Cytoplasmic dynein regulates the subcellular distribution of mitochondria by controlling the recruitment of the fission factor dynamin-related protein-1

Váradi, Anikó; Johnson-Cadwell, Linda I.; Cirulli, Vincenzo; Yoon, Yisang; Allan, Viki; Rutter, Guy A.

doi:10.1242/jcs.01299

Cited by 216 publications

(178 citation statements)

References 51 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2007

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Under physiological conditions, mitochondrial morphology dynamically shifts between a punctuate appearance and tubular networks. However, little is known about upstream signal transduction pathways that regulate mitochondrial morphology. We show that mitochondrial fission is a very early and kinetically invariant event during neuronal cell death, which causally contributes to cytochrome c release and neuronal apoptosis. Using a small molecule CDK5 inhibitor, as well as a dominantnegative CDK5 mutant and RNAi knockdown experiments, we identified CDK5 as an upstream signalling kinase that regulates mitochondrial fission during apoptosis of neurons. Vice versa, our study shows that mitochondrial fission is a modulator contributing to CDK5-mediated neurotoxicity. Thereby, we provide a link that allows integration of CDK5 into established neuronal apoptosis pathways. Mitochondria can acquire a broad range of morphologies, from a punctuate shape to a tubular appearance or even extended networks. Several proteins, most of them belonging to the family of large GTPases, have been identified that energy-dependently regulate mitochondrial morphology and subcellular distribution by promoting either fission (Fis1, dynamin-related protein 1 (Drp1), MTP18) or fusion of mitochondria (Mfn1/2 and Opa1). 1-3 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. 6 However, despite the contribution of mitochondrial dysfunction specifically to the demise of neurons, there is only scarce knowledge about mitochondrial fission during neuronal apoptosis, nor about its functional contribution to neuronal cell death. Furthermore, little is known about upstream regulatory pathways for mitochondrial morphology in general.Cyclin-dependent kinase 5 (CDK5) is a member of the CDK family, but, distinct from other CDKs, it does not participate in cell cycle regulation. 7 Instead, CDK5 is physiologically implicated in cytoskeletal functions, as well as regulation of membrane turnover and morphology, for example cell migration or endocytosis. Moreover, it is involved in neuronspecific functions including, for example, synaptic plasticity, axonal outgrowth or transmitter release. [8][9][10][11] In neurological diseases, deregulated CDK5 turned out to be an apical instigator of neuronal cell death cascades. Amyloid-toxicity was shown to induce calpain-mediated cleavage of the CDK5 activators p35 or p39 to p25 and p29. This leads to redistribution and overactivation of CDK5 after its association...

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Section: Resultsmentioning

confidence: 99%

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

et al. 2007

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“…The aggregation of mitochondria in the perinuclear area of the cells may occur for a variety of reasons. In the main, mitochondria in mammalian cells are moved around along microtubules [63], and disruption of fission protein Drp1 results in perinuclear clustering of mitochondria [63,64]. Perinuclear clustering of mitochondria has also been observed in apoptosis in necrosis [65].…”

Section: Discussionmentioning

confidence: 99%

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages

Mantovani

Raimondo

Haneef

et al. 2012

Experimental Cell Research

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“…Images were captured on a Nipkov disc-based Ultra-VIEW confocal system (PerkinElmer Life Sciences, Boston, MA,USA) [39] using a 63× PL Apo 1.4NA oilimmersion objective lens (Leica, Heidelberg, Germany).…”

Section: Methodsmentioning

confidence: 99%

Intracellular ATP-sensitive K+ channels in mouse pancreatic beta cells: against a role in organelle cation homeostasis

et al. 2006

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Aims/hypothesis: ATP-sensitive K + (K ATP ) channels located on the beta cell plasma membrane play a critical role in regulating insulin secretion and are targets for the sulfonylurea class of antihyperglycaemic drugs. Recent reports suggest that these channels may also reside on insulin-containing dense-core vesicles and mitochondria. The aim of this study was to explore these possibilities and to test the hypothesis that vesicle-resident channels play a role in the control of organellar Ca 2+ concentration or pH. Methods: To quantify the subcellular distribution of the pore-forming subunit Kir6.2 and the sulfonylurea binding subunit SUR1 in isolated mouse islets and clonal pancreatic MIN6 beta cells, we used four complementary techniques: immunoelectron microscopy, density gradient fractionation, vesicle immunopurification and fluorescence-activated vesicle isolation. Intravesicular and mitochondrial concentrations of free Ca 2+ were measured in intact or digitonin-permeabilised MIN6 cells using recombinant, targeted aequorins, and intravesicular pH was measured with the recombinant fluorescent probe pHluorin. Results: SUR1 and Kir6.2 immunoreactivity were concentrated on dense-core vesicles and on vesicles plus the endoplasmic reticulum/Golgi network, respectively, in both islets and MIN6 cells. Reactivity to neither subunit was detected on mitochondria. Glibenclamide, tolbutamide and diazoxide all failed to affect Ca 2+ uptake into mitochondria, and K ATP channel regulators had no significant effect on intravesicular free Ca 2+ concentrations or vesicular pH. Conclusions/Interpretation: A significant proportion of Kir6.2 and SUR1 subunits reside on insulin-secretory vesicles and the distal secretory pathway in mouse beta cells but do not influence intravesicular ion homeostasis. We propose that densecore vesicles may serve instead as sorting stations for the delivery of channels to the plasma membrane.

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Cytoplasmic dynein regulates the subcellular distribution of mitochondria by controlling the recruitment of the fission factor dynamin-related protein-1

Cited by 216 publications

References 51 publications

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

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

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages

Intracellular ATP-sensitive K+ channels in mouse pancreatic beta cells: against a role in organelle cation homeostasis

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