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Molecular mechanism of mitochondrial phosphatidate transfer by Ups1

Jiuwei Lu1,2, Chun Chan3,4, Leiye Yu1,2

  • 1National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.

Communications Biology
|August 27, 2020
PubMed

Insights

The Ups1/Mdm35 protein complex facilitates phosphatidic acid (PA) transfer for cardiolipin synthesis. This study reveals Ups1

Area of Science:

  • Mitochondrial biology
  • Membrane transport
  • Protein-lipid interactions

Background:

  • Cardiolipin is crucial for mitochondrial function and is synthesized in the inner mitochondrial membrane (IMM).
  • Phosphatidic acid (PA) is a precursor to cardiolipin, synthesized in the endoplasmic reticulum and transported to the IMM via the outer mitochondrial membrane (OMM).
  • The Ups1/Mdm35 protein complex mediates PA transfer, but its precise mechanism remains unclear.

Purpose of the Study:

  • To elucidate the detailed mechanism of PA transfer between mitochondrial membranes mediated by the Ups1/Mdm35 complex.
  • To establish a model for Ups1/Mdm35-membrane interactions.

Main Methods:

  • Crystallographic data analysis
  • All-atom molecular dynamics simulations
  • Structural comparisons
  • Biophysical assays

Main Results:

  • Identified specific regions of Ups1 (α2-loop, L2-loop, α3 helix) involved in membrane interaction.
  • Proposed non-complexed Ups1 on membranes as a key transition state for PA transfer.
  • Demonstrated an inverse correlation between the ratio of membrane-bound non-complexed Ups1 to membrane-bound Ups1 and PA transfer activity, regulated by pH.

Conclusions:

  • Established a novel model for the conformational changes of Ups1/Mdm35 during PA transfer.
  • Highlighted the role of membrane-bound non-complexed Ups1 as a critical intermediate in the transfer process.
  • Indicated that environmental pH can modulate Ups1/Mdm35-mediated PA transfer activity.

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