Silencing of the Charcot–Marie–Tooth disease-associated gene GDAP1 induces abnormal mitochondrial distribution and affects Ca2+ homeostasis by reducing store-operated Ca2+ entry

Pla‐Martín, David; Rueda, Carlos B.; Estela, Anna; Sánchez-Piris, Maribel; González-Sánchez, Paloma; Traba, Javier; Fuente, Sergio de la; Scorrano, Luca; Renau‐Piqueras, Jaime; Alvarez, Javier; Satrústegui, Jorgina; Palau, Francesc

doi:10.1016/j.nbd.2013.03.010

Cited by 78 publications

(126 citation statements)

References 55 publications

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“…In addition, the formation of mitochondria-Endoplasmic Reticulum (ER) contacts plays a key role in mitochondrial fission 12,13 and Gdap1 has been shown to participate in the establishment of these contacts in neuroblastoma cells. 23 Thus, it is possible that lack of Gdap1 impairs OSKM-induced mitochondrial fission by interfering with the formation of mitochondria-ER contacts, leading to a decrease in reprogramming efficiency. Interestingly, Gdap1 is absent in pluripotent cells whereas it participates in mediating mitochondrial fission in MEFs before and during the very early stages of reprogramming.…”

Section: Discussionmentioning

confidence: 99%

“…The GDAP1 gene (MIM #606598) is linked to Charcot-Marie-Tooth disease 19 and has been shown to play a role in regulating mitochondrial dynamics in human. 20 Although the mechanisms whereby GDAP1 participates in the regulation of mitochondrial dynamics are not fully understood, its overexpression led to the fragmentation of the mitochondrial network in human cells whereas knockdown of GDAP1 enhanced the tubular aspect of these organelles in mammalian [21][22][23] and insect 24 cells. Somatic cells from mouse or human origin can be reprogrammed to induced-Pluripotent Stem (iPS) cells by forced expression of Oct4 (also known as Pou5f1), Klf4, Sox2 and cMyc [25][26][27] (named as OSKM herein).…”

Section: Introductionmentioning

confidence: 99%

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Dysfunctional mitochondrial fission impairs cell reprogramming

et al. 2016

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We have recently shown that mitochondrial fission is induced early in reprogramming in a Drp1-dependent manner; however, the identity of the factors controlling Drp1 recruitment to mitochondria was unexplored. To investigate this, we used a panel of RNAi targeting factors involved in the regulation of mitochondrial dynamics and we observed that MiD51, Gdap1 and, to a lesser extent, Mff were found to play key roles in this process. Cells derived from Gdap1-null mice were used to further explore the role of this factor in cell reprogramming. Microarray data revealed a prominent down-regulation of cell cycle pathways in Gdap1-null cells early in reprogramming and cell cycle profiling uncovered a G2/M growth arrest in Gdap1-null cells undergoing reprogramming. High-Content analysis showed that this growth arrest was DNA damage-independent. We propose that lack of efficient mitochondrial fission impairs cell reprogramming by interfering with cell cycle progression in a DNA damage-independent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dysfunctional mitochondrial fission impairs cell reprogramming

et al. 2016

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“…3A, Fig. S1B, and Tables S1 and S2) that could make classical colocalization methods of analysis not suitable (20,21). We thus chose a different approach to quantify organelles' colocalization (Materials and Methods), taking into consideration only the perimeter of the mitochondrial structures, not their entire area (Figs.…”

