Choline restores respiration in Psd1-deficient yeast by replenishing mitochondrial phosphatidylethanolamine.

Content Provider	Europe PMC
Author	Iadarola, Donna M. Joshi, Alaumy Caldwell, Cameron B. Gohil, Vishal M.
Copyright Year	2021
Abstract	Phosphatidylethanolamine (PE) is essential for mitochondrial respiration in yeast, Saccharomyces cerevisiae, whereas the most abundant mitochondrial phospholipid, phosphatidylcholine (PC), is largely dispensable. Surprisingly, choline (Cho), which is a biosynthetic precursor of PC, has been shown to rescue the respiratory growth of mitochondrial PE-deficient yeast; however, the mechanism underlying this rescue has remained unknown. Using a combination of yeast genetics, lipid biochemistry, and cell biological approaches, we uncover the mechanism by showing that Cho rescues mitochondrial respiration by partially replenishing mitochondrial PE levels in yeast cells lacking the mitochondrial PE-biosynthetic enzyme Psd1. This rescue is dependent on the conversion of Cho to PC via the Kennedy pathway as well as on Psd2, an enzyme catalyzing PE biosynthesis in the endosome. Metabolic labeling experiments reveal that in the absence of exogenously supplied Cho, PE biosynthesized via Psd2 is mostly directed to the methylation pathway for PC biosynthesis and is unavailable for replenishing mitochondrial PE in Psd1-deleted cells. In this setting, stimulating the Kennedy pathway for PC biosynthesis by Cho spares Psd2-synthesized PE from the methylation pathway and redirects it to the mitochondria. Cho-mediated elevation in mitochondrial PE is dependent on Vps39, which has been recently implicated in PE trafficking to the mitochondria. Accordingly, epistasis experiments placed Vps39 downstream of Psd2 in Cho-based rescue. Our work, thus, provides a mechanism of Cho-based rescue of mitochondrial PE deficiency and uncovers an intricate interorganelle phospholipid regulatory network that maintains mitochondrial PE homeostasis.
ISSN	00219258
Volume Number	296
PubMed Central reference number	PMC8054189
PubMed reference number	33722607
Journal	The Journal of Biological Chemistry [J. Biol. Chem]
e-ISSN	1083351X
DOI	10.1016/j.jbc.2021.100539
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2021-01-01
Access Restriction	Open
Rights License	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). © 2021 The Authors
Subject Keyword	phospholipid mitochondria phosphatidylethanolamine yeast choline ethanolamine Psd1 Psd2 Vps39 CDP-Etn, CDP–ethanolamine Cho, choline CL, cardiolipin ER, endoplasmic reticulum Etn, ethanolamine MRC, mitochondrial respiratory chain PC, phosphatidylcholine PE, phosphatidylethanolamine PS, phosphatidylserine SC, synthetic complete
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry