Specific Interaction with Cardiolipin Triggers Functional Activation of Dynamin-Related Protein 1

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. 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 Innovacion 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.