Intramitochondrial Transport of Phosphatidic Acid in Yeast by a Lipid Transfer Protein

Abstract

Mitochondrial Lipid Trafficking Disturbances in cellular membrane lipid composition have severe functional consequences and are often associated with disease. How mitochondria—dynamic organelles that constantly fuse and divide—maintain their phospholipid composition and adjust it to physiological needs is unknown. Some phospholipids, like cardiolipin and phosphatidylethanolamine, are synthesized in the mitochondrial inner membrane from precursor molecules that are imported from the endoplasmic reticulum. Connerth et al. (p. 815 ) examined mechanisms determining the accumulation of cardiolipin in yeast mitochondria. A combination of quantitative lipidomics, yeast genetics, ultrastructural studies, and biochemical in vitro assays suggested that the protein Ups1 shuttles the precursor lipid phosphatidic acid between outer and inner mitochondrial membranes. Ups1 mediates lipid transport in complex with another mitochondrial protein, Mdm35, which stabilizes Ups1 in a transport-competent conformation and protects it against proteolysis. High cardiolipin concentrations inhibited the transport of phosphatidic acid by Ups1, which appears to provide a feedback control system that limits the accumulation of cardiolipin in mitochondrial membranes.