Homeostatic response of phospholipid pathways to PCYT2 deficiency and impaired de Novo synthesis of phosphatidylethanolamine

Nov 5, 2025Scientific reports

Body’s balancing response to PCYT2 shortage and reduced new production of a key cell membrane fat

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Abstract

Deficiency in the gene is associated with preserved (PE) levels despite impaired synthesis.

Most studies indicate that phosphatidylethanolamine levels remain unchanged in PCYT2-deficient conditions.
Alternative pathways, including phosphatidylcholine synthesis and phosphatidylserine decarboxylation, do not compensate for reduced PE synthesis in PCYT2-knockdown human fibroblasts.
Chronic choline treatment increases transport of ethanolamine and choline but does not impact phosphatidylethanolamine synthesis.
PE homeostasis appears to be maintained through reduced degradation and extensive remodeling of phospholipids via the Lands' cycle.
Metabolic adaptations lead to increased production of reactive oxygen species and enhanced mitochondrial fusion, without significantly affecting cell viability.

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is the key regulatory enzyme in the biosynthesis of (PE) via the CDP-ethanolamine Kennedy pathway. Deficiencies in this gene have been linked to metabolic, neurological, and cardiac disorders; however, most studies report that PE levels remain unchanged. This study aimed to identify the metabolic mechanisms that preserve PE levels when its synthesis is impaired in PCYT2-knockdown human fibroblasts. We investigated alternative pathways that could compensate for reduced PE synthesis, including phosphatidylcholine (PC) and PE base-exchange to phosphatidylserine (PS), followed by PE resynthesis via PS decarboxylation. These pathways were individually assessed using [14 C]-ethanolamine, [3 H]-choline, and [3 H]-serine, and correlated with the expression and activity of the base-exchange genes PTSS1, PTSS2, and the PS decarboxylase PISD. The base-exchange activity was not significantly altered and mitochondrial PS decarboxylation was inhibited, indicating that these routes do not compensate for reduced PE synthesis in PCYT2-deficient cells. Chronic choline treatment increased ethanolamine and choline transport and upregulated the choline/ethanolamine transporter CTL1, yet PC synthesis and base-exchange activity remained unchanged, demonstrating that choline supplementation does not affect PE sythesis. Instead, PE homeostasis was maintained through reduced degradation and extensive phospholipid remodeling via the Lands' cycle, as evidenced by broad changes in fatty acid composition and increased phospholipid unsaturation. Remodeling extended beyond PC, PE, and PS to include phosphatidylinositol and sphingomyelin. These metabolic adaptations led to elevated reactive oxygen species production and enhanced mitochondrial fusion without significantly affecting autophagy or cell viability. Our findings suggest that in the absence of PCYT2 activity, PE levels are preserved primarily through reduced degradation and remodeling, rather than through alternative biosynthetic pathways.

Key numbers

2.85×

Ethanolamine Uptake Increase

Ethanolamine transport in knockdown cells vs. wild-type cells.

1.45×

Uptake Increase

transport in knockdown cells vs. wild-type cells.

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Homeostatic response of phospholipid pathways to PCYT2 deficiency and impaired de Novo synthesis of phosphatidylethanolamine

Abstract

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