Ceramide is a Mediator of Apoptosis in Retina Photoreceptors

This article is available online at http://www.jlr.org signals to the visual centers of the brain ( 1 ). The central region is made up of several layers that include the horizontal, bipolar, and amacrine cells, which collectively process visual information from the photoreceptors, transmitting these signals to the ganglion cells. The outermost retinal neurons, the photoreceptors, are responsible for phototransduction ( 2 ). There are two types of photoreceptors, which include rods that are present in the peripheral retina and cones that are present in the central (macular) region of the retina. Rods function in dim light and manage peripheral and night vision, whereas cones are responsible for central high acuity bright light vision. The outermost layer of the retina, the retinal pigment epithelium (RPE), serves many functions, including the isomerization of all-trans retin ol into 11-cis retin al in the visual cycle, phagocytosis and degradation of shed photoreceptor tips, and the phagocytic clearance of cellular debris resulting from apoptotic and necrotic processes ( 3 ).The lipids present in the retina are highly unique and play a critical role in retina function and disease. The retina is a tissue that is highly enriched in PUFAs with DHA (22:6) (22 carbons with 6 double bonds) accounting for approximately 50% of the fatty acids in the photoreceptors ( 4 ). This large amount of DHA results in a highly fl uid membrane that permits effi cient conformational changes to occur in rhodopsin and its associated G-protein during phototransduction ( 5 ). Moreover, DHA is converted into neuroprotectin D1, a potent mediator that evokes counteracting cell-protective anti-infl ammatory pro-survival repair signaling, including the induction of anti-apoptotic proteins and inhibition of pro-apoptotic proteins, activating signaling pathway(s) that modulate(s) pro-apoptotic Abstract MALDI imaging mass spectrometry (IMS) was used to characterize lipid species within sections of human eyes. Common phospholipids that are abundant in most tissues were not highly localized and observed throughout the accessory tissue, optic nerve, and retina. Triacylglycerols were highly localized in accessory tissue, whereas sulfatide and plasmalogen glycerophosphoethanolamine (PE) lipids with a monounsaturated fatty acid were found enriched in the optic nerve. Additionally, several lipids were associated solely with the inner retina, photoreceptors, or retinal pigment epithelium (RPE); a plasmalogen PE lipid containing DHA ( The retina is a light-sensitive multi-layered tissue that lines the back of the eye and is responsible for converting light into a neural signal. The innermost layer of the retina, which is closest to the lens, contains ganglion cells that are the output neurons which comprise the optic nerve and conduct

Section: Discussionmentioning

confidence: 99%

Section: Maldi Imsmentioning

confidence: 99%

Spatial organization of lipids in the human retina and optic nerve by MALDI imaging mass spectrometry

Berry

Gordon

Murphy

et al. 2014

“…The mitochondrial pathway seems also to participate in Cer-induced apoptosis in photoreceptors. C 2 -Cer induces mitochondrial membrane depolarization, which precedes apoptosis in cultured rat photoreceptors; DHA, a photoreceptor trophic factor ( 181,182 ), prevents this depolarization by upregulating Bcl-2 expression, thus rescuing photoreceptors from Cer-and paraquat-induced apoptosis ( 176,183 ) ( Fig. 4 ).…”

Section: Ceramide In the Retinamentioning

confidence: 99%

Regulating survival and development in the retina: key roles for simple sphingolipids

