Mitochondrial degeneration and not apoptosis is the primary cause of embryonic lethality in ceramide transfer protein mutant mice

Abstract

Ceramide transfer protein (CERT) functions in the transfer of ceramide from the endoplasmic reticulum (ER) to the Golgi. In this study, we show that CERT is an essential gene for mouse development and embryonic survival and, quite strikingly, is critical for mitochondrial integrity. CERT mutant embryos accumulate ceramide in the ER but also mislocalize ceramide to the mitochondria, compromising their function. Cells in mutant embryos show abnormal dilation of the ER and degenerating mitochondria. These subcellular changes manifest as heart defects and cause severely compromised cardiac function and embryonic death around embryonic day 11.5. In spite of ceramide accumulation, CERT mutant mice do not die as a result of enhanced apoptosis. Instead, cell proliferation is impaired, and expression levels of cell cycle–associated proteins are altered. Individual cells survive, perhaps because cell survival mechanisms are activated. Thus, global compromise of ER and mitochondrial integrity caused by ceramide accumulation in CERT mutant mice primarily affects organogenesis rather than causing cell death via apoptotic pathways.

Ablation of Ceramide Synthase 2 Causes Chronic Oxidative Stress Due to Disruption of the Mitochondrial Respiratory Chain

“…There was considerable controversy concerning the role of SLs in mitochondria function (47), but recent studies measuring SL levels both in isolated mitochondria (48) and on isolation of enzymes of SL metabolism from mitochondria (49 -52) have suggested that SLs are involved in regulation of mitochondrial function. This is supported by the involvement of the mitochondrial pathway in the pathology of a CERT-knock-out mouse (53). Unfortunately, no tools are available to determine the precise subcellular (or suborganellar) localization of long or very long chain ceramides.…”

Diverting CERT-mediated ceramide transport to mitochondria triggers Bax-dependent apoptosis

“…Moreover, ER-like membranes associated with isolated mitochondria appear to produce enough ceramides to allow transient penetration of the outer membrane by pro-apoptotic proteins (Stiban et al, 2008). However, the actual contribution of mitochondrial ceramides to the apoptotic response in living cells is a topic of controversy (Ségui et al, 2006;Wang et al, 2009;Chipuk et al, 2012). Resolving this issue is challenging because ceramides are readily metabolized into various other bioactive lipid species, which can influence the sensitivity of cells to apoptosis through multiple pathways (Hait et al, 2006;Hannun and Obeid, 2008).…”

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

“…In mutants lacking Cer kinase, the resulting Cer accumulation alters phosphatidylinositol biphosphate (PIP 2 ) membrane distribution, leading to loss of phospholipase C activity and consequent failure in phototransduction, accompanied by severe degeneration of photoreceptors; overexpression of ceramidase in these mutants leads to Cer decrease and rescues PLC activity ( 145 ). Mouse embryos lacking Cer transport protein (CERT), which transfers Cer from the ER to the Golgi, accumulate Cer in mitochondria in cells from the optic cup and this accumulation alters mitochondria structure ( 146 ). These results underscore the signifi cance of controlling Cer levels to regulate membrane processes and thus prevent the death of retina photoreceptors.…”