Regulation of mitochondrial morphology by APC/C<sup>Cdh1</sup>-mediated control of Drp1 stability

Horn, Sarah R.; Thomenius, Michael J.; Johnson, Einer W.; Freel, Christopher D.; Wu, Judy Qiju; Coloff, Jonathan L.; Yang, Chih‐Sheng; Tang, Wanli; An, Jing; Ilkayeva, Olga; Rathmell, Jeffrey C.; Newgard, Christopher B.; Kornbluth, Sally

doi:10.1091/mbc.e10-07-0567

Cited by 88 publications

(77 citation statements)

References 54 publications

(78 reference statements)

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“…However, it is presumable that LIMK2 would regulate DRP1 expression via cell-cycle related events, which is unknown at present. Horn et al 47 reported that DRP1 level drops when cells enter G1 phase, and in turn, DRP1 level gradually increases following release from G1/S arrest. As cyclin D1 is required for G1/S transition and LIMK2 suppresses cyclin D1 expression, 17 overexpression of cyclin D1 followed by LIMK2 could lead neurons to G1/S arrest-like condition that sustains decrease in DRP1 level.…”

Section: Discussionmentioning

confidence: 99%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

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Although the aberrant activation of cell cycle proteins has a critical role in neuronal death, effectors or mediators of cyclin D1/ cyclin-dependent kinase 4 (CDK4)-mediated death signal are still unknown. Here, we describe a previously unsuspected role of LIM kinase 2 (LIMK2) in programmed necrotic neuronal death. Downregulation of p27 Kip1 expression by Rho kinase (ROCK) activation induced cyclin D1/CDK4 expression levels in neurons vulnerable to status epilepticus (SE). Cyclin D1/CDK4 complex subsequently increased LIMK2 expression independent of caspase-3 and receptor interacting protein kinase 1 activity. In turn, upregulated LIMK2 impaired dynamic-related protein-1 (DRP1)-mediated mitochondrial fission without alterations in cofilin phosphorylation/expression and finally resulted in necrotic neuronal death. Inhibition of LIMK2 expression and rescue of DRP1 function attenuated this programmed necrotic neuronal death induced by SE. Therefore, we suggest that the ROCK-p27 Kip1 -cyclin D1/CDK4-LIMK2-DRP1-mediated programmed necrosis may be new therapeutic targets for neuronal death. The cell cycle is essential for a vital process, including proliferation, differentiation and survival of various cells. Cell cycle progression is regulated by two classes of proteins, the cyclins and the cyclin-dependent kinases (CDKs). Among them, cyclin D1 forms a complex with CDK4 and inactivates retinoblastoma protein (Rb) through phosphorylation resulting in activating E2 promoter-binding factor (E2F) family of transcription factors. Active E2F induces various gene transcriptions involving the cell cycle. 1 In post-mitotic neurons, some pathological conditions upregulate cyclin D1/CDK4 complex expression to induce activation of E2F members that contributes to increased transcription of proapoptotic molecules. 2,3 However, it is unclear whether cyclin D1 expression directly induces neuronal death for a number of following reasons. First, due to a time lag between cyclin D1/CDK4 expression and the onset of DNA fragmentation, most cyclin D1-positive neurons show TUNEL negativity. 4,5 Second, cyclin D1 level is unaltered in cultured embryonic neurons following apoptosis induction. 6 Third, Rb phosphorylation is rarely observed in vivo, 4 although cyclin D1/CDK4 complex phosphorylates Rb protein in apoptotic cultured neurons. 6 Fourth, cyclin D1 induction following ischemia is associated with regeneration and resistance to apoptosis rather than a mediator of apoptosis. 5,7,8 Fifth, effectors or mediators of cyclin D1/CDK4-mediated death signal are still unknown. Finally, neuronal death induced by various insults is morphologically necrotic rather than apoptotic. 9-12 Therefore, it is likely that some essential factors are missing in the cyclin D/CDK4-mediated neuronal death pathway.LIM kinases (LIMK1 and LIMK2) phosphorylate cofilin that is a stimulus-responsive mediator of actin dynamics. [13][14][15] Interestingly, non-phosphorylated cofilin targets mitochondrial membranes in response to apoptotic stimuli for cytochrome c releas...

