Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly

Vogel, Rutger O.; Janßen, Rolf; Brand, Mariël A.M. van den; Dieteren, Cindy E.; Verkaart, Sjoerd; Koopman, Werner J.H.; Willems, Peter H.G.M.; Pluk, Wendy; Heuvel, L.P.W.J. van den; Smeitink, Jan A.M.; Nijtmans, Leo

doi:10.1101/gad.408407

Cited by 177 publications

(188 citation statements)

References 25 publications

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“…Although an altered ECSIT gene expression has not been reported in AD patients to date, its expression is significantly up-regulated in Huntington's patients (Borovecki et al 2005), and we found it to physically interact with genes altered in AD brain, namely peroxiredoxin-2 (PRDX2) and interferon-induced protein with tetratricopeptide repeats 5 (IFIT5) (see Supplemental File 1). This gives further support to the hypothesis that ECSIT might modulate the energetic requirements upon inflammatory response by regulating the rate of complex I synthesis (Vogel et al 2007). Most interestingly, we observed a novel association of ECSIT with the AD gene APOE (Fig.…”

Section: Interactome Network Associated To Adsupporting

confidence: 53%

“…Although ECSIT acts as a cytoplasmic signaling protein in these two pathways, an N-terminal targeting signal directs ECSIT to mitochondria as well (Vogel et al 2007). In fact, cell knockdowns present a disturbed mitochondrial function that supports a role for ECSIT in linking assembly of oxidative phosphorylation complexes to inflammatory response (Vogel et al 2007).…”

Section: Interactome Network Associated To Admentioning

confidence: 99%

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Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

Soler-López¹,

Zanzoni²,

Lluís³

et al. 2010

Genome Res.

108

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Recent advances toward the characterization of Alzheimer's disease (AD) have permitted the identification of a dozen of genetic risk factors, although many more remain undiscovered. In parallel, works in the field of network biology have shown a strong link between protein connectivity and disease. In this manuscript, we demonstrate that AD-related genes are indeed highly interconnected and, based on this observation, we set up an interaction discovery strategy to unveil novel AD causative and susceptibility genes. In total, we report 200 high-confidence protein-protein interactions between eight confirmed AD-related genes and 66 candidates. Of these, 31 are located in chromosomal regions containing susceptibility loci related to the etiology of late-onset AD, and 17 show dysregulated expression patterns in AD patients, which makes them very good candidates for further functional studies. Interestingly, we also identified four novel direct interactions among well-characterized AD causative/susceptibility genes (i.e., APP, A2M, APOE, PSEN1, and PSEN2), which support the suggested link between plaque formation and inflammatory processes and provide insights into the intracellular regulation of APP cleavage. Finally, we contextualize the discovered relationships, integrating them with all the interaction data reported in the literature, building the most complete interactome associated to AD. This general view facilitates the analyses of global properties of the network, such as its functional modularity, and triggers many hypotheses on the molecular mechanisms implicated in AD. For instance, our analyses suggest a putative role for PDCD4 as a neuronal death regulator and ECSIT as a molecular link between oxidative stress, inflammation, and mitochondrial dysfunction in AD.

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Section: Interactome Network Associated To Adsupporting

confidence: 53%

Section: Interactome Network Associated To Admentioning

confidence: 99%

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

Soler-López¹,

Zanzoni²,

Lluís³

et al. 2010

Genome Res.

108

View full text Add to dashboard Cite

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“…All NADH dehydrogenase (ND) subunits are mitochondrial DNA encoded, whereas the remainder are encoded by the nuclear genome. Assembly and maintenance of this large multiprotein complex requires assistance of specific factors, such as the recently discovered NDUFAF1 (65), B17.2L (40), and Ecsit (66). In most cases, CI deficiency is caused by autosomal recessive mutations involving subunits encoded by the nuclear genome (55).…”

mentioning

confidence: 99%

Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology?

Koopman¹,

Verkaart²,

Visch³

et al. 2007

American Journal of Physiology-Cell Physiology

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121

116

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function of NADH:ubiquinone oxidoreductase or complex I (CI), the first and largest complex of the mitochondrial oxidative phosphorylation system, has been implicated in a wide variety of human disorders. To demonstrate a quantitative relationship between CI amount and activity and mitochondrial shape and cellular reactive oxygen species (ROS) levels, we recently combined native electrophoresis and confocal and video microscopy of dermal fibroblasts of healthy control subjects and children with isolated CI deficiency. Individual mitochondria appeared fragmented and/or less branched in patient fibroblasts with a severely reduced CI amount and activity (class I), whereas patient cells in which these latter parameters were only moderately reduced displayed a normal mitochondrial morphology (class II). Moreover, cellular ROS levels were significantly more increased in class I compared with class II cells. We propose a mechanism in which a mutation-induced decrease in the cellular amount and activity of CI leads to enhanced ROS levels, which, in turn, induce mitochondrial fragmentation when not appropriately counterbalanced by the cell's antioxidant defense systems. complex I; reactive oxygen species; microscopy; fluorescence MITOCHONDRIAL FUNCTION AND COMPLEX I DEFICIENCY

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“…Known as extrinsic assembly factors, they are required for producing the complete enzyme. Assembly factors (NDUFAF2-4 and FOXRED1) have been identified via human mutations that impair function (29,30,38), by homology with an assembly factor for complex I in Neurospora crassa (NDUFAF1) or by copurification with other known assembly factors (ECSIT and ACAD9) (31,32). The BN-PAGE comigration pattern of TMEM126B with NDUFAF1, ECSIT, and ACAD9 led to its characterization as a complex I assembly factor (27).…”

Section: Discussionmentioning

confidence: 99%

Assembly factors for the membrane arm of human complex I

Andrews

Carroll

Ding

et al. 2013

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

129

125

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Mitochondrial respiratory complex I is a product of both the nuclear and mitochondrial genomes. The integration of seven subunits encoded in mitochondrial DNA into the inner membrane, their association with 14 nuclear-encoded membrane subunits, the construction of the extrinsic arm from 23 additional nuclear-encoded proteins, iron-sulfur clusters, and flavin mononucleotide cofactor require the participation of assembly factors. Some are intrinsic to the complex, whereas others participate transiently. The suppression of the expression of the NDUFA11 subunit of complex I disrupted the assembly of the complex, and subcomplexes with masses of 550 and 815 kDa accumulated. Eight of the known extrinsic assembly factors plus a hydrophobic protein, C3orf1, were associated with the subcomplexes. The characteristics of C3orf1, of another assembly factor, TMEM126B, and of NDUFA11 suggest that they all participate in constructing the membrane arm of complex I. mitochondria | respiratory chain | NADH:ubiquinone oxidoreductase

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Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly

Abstract: Ecsit is a cytosolic adaptor protein essential for inflammatory response and embryonic development via the[Keywords: Mitochondria; oxidative phosphorylation; complex I; NADH:ubiquinone oxidoreductase; Ecsit; NDUFAF1] Supplemental material is available at http://www.genesdev.org.

Cited by 177 publications

References 25 publications

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease

Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology?

Assembly factors for the membrane arm of human complex I

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