PE homeostasis rebalanced through mitochondria-ER lipid exchange prevents retinal degeneration in Drosophila

PLoS Genet. 2020 Oct 16;16(10):e1009070. doi: 10.1371/journal.pgen.1009070. eCollection 2020 Oct.

Abstract

The major glycerophospholipid phosphatidylethanolamine (PE) in the nervous system is essential for neural development and function. There are two major PE synthesis pathways, the CDP-ethanolamine pathway in the endoplasmic reticulum (ER) and the phosphatidylserine decarboxylase (PSD) pathway in mitochondria. However, the role played by mitochondrial PE synthesis in maintaining cellular PE homeostasis is unknown. Here, we show that Drosophila pect (phosphoethanolamine cytidylyltransferase) mutants lacking the CDP-ethanolamine pathway, exhibited alterations in phospholipid composition, defective phototransduction, and retinal degeneration. Induction of the PSD pathway fully restored levels and composition of cellular PE, thus rescued the retinal degeneration and defective visual responses in pect mutants. Disrupting lipid exchange between mitochondria and ER blocked the ability of PSD to rescue pect mutant phenotypes. These findings provide direct evidence that the synthesis of PE in mitochondria contributes to cellular PE homeostasis, and suggest the induction of mitochondrial PE synthesis as a promising therapeutic approach for disorders associated with PE deficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxy-Lyases / genetics*
  • Carboxy-Lyases / metabolism
  • Cytidine Diphosphate / analogs & derivatives*
  • Cytidine Diphosphate / deficiency
  • Cytidine Diphosphate / genetics
  • Cytidine Diphosphate / metabolism
  • Disease Models, Animal
  • Drosophila melanogaster / genetics
  • Endoplasmic Reticulum / genetics*
  • Endoplasmic Reticulum / metabolism
  • Ethanolamines / metabolism
  • Homeostasis / genetics
  • Humans
  • Lipid Metabolism / genetics
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Phosphatidylserines / genetics
  • Phosphatidylserines / metabolism
  • Retinal Degeneration / genetics*
  • Retinal Degeneration / metabolism
  • Retinal Degeneration / pathology
  • Signal Transduction / genetics

Substances

  • Ethanolamines
  • Phosphatidylserines
  • CDP ethanolamine
  • Cytidine Diphosphate
  • Carboxy-Lyases
  • phosphatidylserine decarboxylase

Grants and funding

T. W. was supported by grants 81670891 and 81870693 from the National Natural Science Foundation of China (NNSFC). http://www.nsfc.gov.cn/ The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.