Characterizing Mitochondrial Phostidylserine Decarboxylase 1

With the ability to synthesize phosphatidic acid, cardiolipin (CL), and phosphatidylethanolamine (PE), the mitochondrion is a major producer of cellular phospholipids. In yeast, there are two enzymes that make PE de novo , one of which, Psd1p, resides in mitochondria. In contrast, mammals only have the mitochondrial pathway for the de novo synthesis of this important cellular phospholipid. Psd1p decarboxylates phosphatidylserine (PS) to form PE. Knowledge about Psd1p is fragmentary. Psd1p is a nuclear encoded protein that is imported into the mitochondrion post‐translationally, where it undergoes proteolytic processing to become an active enzyme. The biogenesis of Psd1p involves three distinct processing events, with the final autocatalytic events generating the active alpha subunit. In my experiments I have shown that two of the processing steps are mediated by the matrix processing peptidase (MPP) and Oct1p. Oct1p is a soluble monomeric metalloprotease localized in the mitochondrial matrix that recognizes and cleaves substrates after initial processing by MPP. Oct1p proteolysis has recently been implicated as an important determinant of protein stability. Interestingly, Psd1p autocatalysis, the final processing step, does not appear to depend on the upstream activity of Oct1p raising the possibility that Oct1p processing is additionally important for Psd1p function. I hypothesize that Oct1p is required for Psd1p activity and/or stability, and in its absence aberrantly processed Psd1p has a reduced half‐life and/or less associated decarboxylase activity. Understanding the biogenesis of Psd1p may uncover potential regulatory steps in Psd1p biogenesis which may be exploited to modulate cellular PE content.