performed in whole tissue and in isolated mitochondria from reperfused hearts. Overall results demonstrated that D609 treatment attenuates cardiac dysfuncion, mitochondrial injury and oxidative stress. Ceramide was accumulated in mitochondria, but not in the microsomal fraction of the ischemic-reperfused (I/R) group. In close association, the activity of nSMase increased, whereas glutathione (GSH) levels diminished in mitochondria after reperfusion. On the other hand, reduction of ceramide levels in mitochondria from I/R+D609 hearts correlated with diminished nSMase activity, coupling of oxidative phosphorylation and with mitochondrial integrity maintenance. These results suggest that mitochondrial nSMase activity contributes to compartmentation and further accumulation of ceramide in mitochondria, deregulating their function during reperfusion.

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

“…We found that acid (a) SMase was an upstream modulator of ceramide and CLC activation, leading to nephrotoxicity. In the pathogenesis of Wilson disease and heart disease, aSMase and ceramide accumulation have been shown to be involved in apoptosis of various causes (87)(88)(89)(90). Two studies indicated that ceramide, as a downstream product of activated aSMase, is crucially involved in the apoptosis of pulmonary epithelial cells and renal podocytes, indicating that ceramide perhaps not only mediates acute cellular stress but also participates in progressive tissue degeneration (91,92).…”

Advances in determining signaling mechanisms of ceramide and role in disease

“…Ceramides are a known cardiotoxin, contributing to heart disease by inducing cell death and inflammation. Ceramide activates cardiac cell death by accumulating in mitochondria of cardiomyocytes (43), resulting in either the formation of mitochondrial channels or general permeabilization (44). New evidence suggests that CBPs and CRPs may also play a role in cardiac cell death.…”

Ceramide and Ischemia/Reperfusion Injury

“…Diverse oxidative stresses induce cell apoptosis or necrosis and tissue damage via activation of SMases, resulting in sphingomyelin hydrolysis with ceramide generation. The accumulation of ceramide has been reported in multiple models of ischemia, including rat cerebral cortex and gerbil hippocampus ischemia [ 18 , 19 ], as well as in models of reperfusion injury, including artery occlusions in rat brain, liver, and heart [ 20 – 22 ]. In renal and cardiac IR injury models, activation of SMase and accumulation of ceramide were observed in the later phase of IR.…”

“…With their own set of ceramide synthesizing and hydrolyzing enzymes, mitochondria serve as a specialized compartment of ceramide metabolism in cells. For example, SMases in mitochondria have been identified from zebrafish, mouse, and rat [ 20 , 49 , 50 ]. Purified ceramide synthase from bovine liver mitochondria showed higher activity than that from the ER [ 51 ].…”

“…Several lines of evidence indicate that sphingomyelin hydrolysis by SMases is responsible for the ceramide elevation in cardiac IR injury [ 25 , 65 , 66 ]. Pharmacological inhibitors of SMases, such as D609, amitriptyline, and desipramine, as well as the expression of domain-negative FAN, prevented IR-induced accumulation of ceramide and attenuated cardiomyocyte apoptosis and IR heart injury [ 20 , 77 , 86 ]. An interesting study in IR-induced mouse heart injury revealed ceramide elevation and inhibition of SPHK, which led to upregulation of the ceramide/S1P ratio resulting in cardiac tissue damage [ 34 ].…”