Lipids Catalyze Mitochondrial Fission via Geometric Instability

Abstract

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 (dynamin-related protein 1), and iii) the final fission carried out by dynamin. While the fission proteins play an inarguably critical role, a growing body of evidence reveals that conical lipids regulate mitochondrial morphology and fission. But how conical lipids contribute to fission remains an open question. Here, we computationally model tubular mitochondria to reveal a new buckling instability-based mechanism for achieving a stable geometry conducive for fission. Employing membrane physics and differential geometry, the study reveals that buckling instabilities, triggered synergistically by cylindrical curvatures from proteins and spherical curvatures from conical lipids, help achieve superconstrictions 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.