Multiple dynamin family members collaborate to drive mitochondrial division

Abstract

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.

Mitochondrial dynamics in neuronal injury, development and plasticity

“…In support of this latter model, recent work by Adachi and colleagues suggests that the fission activity of Drp1 is also dependent upon phospholipid composition of the OMM (Adachi et al, 2016) and requires coordination with dynamin 2 in order to accomplish fission of the OMM (Lee et al, 2016).…”

Structure, function, and regulation of mitofusin‐2 in health and disease

“…Recent evidence in mammalian cells has defined the critical role of the dynamin 2 protein in the fission process . Lee et al (2016) demonstrated that fission occurs through a two-step process, with Drp1 initially providing partial constriction of the mitochondrial membrane, and dynamin 2 subsequently binding and constricting further to split the organelle into two.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Drp1 does not act alone, but different "accomplices" assist Drp1-docking at OMMs: Fis1, the role of which is still controversial in mammals [33,34]; Mff [35,36]; MiD51 and MiD49 [37]. In addition, other "less conventional" proteins can mediate Drp1 recruitment at OMM, and promote mitochondria fission, such as the cytoplasmic kinase leucine-rich-repeat kinase 2 (LRRK2) [38,39], the membrane trafficking and apoptosis regulator small Ras family member G-protein Rab32 [40,41] and the very recently discovered dynamin-2 (Dyn-2) [42]. Moreover, silencing of the MICOS protein Mitofilin induces the formation of giant and enlarged mitochondria by downregulating the expression of several fusion and fission mitochondria-shaping proteins [43], thus indicating a role for this protein on the correct homeostasis of the mitochondrial morphology.…”