Mitochondrial Function and Actin Regulate Dynamin-Related Protein 1-Dependent Mitochondrial Fission

Abstract

Mitochondria display a variety of shapes, ranging from small and spherical or the classical tubular shape to extended networks. Shape transitions occur frequently and include fusion, fission, and branching. It was reported that some mitochondrial shape transitions are developmentally regulated, whereas others were linked to disease or apoptosis. However, if and how mitochondrial function controls mitochondrial shape through regulation of mitochondrial fission and fusion is unclear. Here, we show that inhibitors of electron transport, ATP synthase, or the permeability transition pore (mtPTP) induced reversible mitochondrial fission. Mitochondrial fission depended on dynamin-related protein 1 (DRP1) and F-actin: Disruption of F-actin attenuated fission and recruitment of DRP1 to mitochondria. In contrast, uncoupling of electron transport and oxidative phosphorylation caused mitochondria to adopt a distinct disk shape. This shape change was independent of the cytoskeleton and DRP1 and was most likely caused by swelling. Thus, disruption of mitochondrial function rapidly and reversibly altered mitochondrial shape either by activation of DRP1-dependent fission or by swelling, indicating a close relationship between mitochondrial fission, shape, and function. Furthermore, our results suggest that the actin cytoskeleton is involved in mitochondrial fission by facilitating mitochondrial recruitment of DRP1.

Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis

“…Disruption of the actin cytoskeleton precludes mitochondrial fission in non-neuronal cell lines 4 and neurons (our unpublished observation). The findings of an implication of cytoskelettal proteins in mitochondrial fission prompted us to examine whether CDK5 was a modulator of mitochondrial fission in neurons.…”

“…Parts of the mitochondrial fission machinery colocalizes with cytoskeletal structures, and translocation of Drp1 to mitochondria seems to be actin-dependent. 20,4 CDK5 is known to contribute to the regulation of the actin and tubulin cytoskeleton, as well as regulation of membrane turnover and morphology, for example cell migration or endocytosis. [8][9][10] Altogether, this led us to hypothesize that CDK5, which is an upstream instigator of neuronal demise in various neuronal cell death models, might participate in a signal transduction pathway that links proapoptotic signals to the dynamic changes of mitochondrial morphology we had observed.…”

“…[1][2][3] As a potential upstream regulatory factor, the actin cytoskeleton has been shown to be a prerequisite for mitochondrial fission, possibly by its influence on Drp1 recruitment to mitochondria. 4 Apoptotic release of the mitochondrial cytochrome c and other proapoptotic mitochondrial proteins results in formation of the so-called apoptosome, which in turn activates downstream effector caspases with death executing function. 5 This intrinsic, mitochondrial death pathway is relevant for most forms of neuronal apoptosis, in contrast to extrinsic, for example death receptor mediated, activation of programmed cell death.…”

The many shapes of mitochondrial death

“…This model is substantiated by the fact that interaction between Drp-1 and dynein/dynactin takes place on microtubules, which provide the tracks for mitochondrial movement in mammalian cells (Morris and Hollenbeck, 1995). The second theory, developed by De Vos et al (2005), suggests that F-actin facilitates transport of Drp-1 to mitochondria. Mitochondrial fragmentation induced by inhibitors of electron transport and ATPase is prevented by disruption of the actin cytoskeleton.…”

A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis

“…Mitochondrial movement is highly coordinated with changes in organelle morphology, required to produce mitochondria whose size is compatible with their transport by microtubule-associated cargoes. 35 It is therefore expected that any perturbation of the fusion-fission equilibrium could eventually result in the subcellular distribution of mitochondria and therefore alter functions that critically depend on this. Expression of pro-fusion shaping proteins such as Opa1 and Mfn1 decreases the number of dendritic spines and synapses, showing a role for mitochondrial morphology in the determination of complex cellular patterns.…”