Section: Significancementioning

confidence: 99%

Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling

Filadi

Greotti

Turacchio

et al. 2015

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

483

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The organization and mutual interactions between endoplasmic reticulum (ER) and mitochondria modulate key aspects of cell pathophysiology. Several proteins have been suggested to be involved in keeping ER and mitochondria at a correct distance. Among them, in mammalian cells, mitofusin 2 (Mfn2), located on both the outer mitochondrial membrane and the ER surface, has been proposed to be a physical tether between the two organelles, forming homotypic interactions and heterocomplexes with its homolog Mfn1. Recently, this widely accepted model has been challenged using quantitative EM analysis. Using a multiplicity of morphological, biochemical, functional, and genetic approaches, we demonstrate that Mfn2 ablation increases the structural and functional ER-mitochondria coupling. In particular, we show that in different cell types Mfn2 ablation or silencing increases the close contacts between the two organelles and strengthens the efficacy of inositol trisphosphate (IP3)-induced Ca 2+ transfer from the ER to mitochondria, sensitizing cells to a mitochondrial Ca 2+ overload-dependent death. We also show that the previously reported discrepancy between electron and fluorescence microscopy data on ER-mitochondria proximity in Mfn2-ablated cells is only apparent. By using a different type of morphological analysis of fluorescent images that takes into account (and corrects for) the gross modifications in mitochondrial shape resulting from Mfn2 ablation, we demonstrate that an increased proximity between the organelles is also observed by confocal microscopy when Mfn2 levels are reduced. Based on these results, we propose a new model for ER-mitochondria juxtaposition in which Mfn2 works as a tethering antagonist preventing an excessive, potentially toxic, proximity between the two organelles. mitofusin 2 | ER-mitochondria tethering | inter-organellar communication D uring the last decade, evidence has accumulated showing the existence of a continuous flux of information between the endoplasmic reticulum (ER) and mitochondria, two organelles whose privileged interplay is essential, e.g., for lipid metabolism and modulation of Ca 2+ signaling (1, 2). As to the former, Vance (3) firstly described a partially purified microsomal subfraction pulled down with mitochondria (fraction X, later renamed "mitochondria-associated membrane," MAM) that was found to be enriched in phosphatidylserine synthase and several enzymes involved in lipid and glucose metabolism, cholesterol, and ceramide biosynthesis (4, 5). As far as Ca 2+ signaling is concerned, the ERmitochondria axis plays a critical role in cell Ca 2+ homeostasis (6-8). In parallel, increases of Ca 2+ within mitochondria are essential in tuning physiological organelle activity (9, 10) and in modulating the process of cell death (6,8,11). ER-mitochondria connections and Ca 2+ signals are also critical for mitochondrial fission (12, 13), for autophagosome generation (14), and for the removal of damaged mitochondria by autophagy (15).Several proteins have been suggested to be ...

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“…Ganglioside-induced differentiation-associated protein-1 (GDAP1) mutation can cause several forms of CMT, including CMT4A (Chapter 13), CMT2K (Chapter 10), and AD CMT (Chapter 10) with pyramidal involvement Functional in vitro studies suggest that GDAP1 regulates mitochondrial and peroxisomal fission [38], and mitochondrial movement [39]. An early-onset, severe AR intermediate CMT with variable NCVs and both axonal and demyelinating phenotypes has been observed by several groups [40][41][42][43].…”

Section: Clinical Presentationmentioning

confidence: 99%

Dominant and recessive intermediate CMT (CMTDI and CMTRI)

Weis

Roos

Katona

et al. 2014

Peripheral Nerve Disorders

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In 1978, Davis and colleagues suggested a classification of dominantly inherited peroneal muscular atrophy cases based on upper limb motor nerve conduction velocity (NCV) measurements. Cases with NCVs of >25 m/s were assigned to the demyelinating (or hypertrophic) neuropathy group, patients with NCVs between 25 and 45 m/s comprised the intermediate group and cases with NCVs >45 m/s were assigned to the axonal (or neuronal) sensorimotor neuropathy group [1]. Two years later, Harding and Thomas [2] proposed a median nerve motor NCV of 38 m/s as a cut-off value to distinguish between HMSN I (<38 m/s) and HMSN II (>38 m/s).

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Silencing of the Charcot–Marie–Tooth disease-associated gene GDAP1 induces abnormal mitochondrial distribution and affects Ca2+ homeostasis by reducing store-operated Ca2+ entry

Cited by 78 publications

References 55 publications

Dysfunctional mitochondrial fission impairs cell reprogramming

Dysfunctional mitochondrial fission impairs cell reprogramming

Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling

Dominant and recessive intermediate CMT (CMTDI and CMTRI)

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