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

¹ Laboratory of Cell and Developmental Signaling, ² Laboratory of Proteomics and Analytical Technologies, and ³ Electron Microscopy Facility, Science Applications International Corporation–Frederick, Inc., and ⁴ Mouse Cancer Genetics Program, National Cancer Institute at Frederick, Frederick, MD 21702
⁵ Marlene Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201
⁶ Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605

Correspondence to Jairaj K. Acharya: acharyaj{at}ncifcrf.gov

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.

Abbreviations used in this paper: CERT, ceramide transfer protein; CPE, ceramide phosphoethanolamine; ERK, extracellular signal-regulated kinase; ES, embryonic stem; ESI, electrospray ionization; LC, liquid chromatography; MEF, mouse embryonic fibroblast; MS, mass spectrometry; PERK, protein kinase–like ER kinase; PDI, protein disulfide isomerase; SRM, single reaction monitor; TEM, transmission EM; UPR, unfolded protein response.

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The Rockefeller University Press

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