Biophysical Society Thematic Meeting| Padova 2019

Quantitative Aspects of Membrane Fusion and Fission

Poster Abstracts

43-POS Board 43 STRUCTURAL BASIS OF DRP1-CARDIOLIPIN INTERACTIONS IN MITOCHONDRIAL FISSION Mukesh Mahajan 1 ; Bin Lu 1 ; Abhishek Mandal 2 ; Nikhil Bharambe 1 ; Rihua Wang 1 ; Matthias Buck 1 ; Patrick van der Wel 2 ; Xin Qi 1 ; Rajesh Ramachandran 1 ; 1 Case Western Reserve university, Physiology & Biophysics, Cleveland, Ohio, USA 2 University of Pittsburgh, Structural Biology, Pittsburgh, Pennsylvania, USA Mitochondria form tubular networks that undergo coordinated cycles of fission and fusion. Emerging evidence suggests that a direct yet unresolved interaction of the mechanoenzymatic GTPase dynamin-related protein 1 (Drp1) with mitochondrial surface-localized cardiolipin (CL) catalyzes mitochondrial fission. Here, using a comprehensive set of structural, biophysical and cell biological tools, we have uncovered a CL-binding motif (CBM) conserved between the Drp1 variable domain (VD) and the unrelated ADP/ATP carrier that intercalates into the hydrocarbon membrane core via a disorder-to-order helical structural transition to likewise effect specific CL acyl chain interactions. Yet, membrane insertion and GTP-dependent conformational rearrangements induce only transient CL nonbilayer topological forays, which favor high local membrane constriction but not fission. A conservative CBM mutation that weakens CL interactions induces ‘donut’ mitochondria formation triggered by impaired Drp1-dependent fission coupled to excessive mitofusin-enabled mitochondrial back-fusion. Our studies, for the first time, firmly establish an indispensable role for Drp1 VD-CL interactions in productive physiological mitochondrial fission.

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