An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages

SUMMARY ECSIT is a mitochondrial complex I (CI)-associated protein that has been shown to regulate the production of mitochondrial reactive oxygen species (mROS) following engagement of Toll-like receptors (TLRs). We have generated an Ecsit conditional knockout (CKO) mouse strain to study the in vivo role of ECSIT. ECSIT deletion results in profound alteration of macrophage metabolism, leading to a striking shift to reliance on glycolysis, complete disruption of CI activity, and loss of the CI holoenzyme and multiple subassemblies. An increase in constitutive mROS production in ECSIT-deleted macrophages prevents further TLR-induced mROS production. Surprisingly, ECSIT-deleted cells accumulate damaged mitochondria because of defective mitophagy. ECSIT associates with the mitophagy regulator PINK1 and exhibits Parkin-dependent ubiquitination. However, upon ECSIT deletion, we observed increased mitochondrial Parkin without the expected increase in mitophagy. Taken together, these results demonstrate a key role of ECSIT in CI function, mROS production, and mitophagy-dependent mitochondrial quality control.

• Publication year

  2018

• Venue

  Cell Reports

• Publication date

  2018-03-06

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.celrep.2018.02.051PMID 29514094PMCID 5909989
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Recurrent ECSIT mutation encoding V140A triggers hyperinflammation and promotes hemophagocytic syndrome in extranodal NK/T cell lymphoma

  2018cited by this paper
• NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect

  2017cited by this paper
• The Assembly Pathway of Mitochondrial Respiratory Chain Complex I.

  2017influential reference
• ELMO1 Regulates Autophagy Induction and Bacterial Clearance During Enteric Infection

  2017cited by this paper
• Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense

  2016cited by this paper
• A LON-ClpP Proteolytic Axis Degrades Complex I to Extinguish ROS Production in Depolarized Mitochondria

  2016influential reference
• Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype

  2016cited by this paper
• The Legionella Kinase LegK2 Targets the ARP2/3 Complex To Inhibit Actin Nucleation on Phagosomes and Allow Bacterial Evasion of the Late Endocytic Pathway

  2015cited by this paper
• Metformin Inhibits the Production of Reactive Oxygen Species from NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated Macrophages*

  2015cited by this paper
• The kinases Mst1 and Mst2 positively regulate phagocyte ROS induction and bactericidal activity

  2015cited by this paper
• A giant molecular proton pump: structure and mechanism of respiratory complex I

  2015cited by this paper
• Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization.

  2014cited by this paper
• Self and nonself: how autophagy targets mitochondria and bacteria.

  2014cited by this paper
• An update on complex I assembly: the assembly of players

  2014cited by this paper
• Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies: Toward Mitochondria-Targeted Clinical Strategies

  2014cited by this paper
• Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice

  2014cited by this paper
• Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release.

  2014cited by this paper
• The role of mitochondrial OXPHOS dysfunction in the development of neurologic diseases.

  2013cited by this paper
• Intestinal epithelial autophagy is essential for host defense against invasive bacteria.

  2013cited by this paper
• Faculty Opinions recommendation of The ubiquitin ligase parkin mediates resistance to intracellular pathogens.

  2013cited by this paper
• Assembly factors for the membrane arm of human complex I

  2013cited by this paper
• Mitochondria and Reactive Oxygen Species: Physiology and Pathophysiology

  2013cited by this paper
• PARKIN ubiquitin ligase mediates resistance to intracellular pathogens

  2013cited by this paper
• TIMMDC1/C3orf1 Functions as a Membrane-Embedded Mitochondrial Complex I Assembly Factor through Association with the MCIA Complex

  2013influential reference
• Loss of cytochrome c oxidase promotes RAS-dependent ROS production from the ER resident NADPH oxidase, Yno1p, in yeast.

  2013cited by this paper
• Understanding mitochondrial complex I assembly in health and disease.

  2012cited by this paper
• Complexome profiling identifies TMEM126B as a component of the mitochondrial complex I assembly complex.

  2012influential reference
• The pathways of mitophagy for quality control and clearance of mitochondria

  2012cited by this paper
• Progression of Chronic Liver Inflammation and Fibrosis Driven by Activation of c-JUN Signaling in Sirt6 Mutant Mice*

  2012cited by this paper
• YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation

  2012cited by this paper
• Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases

  2012cited by this paper
• TLR signaling augments macrophage bactericidal activity through mitochondrial ROS

  2011influential reference
• Ubiquitin-proteasome system and mitochondria - reciprocity.

  2011cited by this paper
• Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells

  2011cited by this paper
• A hyperactive piggyBac transposase for mammalian applications

  2011cited by this paper
• Mutations in the mitochondrial complex I assembly factor NDUFAF1 cause fatal infantile hypertrophic cardiomyopathy

  2011cited by this paper
• Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation.

  2011cited by this paper
• Ubiquitin-dependent mitochondrial protein degradation.

  2011cited by this paper
• Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane*♦

  2011influential reference
• PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin

  2010influential reference
• Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I.

  2010influential reference
• Assembly factors of human mitochondrial complex I and their defects in disease

  2010cited by this paper
• Evaluation of the Mitochondrial Respiratory Chain and Oxidative Phosphorylation System Using Blue Native Gel Electrophoresis

  2009cited by this paper
• High efficiency of ROS production by glycerophosphate dehydrogenase in mammalian mitochondria.

  2009cited by this paper
• A drug-inducible system for direct reprogramming of human somatic cells to pluripotency.

