Specific interaction with cardiolipin triggers functional activation of Dynamin-Related Protein 1

PLoS One. 2014 Jul 18;9(7):e102738. doi: 10.1371/journal.pone.0102738. eCollection 2014.


Dynamin-Related Protein 1 (Drp1), a large GTPase of the dynamin superfamily, is required for mitochondrial fission in healthy and apoptotic cells. Drp1 activation is a complex process that involves translocation from the cytosol to the mitochondrial outer membrane (MOM) and assembly into rings/spirals at the MOM, leading to membrane constriction/division. Similar to dynamins, Drp1 contains GTPase (G), bundle signaling element (BSE) and stalk domains. However, instead of the lipid-interacting Pleckstrin Homology (PH) domain present in the dynamins, Drp1 contains the so-called B insert or variable domain that has been suggested to play an important role in Drp1 regulation. Different proteins have been implicated in Drp1 recruitment to the MOM, although how MOM-localized Drp1 acquires its fully functional status remains poorly understood. We found that Drp1 can interact with pure lipid bilayers enriched in the mitochondrion-specific phospholipid cardiolipin (CL). Building on our previous study, we now explore the specificity and functional consequences of this interaction. We show that a four lysine module located within the B insert of Drp1 interacts preferentially with CL over other anionic lipids. This interaction dramatically enhances Drp1 oligomerization and assembly-stimulated GTP hydrolysis. Our results add significantly to a growing body of evidence indicating that CL is an important regulator of many essential mitochondrial functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cardiolipins / metabolism*
  • Cytosol / metabolism
  • Dynamins / metabolism*
  • Escherichia coli / metabolism
  • GTP Phosphohydrolases / metabolism
  • Guanosine Triphosphate / metabolism
  • Lipid Bilayers / metabolism
  • Microtubule-Associated Proteins / metabolism*
  • Mitochondria / metabolism
  • Mitochondrial Dynamics / physiology
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / metabolism*
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Sequence Alignment


  • Cardiolipins
  • Lipid Bilayers
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Guanosine Triphosphate
  • GTP Phosphohydrolases
  • Dynamins

Grants and funding

This work was funded by the Swiss National Science Foundation (31993A-141068/1), IGE3 and the State of Geneva (J.-C.M.), the Spanish Ministerio de Ciencia e Innovación grant BFU2011-28566 and the Basque Government grant IT838-13 (G.B., O.T.). O.T. was supported by a postdoctoral Juan de la Cierva fellow, Spanish Government, and by a FEBS Short-Term fellowship. I.B.-Z. was supported by a predoctoral fellowship from the Basque Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.