Biophysical Society Thematic Meeting| Padova 2019

Quantitative Aspects of Membrane Fusion and Fission

Poster Abstracts

1-POS Board 1 GEOMETRIC INSTABILITY CATALYZES MITOCHONDRIAL FISSION Ehsan Irajizad 1 ; Rajesh Ramachandran 2 ; Ashutosh Agrawal 1 ; 1 University of Houston, Mechanical Engineering, Houston, Texas, USA 2 Case Western Reserve University, Department of Physiology and Biophysics, Cleveland, Ohio, USA In eukaryotic cells, tubular mitochondria form intricate networks and undergo incessant fission and fusion. While balanced mitochondrial dynamics is believed to be essential for apoptosis, disrupted dynamics is linked to lung cancer, cardiac dysfunction and neurogenerative disorders. Pioneering experimental studies have provided insights into the molecular machinery that executes mitochondrial constriction and fission. The fission pathway is characterized by three key steps: i) the initial constriction carried out by actin polymerization and actomyosin contraction, ii) the intermediate constriction executed by Drp1, and iii) the final fission carried out by dynamin.While the membrane-squeezing proteins are recognized as the key drivers of fission, there is a growing body of evidence that strongly suggests that conical lipids play a critical role in regulating mitochondrial morphology and fission. However, the mechanisms by which proteins and lipids cooperate to execute fission have not been quantitatively investigated. Here, we computationally model tubular mitochondria to reveal a new buckling instability-based mechanism for achieving super constrictions. Employing membrane physics and differential geometry, the study reveals that buckling instabilities, triggered synergistically by cylindrical curvatures generated by proteins and spherical curvatures generated by conical lipids, can lead to extreme necking required for fission. We validate the role of conical lipids by an in vitro study in which membrane tubules with reduced concentration of conical lipids (PE) fail to undergo necking despite the presence of Drp1 proteins. Our study suggests that the buckling-induced geometric plasticity imparts significant robustness to the fission reaction by arresting the elastic tendency of the membrane to rebound during protein polymerization and depolymerization cycles. Since protein/lipid-induced curvatures are ubiquitous mechanisms for driving membrane remodeling in cells, energetic frustration due to incompatible curvatures leading to instability could be a general mechanism at play in other interfacial remodeling events in cells.

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