A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis

Choi, Seok‐Yong; Huang, Ping; Jenkins, Gary M.; Chan, David C.; Schiller, Juergen; Frohman, Michael A.

doi:10.1038/ncb1487

Cited by 423 publications

(417 citation statements)

References 32 publications

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“…The present report describes RSK2 as a critical regulator of PLD1 in the course of exocytosis. PLD1 has been implicated in the release process of a variety of hormones (6,(8)(9)(10)(11), most likely at a late stage of exocytosis through the production of lipids that are essential for the fusion process. PLD1 seems to be also essential for fast neurotransmitter release (7).…”

Section: Discussionmentioning

confidence: 99%

The Coffin–Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1

Zeniou-Meyer

Liu

Béglé

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Exocytosis of neurotransmitters and hormones occurs through the fusion of secretory vesicles with the plasma membrane. This highly regulated process involves key proteins, such as SNAREs, and specific lipids at the site of membrane fusion. Phospholipase D (PLD) has recently emerged as a promoter of membrane fusion in various exocytotic events potentially by providing fusogenic cone-shaped phosphatidic acid. We show here that PLD1 is regulated by ribosomal S6 kinase 2 (RSK2)-dependent phosphorylation. RSK2 is activated by a high K + -induced rise in cytosolic calcium. Expression of inactive RSK2 mutants or selective knockdown of endogenous RSK2 dramatically affects the different kinetic components of the exocytotic response in chromaffin cells. RSK2 physically interacts with and stimulates PLD activity through the phosphorylation of Thr-147 in the PLD1 amino-terminal phox homology domain. Expression of PLD1 phosphomimetic mutants fully restores secretion in cells depleted of RSK2, suggesting that RSK2 is a critical upstream signaling element in the activation of PLD1 to produce the lipids required for exocytosis. We propose that PLD-related defects in neuronal and endocrine activities could contribute to the effect observed after the loss-of-function mutations in Rsk2 that lead to Coffin–Lowry syndrome, an X-linked form of growth and mental retardation.

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Section: Discussionmentioning

confidence: 99%

The Coffin–Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1

Zeniou-Meyer

Liu

Béglé

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…All of these domains are tailored to the cellular function associated with the individual proteins while maintaining the conserved GTPase, middle, and GED topology. For mitofusins, the TM domains anchor the protein in opposing membranes and likely act as tethers during mitochondrial fusion (Koshiba et al, 2004) in a mechanism believed to be similar to SNARE fusion events (Choi et al, 2006). The MTS found in Mgm1/OPA1 is essential for targeting the protein to the intermembrane space in mitochondria, where it is responsible for fusion events at the inner mitochondrial membrane and regulating cristae structure (Frezza et al, 2006;Meeusen et al, 2006;Meeusen and Nunnari, 2005).…”

Section: Introductionmentioning

confidence: 99%

Chapter 13 Visualization of Dynamins

Mears

Hinshaw

2008

Methods in Cell Biology

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“…The outer membranes of adjoining mitochondria are tethered together by the dimerization of mitofusins, whereas cardiolipin is hydrolyzed by mitochondrial phospholipase D, allowing complementary curvature of the membranes. 51 During this phase, various other proteins have been identified to affect fusion, although the specificity of accessory proteins is likely to be highly context dependent. The second phase involves the motorlike process driven by Opa-1, a dynamin-like GTPase protein that associates with the inner membrane.…”

Section: Components Of Mitochondrial Dynamics: Fission and Fusionmentioning

confidence: 99%

The Dynamics of the Mitochondrial Organelle as a Potential Therapeutic Target

Stetler

Leak

Gao

et al. 2012

J Cereb Blood Flow Metab

100

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Mitochondria play a central role in cell fate after stressors such as ischemic brain injury. The convergence of intracellular signaling pathways on mitochondria and their release of critical factors are now recognized as a default conduit to cell death or survival. Besides the individual processes that converge on or emanate from mitochondria, a mitochondrial organellar response to changes in the cellular environment has recently been described. Whereas mitochondria have previously been perceived as a major center for cellular signaling, one can postulate that the organelle's dynamics themselves affect cell survival. This brief perspective review puts forward the concept that disruptions in mitochondrial dynamics-biogenesis, clearance, and fission/fusion events-may underlie neural diseases and thus could be targeted as neuroprotective strategies in the context of ischemic injury. To do so, we present a general overview of the current understanding of mitochondrial dynamics and regulation. We then review emerging studies that correlate mitochondrial biogenesis, mitophagy, and fission/fusion events with neurologic disease and recovery. An overview of the system as it is currently understood is presented, and current assessment strategies and their limitations are discussed.

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A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis

Cited by 423 publications

References 32 publications

The Coffin–Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1

The Coffin–Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1

Chapter 13 Visualization of Dynamins

The Dynamics of the Mitochondrial Organelle as a Potential Therapeutic Target

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