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Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps
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DOI：10.1016/j.jlr.2026.101083.png)
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Abstract
En 中文
The distinct compositions of the two mitochondrial membranes are generated through a combination of phospholipids that mitochondria can make and those they take; both processes depend on a series of distinct lipid trafficking steps. Mitochondria make phosphatidylethanolamine (PE) through the action of the phosphatidylserine decarboxylase Psd1, an intermembrane space (IMS)-facing integral inner membrane (IM) protein. Psd1 has been proposed to act on its endoplasmic reticulum-derived substrate, phosphatidylserine (PS), after its transport to the mitochondrial outer membrane (OM) and either following its Ups2/Mdm35-mediated transport across the IMS to the IM or instead, on the IMS-side of the OM in a process enabled by the mitochondrial contact site and cristae organizing system (MICOS). Here, we implement a two-pronged Psd1 rewiring-based strategy predicted to either 1) circumvent the need for Ups2/Mdm35 and/or MICOS; or 2) selectively ablate the ability of Psd1 to work in trans. Our results with yeast harboring Psd1 targeted to the OM demonstrate that, with respect to mitochondrial PE production, Ups2/Mdm35 and MICOS indeed function within the IMS. Using yeast expressing a topologically inverted Psd1 chimera that faces the matrix, we identify previously unappreciated transbilayer lipid trafficking steps within the IM and show that Psd1 does not operate via a MICOS-organized in trans mechanism. Further, retained flux through inverted Psd1 when both Ups2/Mdm35 and MICOS are absent strongly implicates the existence of a major, yet presently unknown, mediator(s) of lipid movement across the IMS. Collectively, these data suggest a new model of how mitochondrial membrane diversity is established and maintained.
Keywords:
Glycerophospholipids
mitochondria
phospholipids
phospholipids/biosynthesis
phospholipids/metabolism
phospholipids/trafficking
membrane diversity
metabolic rewiring
CL
cardiolipin
ER
endoplasmic reticulum
IM
inner membrane
IMS
intermembrane space
Inv-Psd1
inverted Psd1
MICOS
mitochondrial contact site and cristae organizing system
MP
OM-ruptured mitoplasts
OM
outer membrane
PC
phosphatidylcholine
PE
phosphatidylethanolamine
PS
phosphatidylserine
Psd1
phosphatidylserine decarboxylase 1
SAM
Sorting and Assembly Machinery
SD
synthetic defined dextrose media
SDLac
synthetic defined lactate media
TOM
Translocase of the Outer Membrane
Journal
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5.8K
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2.4W
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