Impaired phosphatidylethanolamine metabolism activates a reversible stress response that detects and resolves mutant mitochondrial precursors

Abstract

Phosphatidylethanolamine (PE) made in mitochondria has long been recognized as an important precursor for phosphatidylcholine production that occurs in the endoplasmic reticulum (ER). Recently, the strict mitochondrial localization of the enzyme that makes PE in the mitochondrion, phosphatidylserine decarboxylase 1 (Psd1), was questioned. Since a dual localization of Psd1 to the ER would have far-reaching implications, we initiated our study to independently re-assess the subcellular distribution of Psd1. Our results support the unavoidable conclusion that the vast majority, if not all, of functional Psd1 resides in the mitochondrion. Through our efforts, we discovered that mutant forms of Psd1 that impair a self-processing step needed for it to become functional are dually localized to the ER when expressed in a PE-limiting environment. We conclude that severely impaired cellular PE metabolism provokes an ER-assisted adaptive response that is capable of identifying and resolving nonfunctional mitochondrial precursors.

Molecular species selectivity of lipid transport creates a mitochondrial sink for di‐unsaturated phospholipids

“…The endomembrane system may suffer from a lower PE level or from a shortage of specific PE molecular species that are insufficiently supplied from the mitochondria. The notion that a minimum of PE synthesized in the ER is required for optimal growth is supported by the recent finding that several independent Psd1 constructs that localize exclusively to the mitochondrial inner membrane do rescue the ethanolamine auxotrophy of a psd1Δpsd2Δ mutant in which Dpl1p supplies the CDP‐ethanolamine route with phosphoethanolamine (Sam et al , 2021 ).…”

“…A twist to the longstanding concept of PSD activity residing exclusively outside the ER, came with the recent finding of a dual localization of Psd1p to mitochondria and ER, the distribution depending on metabolic demand (Friedman et al , 2018 ). However, the presence of a functional subpopulation of Psd1 in the ER was not confirmed in an independent re‐evaluation (Sam et al , 2021 ), leaving it under debate.…”

ER-localized phosphatidylethanolamine synthase plays a conserved role in lipid droplet formation

“…Despite this, the ER-localized Psd1 pool is less abundant than mitochondrial Psd1 and is difficult to detect, particularly in nutrient-rich or respiratory-demanding growth conditions ( Friedman et al. , 2018 ; Sam et al. , 2021 ).…”

Dissociation of ERMES clusters plays a key role in attenuating the endoplasmic reticulum stress

“…( Friedman et al., 2018 ). However, most Psd1 was detected as a mitochondria-localized form, whereas only a small amount of ER-localized Psd1 was found in the heavy membranes ( Figure 4 L) ( Sam et al., 2021 ). We also confirmed that amounts of phospholipid synthetic enzymes such as Cho1, Psd1, Cho2, and Opi3 were comparable or increased in the membrane fractions isolated from DTT- or tunicamycin-treated cells compared with those of control membranes ( Figure 4 L).…”