Understanding How Organelle Membranes are Made

Three dimensional rendering of the inside of a cell. Organelles like the nucleus, endoplasmic reticulum, and Golgi bodies are visible.

Eukaryotic cells have membrane-enclosed organelles that feature a unique lipid composition that is critical for their proper functions. While most lipids are synthesized in the endoplasmic reticulum (ER), there is a steady-state enrichment of specific lipids in other organelle membranes. Therefore, lipids must be selectively transported out from the ER to other organelles, but the underlying processes are not well understood. Alterations in organelle membrane lipid composition have also been shown to cause a wide variety of human diseases.

  • In a study from the Balla Lab, researchers found that non-vesicular transfer of a precursor lipid—phosphatidylinositol (PI), which is converted to phosphoinositides (PPIns), a minor lipid class—is essential for multiple functions in eukaryotic cells and for playing critical roles in defining organelle lipid composition.
  • Prior to this work, researchers did not fully understand how Pl, which is synthesized in the ER, reaches membranes where PPIns are formed.
  • The study team used VT01454, a recently identified inhibitor of class I PI transfer proteins (PITPs), to understand their roles in PI distribution and lipid metabolism.
  • They found that class I PITPs not only distribute PI to various organelles for PPIns production, but that their inhibition also significantly changed the levels of many other lipids, including phosphatidylserine and phosphatidic acid, as well as the storage lipid triacylglycerol.
  • Unexpectedly, VT01454 did not affect the levels of some of the PPIns, such as Golgi PI4P or the resting levels of PI(4,5)P2 in the plasma membrane.
  • However, the team found that the maintenance of PI(4,5)P2 levels in the plasma membrane during receptor-stimulation required both class I and class II PITPs.
  • Overall, these findings show that class I PITPs are critically important for regulating some PPIns pools and for establishing the overall cellular lipid landscape.

Reference

Kim YJ, Pemberton JG, Eisenreichova A, Mandal A, Koukalova A, Rohilla P, Sohn M, Konradi AW, Tang TT, Boura E, and Balla T. Non-vesicular phosphatidylinositol transfer plays critical roles in defining organelle lipid composition. EMBO J DOI: 10.1038/s44318-024-00096-3 (2024)

Learn more about the Neurosciences Affinity Group: https://www.nichd.nih.gov/about/org/dir/affinity-groups/neurosciences.

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