Rotstein

Miranda

Abrahan

et al. 2010

Self Cite

tions as structural membrane components and energetic fuels. However, the fi ndings of the previous half century have extended these roles, shedding light on their indisputable relevance as signaling molecules controlling key aspects of cellular life and development. The identifi cation of diacylglycerol and inositol 1,4,5 triphosphate ( 1 ) as second messengers seemed at the time a peculiarity of these lipids. The subsequent fi ndings of the roles of arachidonic acid metabolites ( 2 ), platelet activating factor ( 3 ), and other minor inositol lipids ( 4 ) in cell signaling began to establish that being intracellular messengers was not an oddity but a habitual task for lipids in cells. The family of lipid signaling molecules largely expanded in the last two decades, when several sphingolipids were successively shown to regulate a multiplicity of cell functions. Sphingosine (Sph) was the fi rst sphingolipid to be established as a bioactive lipid, involved in the regulation of protein kinase (PK)C activity ( 5 ). Ceramide (Cer) and sphingosine-1-phosphate (S1P) were next shown to signal a myriad of cell functions and the number of sphingolipid molecules with bioactive properties has gone on enlarging in recent years ( 6, 7 ).Though a vast literature exists on the functions of sphingolipids in several tissues, less is known concerning its roles in the eye, and in the retina in particular. Accumulation of sphingolipids originated in defects in the lysosomal Abstract Many sphingolipids have key functions in the regulation of crucial cellular processes. Ceramide (Cer) and sphingosine (Sph) induce growth arrest and cell death in multiple situations of cellular stress. On the contrary, sphingosine-1-phosphate (S1P), the product of Sph phosphorylation, promotes proliferation, differentiation, and survival in different cell systems. This review summarizes the roles of these simple sphingolipids in different tissues and then analyzes their possible functions in the retina. Alterations in proliferation, neovascularization, differentiation, and cell death are critical in major retina diseases and collective evidence points to a role for sphingolipids in these processes. Cer induces infl ammation and apoptosis in endothelial and retinal pigmented epithelium cells, leading to several retinopathies. S1P can prevent this death but also promotes cell proliferation that might lead to neovascularization and fibrosis. Recent data support Cer and Sph as crucial mediators in the induction of photoreceptor apoptosis in diverse models of oxidative damage and neurodegeneration, and suggest that regulating their metabolism can prevent this death. New evidence proposes a central role for S1P controlling photoreceptor survival and differentiation. Finally, this review discusses the ability of trophic factors to regulate sphingolipid metabolism and transactivate S1P signaling pathways to control survival and development in retina photoreceptors. When asked about the roles of cellular lipids, the fi rst thought usually coming to our minds re...

“…Cer-induced inhibition of DAG production from PA has been observed. Additionally, Cer has been found to be involved in the activation of photoreceptor apoptosis ( 166 ). Furthermore, it has been suggested that LPP2 and LPP3 play an important role in apoptotic processes.…”

Section: Daglmentioning

confidence: 99%

Lipid second messengers and related enzymes in vertebrate rod outer segments

Giusto

Pasquaré

Salvador

et al. 2010

outer segment of the cell is comprised of a stack of many hundreds of densely packed discs, each of which represents a double layer of infolded plasma membrane. It has been suggested that phospholipid moieties in these membranes are metabolically active and are closely involved in the generation of physiological mediators. Modifi cations in the metabolism of photoreceptor membrane glycerolipids have been linked to the transduction of visual stimuli ( 3 ). Rod outer segment (ROS) membranes are composed of 50% protein and 50% lipid, by weight ( 2 ). Phospholipids and cholesterol represent nearly 90-95% and 4-6% (w/w) of total lipids, respectively. Rhodopsin accounts for at least 80-85% (w/w) of the total proteins ( 4-6 ) in disc ROS membranes. The rest are mainly proteins involved in phototransduction. The composition of mammalian ROS membrane phospholipids indicates that the major phospholipids are phosphatidylethanolamine (PE) and phosphatidylcholine (PC), along with relatively large amounts of phosphatidylserine (PS) (15%). Small amounts (less than 1% each) of sphingomyelin, phosphatidylinositol (PI) and phosphatidic acid (PA) are found in these membranes ( 7-13 ). In vertebrates, cholesterol (exclusively as the free sterol) is the principal neutral lipid, comprising The vertebrate photoreceptor cell is composed of different cellular compartments [outer segment (OS), inner segment (IS), and synaptic terminal (ST)], all of which differ in their lipid and protein content ( 1, 2 ). The photoreceptor is a highly specialized cell that responds to light stimulus and transmits this response to adjoining neurons for ultimate relay to the visual centers of the brain. TheThis work was supported