Article

Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria.

Dulbecco-Telethon Institute, Padua, Italy.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 11/2008; 105(41):15803-8. DOI: 10.1073/pnas.0808249105
Source: PubMed

ABSTRACT Changes in mitochondrial morphology that occur during cell cycle, differentiation, and death are tightly regulated by the balance between fusion and fission processes. Excessive fragmentation can be caused by inhibition of the fusion machinery and is a common consequence of dysfunction of the organelle. Here, we show a role for calcineurin-dependent translocation of the profission dynamin related protein 1 (Drp1) to mitochondria in dysfunction-induced fragmentation. When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. Thus, fragmentation of depolarized mitochondria depends on a loop involving sustained Ca(2+) rise, activation of calcineurin, and dephosphorylation of Drp1 and its translocation to the organelle.

0 Bookmarks
 · 
101 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite improvements in cardiopulmonary resuscitation (CPR) quality, defibrillation technologies, and implementation of therapeutic hypothermia, less than 10 % of out-of-hospital cardiac arrest (OHCA) victims survive to hospital discharge. New resuscitation therapies have been slow to develop, in part, because the pathophysiologic mechanisms critical for resuscitation are not understood. During cardiac arrest, systemic cessation of blood flow results in whole body ischemia. CPR and the restoration of spontaneous circulation (ROSC), both result in immediate reperfusion injury of the heart that is characterized by severe contractile dysfunction. Unlike diseases of localized ischemia/reperfusion (IR) injury (myocardial infarction and stroke), global IR injury of organs results in profound organ dysfunction with far shorter ischemic times. The two most commonly injured organs following cardiac arrest resuscitation, the heart and brain, are critically dependent on mitochondrial function. New insights into mitochondrial dynamics and the role of the mitochondrial fission protein Dynamin-related protein 1 (Drp1) in apoptosis have made targeting these mechanisms attractive for IR therapy. In animal models, inhibiting Drp1 following IR injury or cardiac arrest confers protection to both the heart and brain. In this review, the relationship of the major mitochondrial fission protein Drp1 to ischemic changes in the heart and its targeting as a new therapeutic target following cardiac arrest are discussed.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria sense and amplify apoptotic signals, releasing cytochrome c and other cofactors required for the activation of caspases and downstream cell death (Danial and Korsmeyer, 2004). Cytochrome c release requires mitochondrial outer membrane permeabilization (MOMP), is tightly regulated by proteins of the Bcl-2 family, and is associated with mitochondrial morphology changes (Frank et al., 2001). Mitochondrial morphology is modulated by large dynamin-like GTPases: the cytosolic dynamin-related protein 1 (DRP1), which translocates to mitochondria, binding to its receptor on the outer membrane (OMM) mitochondrial fission factor (MFF) (Otera et al., 2010), constricting and fragmenting mitochondria. Pro-fusion proteins display pleiotropic functions: the inner mitochondrial membrane (IMM) protein Optic Atrophy 1 (OPA1) not only promotes fusion (Cipolat et al., 2004), but it also regulates cristae shape and remodeling to control cytochrome c release (Frezza et al., 2006) and mitochondrial function (Cogliati et al., 2013). Of the two mammalian OMM mitofusins (MFNs) (Chen et al., 2003), MFN1 mediates organelle fusion together with OPA1 (Cipolat et al., 2004), whereas MFN2 tethers mitochondria either in trans (Koshiba et al., 2004) or to the endoplasmic reticulum (ER) (de Brito and Scorrano, 2008).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sphingolipids are bioactive lipid effectors, which are involved in the regulation of various cellular signaling pathways. Sphingolipids play essential roles in controlling cell inflammation, proliferation, death, migration, senescence, metastasis and autophagy. Alterations in sphingolipid metabolism has been also implicated in many human cancers. Macroautophagy (referred to here as autophagy) is a form of nonselective sequestering of cytosolic materials by double membrane structures, autophagosomes, which can be either protective or lethal for cells. Ceramide, a central molecule of sphingolipid metabolism is involved in the regulation of autophagy at various levels, including the induction of lethal mitophagy, a selective autophagy process to target and eliminate damaged mitochondria. In this review, we focused on recent studies with regard to the regulation of autophagy, in particular lethal mitophagy, by ceramide, and aimed at providing discussion points for various context-dependent roles and mechanisms of action of ceramide in controlling mitophagy. Copyright © 2015 Elsevier B.V. All rights reserved.

Full-text (2 Sources)

Download
45 Downloads
Available from
May 15, 2014