Coincident Phosphatidic Acid Interaction Restrains Drp1 in Mitochondrial Division

Mol Cell. 2016 Sep 15;63(6):1034-43. doi: 10.1016/j.molcel.2016.08.013.

Abstract

Mitochondria divide to control their size, distribution, turnover, and function. Dynamin-related protein 1 (Drp1) is a critical mechanochemical GTPase that drives constriction during mitochondrial division. It is generally believed that mitochondrial division is regulated during recruitment of Drp1 to mitochondria and its oligomerization into a division apparatus. Here, we report an unforeseen mechanism that regulates mitochondrial division by coincident interactions of Drp1 with the head group and acyl chains of phospholipids. Drp1 recognizes the head group of phosphatidic acid (PA) and two saturated acyl chains of another phospholipid by penetrating into the hydrophobic core of the membrane. The dual phospholipid interactions restrain Drp1 via inhibition of oligomerization-stimulated GTP hydrolysis that promotes membrane constriction. Moreover, a PA-producing phospholipase, MitoPLD, binds Drp1, creating a PA-rich microenvironment in the vicinity of a division apparatus. Thus, PA controls the activation of Drp1 after the formation of the division apparatus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Dynamins / genetics*
  • Dynamins / metabolism
  • Fibroblasts / metabolism
  • Fibroblasts / ultrastructure
  • Gene Expression Regulation
  • Guanosine Triphosphate / metabolism
  • Male
  • Mice
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitochondrial Dynamics / genetics*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Membranes / ultrastructure
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Phosphatidic Acids / metabolism*
  • Phospholipase D / genetics*
  • Phospholipase D / metabolism
  • Protein Binding
  • Signal Transduction
  • Stearoyl-CoA Desaturase / genetics
  • Stearoyl-CoA Desaturase / metabolism
  • Testis / metabolism*
  • Testis / ultrastructure

Substances

  • Mitochondrial Proteins
  • Phosphatidic Acids
  • Guanosine Triphosphate
  • Scd1 protein, mouse
  • Stearoyl-CoA Desaturase
  • Phospholipase D
  • mitoPLD protein, mouse
  • Dnm1l protein, mouse
  • Dynamins