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Section: Discussionmentioning

confidence: 99%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

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“…DRP1 contains several canonical and non-canonical degradation box motifs. Upon release from synchronized cell cycle arrest DRP1 undergoes cell cycle dependent degradation [68]. The ubiquitylation sites of DRP1 have not been identified as of yet and how ubiquitylation of DRP1 is regulated also needs further investigation.…”

Section: Outer Mitochondrial Membrane Fission and Fusionmentioning

confidence: 99%

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Ali

McStay

2017

Preprint

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The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as ATP synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond to pathophysiologic signals to coordinate appropriate mitochondrial processes. Mitochondrial fusion and fission are regulated by proteins that either reside or translocate to the inner or outer mitochondrial membranes or are soluble in the inter-membrane space. Mitochondrial fission and fusion are performed by GTPases on the outer and inner mitochondrial membranes with the assistance of other mitochondrial proteins. Due to the essential nature of mitochondrial function for cellular homeostasis regulation of mitochondrial dynamics is under strict control. Some of the mechanisms used to regulate the function of these proteins are post-translational proteolysis and/or turnover and this review will discuss these mechanisms required for correct mitochondrial network organization. IntroductionMitochondria are the power houses of every nucleated cell, generating chemical energy in the form of adenosine triphosphate (ATP) by the oxidative phosphorylation (OXPHOS) system. Mitochondria are also important for the normal functioning of the cells as they regulate several crucial activities like differentiation, cell cycle, intracellular signaling and cell death [1]. Mitochondria are unique because of their autonomous DNA (mtDNA), which encodes for proteins required for ATP synthesis. Therefore maintenance of mtDNA is important for normal mitochondrial function and for the diversity of mitochondrial genome [2]. Mitochondria form elongated tubules that continually divide and fuse to form a complex, interconnected and highly dynamic network inside of cells. These dynamics processes not only regulate mitochondrial function but also mitochondrial shape, content exchange and mitochondrial communication with the cytoskeleton [3]. Due to the involvement of mitochondria in a large spectrum of cellular functions, these organelles play a key role in mediating cellular homeostasis. As a result a healthy population of mitochondria is critical for cell survival.

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“…Reduction of the levels or activity of the key mitochondrial fission protein, dynamin-related protein 1 (Drp1, SwissProt O00429 in humans) leads to elevation of CycE levels in various mammalian cells and in Drosophila (Mitra et al, 2012(Mitra et al, , 2009Qian et al, 2012). The emerging model suggests that cell cycle regulators regulate Drp1 (Taguchi et al, 2007;Kashatus et al, 2011;Horn et al, 2011), which, in turn, further regulates CycE levels in proliferating cells (Mitra, 2013). We have previously shown that although loss of Drp1 deregulates CycE in various cell contexts, it promotes aberrant cell proliferation only in the presence of EGFR signaling (Mitra et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

A novel mitochondrial pool of Cyclin E, regulated by Drp1, is linked to cell density dependent cell proliferation

Parker

Iyer

Shah

et al. 2015

Journal of Cell Science

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The regulation and function of the crucial cell cycle regulator cyclin E (CycE) remains elusive. Unlike other cyclins, CycE can be uniquely controlled by mitochondrial energetics, the exact mechanism being unclear. Using mammalian cells (in vitro) and Drosophila (in vivo) model systems in parallel, we show that CycE can be directly regulated by mitochondria through its recruitment to the organelle. Active mitochondrial bioenergetics maintains a distinct mitochondrial pool of CycE (mtCycE) lacking a key phosphorylation required for its degradation. Loss of the mitochondrial fission protein dynaminrelated protein 1 (Drp1, SwissProt O00429 in humans) augments mitochondrial respiration and elevates the mtCycE pool allowing CycE deregulation, cell cycle alterations and enrichment of stem cell markers. Such CycE deregulation after Drp1 loss attenuates cell proliferation in low-cell-density environments. However, in high-celldensity environments, elevated MEK-ERK signaling in the absence of Drp1 releases mtCycE to support escape of contact inhibition and maintain aberrant cell proliferation. Such Drp1-driven regulation of CycE recruitment to mitochondria might be a mechanism to modulate CycE degradation during normal developmental processes as well as in tumorigenic events.

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Regulation of mitochondrial morphology by APC/C^Cdh1-mediated control of Drp1 stability

Cited by 88 publications

References 54 publications

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

A novel mitochondrial pool of Cyclin E, regulated by Drp1, is linked to cell density dependent cell proliferation

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Regulation of mitochondrial morphology by APC/CCdh1-mediated control of Drp1 stability

Cited by 88 publications

References 54 publications

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

A novel mitochondrial pool of Cyclin E, regulated by Drp1, is linked to cell density dependent cell proliferation

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Regulation of mitochondrial morphology by APC/C^Cdh1-mediated control of Drp1 stability