Disturbed intramitochondrial phosphatidic acid transport impairs cellular stress signaling

J Biol Chem. 2021 Jan-Jun;296:100335. doi: 10.1016/j.jbc.2021.100335. Epub 2021 Jan 23.


Lipid transfer proteins of the Ups1/PRELID1 family facilitate the transport of phospholipids across the intermembrane space of mitochondria in a lipid-specific manner. Heterodimeric complexes of yeast Ups1/Mdm35 or human PRELID1/TRIAP1 shuttle phosphatidic acid (PA) mainly synthesized in the endoplasmic reticulum (ER) to the inner membrane, where it is converted to cardiolipin (CL), the signature phospholipid of mitochondria. Loss of Ups1/PRELID1 proteins impairs the accumulation of CL and broadly affects mitochondrial structure and function. Unexpectedly and unlike yeast cells lacking the CL synthase Crd1, Ups1-deficient yeast cells exhibit glycolytic growth defects, pointing to functions of Ups1-mediated PA transfer beyond CL synthesis. Here, we show that the disturbed intramitochondrial transport of PA in ups1Δ cells leads to altered unfolded protein response (UPR) and mTORC1 signaling, independent of disturbances in CL synthesis. The impaired flux of PA into mitochondria is associated with the increased synthesis of phosphatidylcholine and a reduced phosphatidylethanolamine/phosphatidylcholine ratio in the ER of ups1Δ cells which suppresses the UPR. Moreover, we observed inhibition of target of rapamycin complex 1 (TORC1) signaling in these cells. Activation of either UPR by ER protein stress or of TORC1 signaling by disruption of its negative regulator, the Seh1-associated complex inhibiting TORC1 complex, increased cytosolic protein synthesis, and restored glycolytic growth of ups1Δ cells. These results demonstrate that PA influx into mitochondria is required to preserve ER membrane homeostasis and that its disturbance is associated with impaired glycolytic growth and cellular stress signaling.

Keywords: PRELID1; TORC1; Ups1; endoplasmic reticulum; lipid transfer; mitochondria; phospholipid; unfolded protein response; yeast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mitochondria / metabolism*
  • Phosphatidic Acids / metabolism*
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Signal Transduction*
  • Unfolded Protein Response


  • Phosphatidic Acids
  • Saccharomyces cerevisiae Proteins
  • Mechanistic Target of Rapamycin Complex 1