Novel roles for actin in mitochondrial fission

Abstract

Mitochondrial dynamics, including fusion, fission and translocation, are crucial to cellular homeostasis, with roles in cellular polarity, stress response and apoptosis. Mitochondrial fission has received particular attention, owing to links with several neurodegenerative diseases. A central player in fission is the cytoplasmic dynaminrelated GTPase Drp1, which oligomerizes at the fission site and hydrolyzes GTP to drive membrane ingression. Drp1 recruitment to the outer mitochondrial membrane (OMM) is a key regulatory event, which appears to require a pre-constriction step in which the endoplasmic reticulum (ER) and mitochondrion interact extensively, a process termed ERMD (ER-associated mitochondrial division). It is unclear how ER-mitochondrial contact generates the force required for pre-constriction or why pre-constriction leads to Drp1 recruitment. Recent results, however, show that ERMD might be an actin-based process in mammals that requires the ER-associated formin INF2 upstream of Drp1, and that myosin II and other actinbinding proteins might be involved. In this Commentary, we present a mechanistic model for mitochondrial fission in which actin and myosin contribute in two ways; firstly, by supplying the force for preconstriction and secondly, by serving as a coincidence detector for Drp1 binding. In addition, we discuss the possibility that multiple fission mechanisms exist in mammals.

Mitochondrial dynamics in neuronal injury, development and plasticity

“…Drp1 has been put forward as a drug target for preventing mitochondrial fragmentation under diverse pathological conditions (Rosdah et al, 2016). Indeed, currently available Drp1 inhibitors have shown neuroprotective properties in animal models of HD (Guo et al, 2013b), PD (Hatch et al, 2014;Filichia et al, 2016) and ischemic stroke (Grohm et al, 2012;Li et al, 2015;Zhang et al, 2013). However, given the widespread expression of the fission enzyme and the detrimental consequences on the development and function of the nervous system upon deletion of Drp1, targeting neuron-specific regulators of Drp1 or other components of the mitochondrial fission/fusion machinery are potentially safer therapeutic strategies.…”

“…the OMM (Hatch et al, 2014(Hatch et al, , 2016Ji et al, 2015). 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).…”

“…It should be noted that, in addition to its role in promoting mitochondrial fusion, recent evidence suggests that Mfn2 plays an important role in regulating the association between the endoplasmic reticulum (ER) and mitochondria, and can localize to both the ER and to mitochondria. Importantly, ERmitochondrial contact is necessary for both ER-mitochondrial Ca have been proposed to mark fission sites on the OMM through preconstriction of the OMM by promoting assembly of the mitochondrial fission machinery (Friedman et al, 2011;Hatch et al, 2014;Lee and Yoon, 2014). However, there is currently a debate as to whether Mfn2 promotes or inhibits the apposition between ER and mitochondrial membranes.…”

Assembly and Turnover of Short Actin Filaments by the Formin INF2 and Profilin

“…These filaments can be of relatively uniform size, and their length (200 -300 nm) can be on the order of those postulated to participate in mitochondrial fission through the ER-bound INF2-CAAX isoform (46). Given that a cytosolic isoform, INF2-non-CAAX, participates in Golgi dynamics (4), it is possible that INF2-generated short, transient actin filaments might be used in other organellar membrane fission processes.…”

Analysis of ER-mitochondria contacts by correlative fluorescence microscopy and soft X-ray tomography of mammalian cells

“…However, in cells that have been depleted of Drp1 or Mff, mitochondrial constriction at sites of ER contact are observed, indicating that ER-mediated constriction of mitochondrial tubules proceeds independently of both Mff and Drp1 (Friedman et al, 2011). Recent studies have provided further insight into the process of 'ER-associated mitochondrial division' in yeast Murley et al, 2013;Friedman and Nunnari, 2014) and mammalian cells, which include the additional involvement of INF2, actin and myosin II (Korobova et al, 2013(Korobova et al, , 2014Hatch et al, 2014).…”