Structural mechanism of mitochondrial membrane remodelling by human OPA1

Alexander Malsburg, Gracie M. Sapp, Kelly E. Zuccaro, Alexander Appen, Frank R. Moss, Raghav Kalia, Jeremy A. Bennett, Luciano A. Abriata, Matteo Dal Peraro, Martin Laan, Adam Frost () and Halil Aydin ()
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Alexander Malsburg: Saarland University Medical School
Gracie M. Sapp: University of Colorado Boulder
Kelly E. Zuccaro: University of Colorado Boulder
Alexander Appen: University of California, San Francisco
Frank R. Moss: University of California, San Francisco
Raghav Kalia: University of California, San Francisco
Jeremy A. Bennett: University of Colorado Boulder
Luciano A. Abriata: École Polytechnique Fédérale de Lausanne
Matteo Dal Peraro: École Polytechnique Fédérale de Lausanne
Martin Laan: Saarland University Medical School
Adam Frost: University of California, San Francisco
Halil Aydin: University of Colorado Boulder

Nature, 2023, vol. 620, issue 7976, 1101-1108

Abstract: Abstract Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate1–3. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane4,5. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.

Date: 2023
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DOI: 10.1038/s41586-023-06441-6

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