Article

Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria

Dulbecco-Telethon Institute, Padua, Italy.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 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.

Download full-text

Full-text

Available from: Luca Scorrano
    • "This general stress response is often observed under pathologic conditions (Ong et al., 2013;Burté et al., 2015) and involves regulatory steps at both mitochondrial membranes. Mitochondrial depolarization triggers ubiquitin-dependent degradation of mitofusins as well as dephosphorylation and activation of DRP1 at the OMM (Cribbs and Strack, 2007;Cereghetti et al., 2008). At the same time, stress-induced proteolytic cleavage of OPA1 inhibits IMM fusion (Ishihara et al., 2006;Griparic et al., 2007;Song et al., 2007). "

    No preview · Article · Jan 2016 · The Journal of Cell Biology
  • Source
    • "Other studies in neonatal rat cardiac myocytes exposed to phenylephrine to induce hypertrophy (Fang et al. 2007), as well as in vivo models of cardiac hypertrophy, also described decreases in Mfn2 mRNA levels (Fang et al. 2007). Calcineurin is an essential regulator of cardiac hypertrophy and heart failure (Heineke & Molkentin, 2006) and participates in the regulation of mitochondrial fission by DRP1 dephosphorylation (Cereghetti et al. 2008).Wang et al.showed that both the A and B isoforms of the calcineurin catalytic subunit are direct targets of microRNA (miR)-499, increasing DRP1 phosphorylation at residue Ser 656 , thereby reducing mitochondrial fission (Wang et al. 2011). Interestingly, miR-499 transgenic mice manifested a decline in hypertrophic parameters assessed by heart/body weight ratio, cardiac myocyte cross-sectional area, collagen content, heart chamber dimensions and cardiac function after ischaemia–reperfusion (I/R). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac hypertrophy is often initiated as an adaptive response to hemodynamic stress or myocardial injury, and allows the heart to meet an increased demand for oxygen. Although initially beneficial, hypertrophy can ultimately contribute to the progression of cardiac disease, leading to an increase in interstitial fibrosis and a decrease in ventricular function. Metabolic changes have emerged as key mechanisms involved in the development and progression of pathological remodelling. As a highly oxidative tissue, mitochondria play a central role in maintaining optimal performance of the heart. "Mitochondrial dynamics", the processes of mitochondrial fusion, fission, biogenesis and mitophagy that determine mitochondrial morphology, quality, and abundance, have recently been implicated in cardiovascular disease. Studies link mitochondrial dynamics to the balance between energy demand and nutrient supply, suggesting that changes in mitochondrial morphology may act as a mechanism for bioenergetic adaptation during cardiac pathological remodelling. Another critical function of mitochondrial dynamics is the removal of damaged and dysfunctional mitochondria through mitophagy, which is dependent on the fission/fusion cycle. In this article, we discuss the latest findings regarding the impact of mitochondrial dynamics and mitophagy on the development and progression of cardiovascular pathologies, including diabetic cardiomyopathy, atherosclerosis, damage from ischemia-reperfusion, cardiac hypertrophy and decompensated heart failure. We will address the ability of mitochondrial fusion and fission to impact all cell types within the myocardium, including cardiac myocytes, cardiac fibroblasts and vascular smooth muscle cells. Finally, we will discuss how these findings can be applied to improve the treatment and prevention of cardiovascular diseases. This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2015 · The Journal of Physiology
  • Source
    • "We next asked if the elongated phenotype of SPG7 KD contributed to increased [Ca 2+ ] m retention. To test this, we measured [Ca 2+ ] m retention in wild-type cells overexpressing mitochondrial fission dominant-negative Drp1 K38A , known to result in elongated mitochondria (Cereghetti et al., 2008; Frank et al., 2001; Smirnova et al., 2001). As expected Drp1 K38A overexpression resulted in elongated mitochondria (Figures S2C–S2E). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens, resulting in mitochondrial membrane potential (ΔΨm) dissipation, loss of ATP production, and cell death. Several genetic candidates have been proposed to form the PTP complex, however, the core component is unknown. We identified a necessary and conserved role for spastic paraplegia 7 (SPG7) in Ca2+- and ROS-induced PTP opening using RNAi-based screening. Loss of SPG7 resulted in higher mitochondrial Ca2+ retention, similar to cyclophilin D (CypD, PPIF) knockdown with sustained ΔΨm during both Ca2+ and ROS stress. Biochemical analyses revealed that the PTP is a heterooligomeric complex composed of VDAC, SPG7, and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca2+- and ROS-induced ΔΨm depolarization and cell death. This study identifies an ubiquitously expressed IMM integral protein, SPG7, as a core component of the PTP at the OMM and IMM contact site.
    Full-text · Article · Sep 2015 · Molecular Cell
Show more