A role for septin 2 in Drp1‐mediated mitochondrial fission

Abstract

Mitochondria are essential eukaryotic organelles often forming intricate networks. The overall network morphology is determined by mitochondrial fusion and fission. Among the multiple mechanisms that appear to regulate mitochondrial fission, the ER and actin have recently been shown to play an important role by mediating mitochondrial constriction and promoting the action of a key fission factor, the dynamin‐like protein Drp1. Here, we report that the cytoskeletal component septin 2 is involved in Drp1‐dependent mitochondrial fission in mammalian cells. Septin 2 localizes to a subset of mitochondrial constrictions and directly binds Drp1, as shown by immunoprecipitation of the endogenous proteins and by pulldown assays with recombinant proteins. Depletion of septin 2 reduces Drp1 recruitment to mitochondria and results in hyperfused mitochondria and delayed FCCP‐induced fission. Strikingly, septin depletion also affects mitochondrial morphology in Caenorhabditis elegans, strongly suggesting that the role of septins in mitochondrial dynamics is evolutionarily conserved.

Septins As Modulators of Endo-Lysosomal Membrane Traffic

“…As outlined above individual septin family members can thereby exert distinct effects, depending on their subcellular localizations. This is exemplified by SEPT2, which is recruited to the plasma membrane, to endosomal membranes or to the surface of mitochondria, where it controls unique events (the formation of phagocytic carriers, endosomal membrane fusion or organelle fission, respectively) (Huang et al, 2008; Mostowy and Cossart, 2011; Phan et al, 2013; Dolat and Spiliotis, 2016; Pagliuso et al, 2016). Thus, specificity in SEPT2 membrane recruitment and function must be accomplished through additional factors.…”

Septins and Bacterial Infection

“…In contrast, septin association with sources of membrane in the cytosol remains to be established. New studies have shown that septins interact with mitochondria and enable mitochondrial fission, in a process called mitokinesis (Pagliuso et al, 2016; Sirianni et al, 2016). Strikingly, septin function at the plasma membrane (e.g., phagocytosis, cytokinesis) and in the cytosol (e.g., septin caging, mitokinesis) all involve actin and non-muscle myosin II (Mostowy and Cossart, 2012; Sirianni et al, 2016).…”

Cancer-Related Functions and Subcellular Localizations of Septins

“…SEPT2 and 7, by interacting with DRP1 would concentrate it at the sites of mitochondrial constriction and facilitate their fission (Pagliuso et al, 2016; Sirianni et al, 2016). Mitochondria-associated septins also comprise the isoform 2 of SEPT4 (SEPT4_i2) also called ARTS, which upon pro-apoptotic stimuli, is released in the cytosol where it binds to the XIAP proteins to release the inhibition of caspases and thus promote apoptosis (Edison et al, 2012).…”