  2008cited by this paper
• Parkin is recruited selectively to impaired mitochondria and promotes their autophagy

  2008cited by this paper
• Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly.

  2007influential reference
• Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases

  2006cited by this paper
• Itch/AIP4 mediates Deltex degradation through the formation of K29‐linked polyubiquitin chains

  2006cited by this paper
• Blue native PAGE

  2006cited by this paper
• Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability.

  2005cited by this paper
• Generation of Reactive Oxygen Species in the Reaction Catalyzed by α-Ketoglutarate Dehydrogenase

  2004cited by this paper
• Generation of reactive oxygen species in the reaction catalyzed by alpha-ketoglutarate dehydrogenase.

  2004cited by this paper
• Mitochondrial α-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species

  2004cited by this paper
• Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species.

  2004cited by this paper
• A highly efficient recombineering-based method for generating conditional knockout mutations.

  2003cited by this paper
• Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy

  2003cited by this paper
• Architecture of Succinate Dehydrogenase and Reactive Oxygen Species Generation

  2003cited by this paper
• Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis.

  2003influential reference
• Mutations in human nuclear genes encoding for subunits of mitochondrial respiratory complex I: the NDUFS4 gene.

  2002cited by this paper
• Blue Native electrophoresis to study mitochondrial and other protein complexes.

  2002cited by this paper
• Mitochondrial ROS Metabolism: Modulation by Uncoupling Proteins

  2001cited by this paper
• Isolated complex I deficiency in children: Clinical, biochemical and genetic aspects

  2000cited by this paper
• The Contribution of Mitochondrial Respiratory Complexes to the Production of Reactive Oxygen Species

  2000cited by this paper
• Respiratory chain complex I deficiency

  1999cited by this paper
• ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway.

  1999influential reference
• The YTA10-12 complex, an AAA protease with chaperone-like activity in the inner membrane of mitochondria.

  1996cited by this paper
• Afg3p, a mitochondrial ATP‐dependent metalloprotease, is involved in degradation of mitochondrially‐encoded Cox1, Cox3, Cob, Su6, Su8 and Su9 subunits of the inner membrane complexes III, IV and V

  1996cited by this paper
• Fatal mitochondrial myopathy, lactic acidosis, and complex I deficiency associated with a heteroplasmic A→G mutation at position 3251 in the mitochondrial tRNALeu(UUR) gene

  1996cited by this paper
• Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase.

  1996cited by this paper
• Tumoricidal alveolar macrophage and tumor infiltrating macrophage cell lines

  1991cited by this paper
• A case of mitochondrial myopathy, lactic acidosis and complex I deficiency

  1990cited by this paper
• Generation of macrophage cell line from fresh bone marrow cells with a myc/raf recombinant retrovirus.

  1989cited by this paper
• A murine macrophage cell line, immortalized by v‐raf and v‐myc oncogenes, exhibits normal macrophage functions

  1987cited by this paper

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  2025cites this paper
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  2025cites this paper
• Mitochondrial dysfunction in hepatocellular carcinoma: from metabolism to targeted therapies

  2025cites this paper
• Mitochondria reactive oxygen species signaling-dependent immune responses in macrophages and T cells.

  2025cites this paper
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  2025cites this paper
• Mitochondrial dynamics and metabolism in macrophages for cardiovascular disease: A review.

  2025cites this paper
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  2025cites this paper
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  2025cites this paper
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• Nature conference on mitochondria and immunity: Uncovering Mitochondria–Immunity crosstalk and fostering global scientific exchanges

  2024cites this paper
• ECSIT: Biological function and involvement in diseases.

  2024cites this paper
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• Mitochondrial electron transport chain in macrophage reprogramming: Potential role in antibacterial immune response

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• ECSIT facilitates memory CD8+ T cell development by mediating fumarate synthesis during viral infection and tumorigenesis

  2024cites this paper
• Role of mitochondria in regulating immune response during bacterial infection.

  2023cites this paper
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  2023cites this paper
• ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein

  2023cites this paper
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  2023cites this paper
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• Molecular characteristics of the multi‐functional FAO enzyme ACAD9 illustrate the importance of FADH2/NADH ratios for mitochondrial ROS formation

  2022cites this paper
• Multistability in Macrophage Activation Pathways and Metabolic Implications

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• A novel mechanism for NLRP3 inflammasome activation

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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
• Mitophagy Receptors and Mediators: Therapeutic Targets in the Management of Cardiovascular Ageing.

  2020cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
• Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly (MCIA) Complex Factors in the Biogenesis of Complex I

  2019cites this paper
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  2019cites this paper
• Understanding ACAD9 function and the physiologic consequences of its deficiency

  2019cites this paper
• Metabolic Reprogramming in Mitochondria of Myeloid Cells

  2019cites this paper
• Emerging perspectives on mitochondrial dysfunction and inflammation in Alzheimer’s disease

  2019influential citation
• TLR2 signaling pathway combats Streptococcus uberis infection by inducing production of mitochondrial reactive oxygen species

  2019cites this paper
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  2019cites this paper
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  2019cites this paper
• Transcriptome analysis reveals negative correlation between transcripts of mitochondrial genes and L1HS, and positive correlation between KRAB-ZFPs and older LINE elements in normal somatic tissue

  2018cites this paper
• Mitochondria in innate immune signaling.

  2018cites this paper
• How Mitochondrial Metabolism Contributes to Macrophage Phenotype and Functions.

  2018cites this paper
• Title: Mitochondrial respiration contributes to the interferon gamma response in antigen

  year unknowncites this paper