Multiple Dynamin family members collaborate to drive mitochondrial division

Mitochondria cannot be generated de novo; they must grow, replicate their genome, and divide in order to be inherited to each daughter cell during mitosis. Mitochondrial division is a structural challenge that requires a massive remodeling of membrane morphology (1–3). Although division factors differ across organisms, the need for multiple constriction steps and a dynamin-related protein (Drp1, Dnm1 in yeast) has been conserved (4–6). In mammalian cells, mitochondrial division has been shown to proceed with at least two sequential constriction steps: 1. endoplasmic reticulum (ER) and actin collaborate to generate constrictions suitable for Drp1 assembly; 2. Drp1 further constricts membranes until fission occurs (2,7–9). However, in vitro experiments argue that Drp1 does not have the dynamic range to complete membrane fission per se (7). In contrast to Drp1, the neuronal-specific classical Dynamin-1 (Dyn1) has been shown to assemble on narrower lipid profiles and facilitates spontaneous membrane fission upon GTP hydrolysis (10,11). Here we discovered that the ubiquitously-expressed classical Dynamin-2 (Dyn2) is a fundamental component of the mitochondrial division machinery. A combination of live-cell and electron microscopy reveals that Dyn2 works in concert with Drp1 to orchestrate sequential constriction events leading up to division. Our work underscores the biophysical limitations of Drp1 and positions Dyn2, which has intrinsic membrane fission properties, at the final step of mitochondrial division.