Pharmaceutical Sciences Faculty Publications

Title

Mitochondrial Degeneration and Not Apoptosis is the Primary Cause of Embryonic Lethality in Ceramide Transfer Protein Mutant Mice

Document Type

Article

Publication Date

1-12-2009

Journal Title

The Journal of Cell Biology

ISSN

1540-8140

Volume

184

Issue

1

First Page

143

Last Page

158

DOI

10.1083/jcb.200807176

PubMed ID

19139267

PubMed Central® ID

PMC2615084

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.

Keywords

Apoptosis, biological transport, cell cycle, cell proliferation, ceramides, crosses, genetic, embryo, mammalian, embryonic development, endoplasmic reticulum, genotype, heart defects, congenital, mice, mitochondria, mutation, organogenesis, signal transduction

Share

COinS