Dynamin-like Proteins Combine Mechano-constriction and Membrane Remodeling to Enable Two-Step Mitochondrial Fission via a "Snap-through" Instability.

Journal: Journal of the American Chemical Society
Published Date: Jul 8, 2025

Abstract

Mitochondrial fission is controlled by dynamin-like proteins, the dysregulation of which is correlated with diverse diseases. Fission dynamin-like proteins are GTP hydrolysis-driven mechanoenzymes that self-oligomerize into helical structures that constrict membranes to achieve fission while also remodeling membranes by inducing negative Gaussian curvature, which is essential for the completion of fission. Despite advances in optical and electron imaging technologies, the underlying mechanics of mitochondrial fission remain unclear due to the multiple times involved in the dynamics of mechanoenzyme activity, oligomer disassembly, and membrane remodeling. Here, we examine how multiscale phenomena in dynamin Drp1 synergistically influence membrane fission using a mechanical model calibrated with small-angle X-ray scattering structural data and informed by a machine learning analysis of the Drp1 sequence, and tested the concept using optogenetic mechanostimulation of mitochondria in live cells. We find that free dynamin-like proteins can trigger a "snap-through instability" that enforces a shape transition from an oligomer-confined cylindrical membrane to a drastically narrower catenoid-shaped neck within the spontaneous hemi-fission regime, in a manner that depends critically on the length of the confined tube. These results indicate how the combination of assembly and paradoxically disassembly of dynamin-like proteins can lead to diverse pathways to scission.

Authors

  • Haleh Alimohamadi
    Department of Bioengineering, University of California, Los Angeles, California 90025, United States.
  • Elizabeth Wei-Chia Luo
    Department of Bioengineering, University of California, Los Angeles, California 90025, United States.
  • Xiaoying Liu
    Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
  • Wasi Iqbal
    Department of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong, Sha Tin, China.
  • Rena Yang
    Department of Bioengineering, University of California, Los Angeles, Los Angeles, California 90025, United States.
  • Shivam Gupta
    Private Dental Practitioner, New Delhi, Delhi, India.
  • Kelsey A Nolden
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
  • Taraknath Mandal
    Department of Physics, Indian Institute of Technology Kanpur, Kanpur 208016, India.
  • R Blake Hill
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
  • Liting Duan
    Department of Biomedical Engineering, The Chinese University of Hong Kong, Sha Tin, Hong Kong 999077, China.
  • Gerard C L Wong
    Department of Bioengineering, Department of Chemistry, California NanoSystems Institute, University of California, Los Angeles, CA 90095, United States.

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