Research News
Studies from Dr. Tao Wang’s laboratory discover that mitochondria-ER lipid exchange is required for cell survival and function
Publication Date：2020/11/12
On October 28, 2020, Dr. Tao Wang's laboratory published online a paper titled “PE homeostasis rebalanced through mitochondria-ER lipid exchange prevents retinal degeneration in Drosophila” in PLOS Genetics. This paper reports that PE deficiency cause retinal degeneration in Drosophila. Phosphatidylethanolamine (PE) synthesized in the mitochondria can be exported to the ER through ER-mitochondria contacts to compensate for cellular PE deficiency, thus rescued the retinal degeneration in Drosophila.
PE is a critical component of all cellular membranes, and maintaining cellular PE homeostasis is critical for survival and function of cells. There are two major PE synthesis pathways in eukaryotes, the CDP-ethanolamine pathway in the endoplasmic reticulum (ER) and the PSD pathway in mitochondria. The majority of PE in the cell is synthesized through CDP-ethanolamine pathway in the ER. However, the role played by mitochondrial PE synthesis in maintaining cellular PE homeostasis is unknown.
From a genome-wide genetic screen for genes necessary for photoreceptor cell survival, the authors identified mutations in the gene pect, which encodes phosphoethanolamine cytidylyltransferase (PECT), a rate-limiting enzyme in the CDP-ethanolamine pathway. The pect mutants displayed defective visual responses and light-independent retinal degeneration. Lipidomic analysis revealed that the major phospholipid composition was changed in pect mutants. The relative PC and PI levels were increased, whereas the relative PE and PS levels were decreased. Next, the authors performed genetic manipulation of enzymes involved in the phospholipid metabolism and investigated the contribution of each phospholipid to the mutant phenotypes. Strikingly, when the authors expressed PSD to generate PE from PS in mitochondria, the retinal degeneration in pect mutants was suppressed. PSD expression also partially rescued the visual responses in pect mutants. The lipidomic analysis revealed that expressing PSD fully restored PE levels in pect mutants, which indicate that PE synthesized in mitochondria can transport to the ER when cellular PE levels were deficient. Lipid trafficking between ER and mitochondria occurs at ER-mitochondria contact sites (ERMCS). Disrupting ERMCS prevented PSD overexpression from rescuing the retinal degeneration in pect mutants. These results suggest that ER-mitochondria contacts are required for the export of PE from mitochondria to the ER to maintain cellular PE levels.
In summary, this study demonstrates that PE deficiency caused neuronal cell death, highlights a fundamental function of mitochondria in cellular phospholipid homeostasis and suggests the induction of mitochondrial PE synthesis as a promising therapeutic approach for disorders associated with PE deficiency.
Haifang zhao, a postdoctoral fellow from Dr. Tao Wang’s lab is the first author of this article. Dr. Tao Wang is the corresponding author. The study was supported by the Chinese Ministry of Science and Technology 973 Grants, and was conducted at the National Institute of Biological Sciences, Beijing.
Full text link:
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009070
PE is a critical component of all cellular membranes, and maintaining cellular PE homeostasis is critical for survival and function of cells. There are two major PE synthesis pathways in eukaryotes, the CDP-ethanolamine pathway in the endoplasmic reticulum (ER) and the PSD pathway in mitochondria. The majority of PE in the cell is synthesized through CDP-ethanolamine pathway in the ER. However, the role played by mitochondrial PE synthesis in maintaining cellular PE homeostasis is unknown.
From a genome-wide genetic screen for genes necessary for photoreceptor cell survival, the authors identified mutations in the gene pect, which encodes phosphoethanolamine cytidylyltransferase (PECT), a rate-limiting enzyme in the CDP-ethanolamine pathway. The pect mutants displayed defective visual responses and light-independent retinal degeneration. Lipidomic analysis revealed that the major phospholipid composition was changed in pect mutants. The relative PC and PI levels were increased, whereas the relative PE and PS levels were decreased. Next, the authors performed genetic manipulation of enzymes involved in the phospholipid metabolism and investigated the contribution of each phospholipid to the mutant phenotypes. Strikingly, when the authors expressed PSD to generate PE from PS in mitochondria, the retinal degeneration in pect mutants was suppressed. PSD expression also partially rescued the visual responses in pect mutants. The lipidomic analysis revealed that expressing PSD fully restored PE levels in pect mutants, which indicate that PE synthesized in mitochondria can transport to the ER when cellular PE levels were deficient. Lipid trafficking between ER and mitochondria occurs at ER-mitochondria contact sites (ERMCS). Disrupting ERMCS prevented PSD overexpression from rescuing the retinal degeneration in pect mutants. These results suggest that ER-mitochondria contacts are required for the export of PE from mitochondria to the ER to maintain cellular PE levels.
In summary, this study demonstrates that PE deficiency caused neuronal cell death, highlights a fundamental function of mitochondria in cellular phospholipid homeostasis and suggests the induction of mitochondrial PE synthesis as a promising therapeutic approach for disorders associated with PE deficiency.
Haifang zhao, a postdoctoral fellow from Dr. Tao Wang’s lab is the first author of this article. Dr. Tao Wang is the corresponding author. The study was supported by the Chinese Ministry of Science and Technology 973 Grants, and was conducted at the National Institute of Biological Sciences, Beijing.
Full text link:
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009070
