Affinage

NDUFC2

NADH dehydrogenase [ubiquinone] 1 subunit C2 · UniProt O95298

Length
119 aa
Mass
14.2 kDa
Annotated
2026-06-10
10 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NDUFC2 is a structural subunit of mitochondrial respiratory chain complex I required for assembly of the membrane arm, and its loss compromises oxidative phosphorylation while driving downstream oxidative and inflammatory signaling (PMID:26888427, PMID:32969598). Bi-allelic loss-of-function variants in NDUFC2 produce severe defects in complex I activity, subunit expression, and assembly, with complexome profiling localizing the block to stalled biogenesis of the ND2 module of the membrane arm; lentiviral re-expression of wild-type NDUFC2 restores assembly, establishing it as causal and sufficient for this assembly step (PMID:32969598). Genetic disruption reduces complex I activity, mitochondrial membrane potential, and ATP while elevating reactive oxygen species and inflammation, accompanied by loss of cristae and ultrastructural mitochondrial damage that is exacerbated by high-NaCl and LPS stress and counteracted by resveratrol (PMID:26888427, PMID:28973657). This NDUFC2-dependent mitochondrial output sits upstream of vascular and cardiac pathology: loss in endothelial and smooth muscle cells impairs viability and angiogenesis and induces atherogenic markers (PMID:30808603), silencing in cardiomyocytes drives hypertrophy via SIRT3-AMPK-AKT-MnSOD signaling (PMID:37558995), and NDUFC2 overexpression suppresses NLRP3 inflammasome activation and endothelial-mesenchymal transformation in ischemia-reperfusion injury (PMID:37506315).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2016 High

    Established that NDUFC2 is functionally required for mitochondrial complex I, linking its loss to a coherent bioenergetic and oxidative phenotype rather than a single readout.

    Evidence Ndufc2 knock-out rat model plus in vitro assays for complex I activity, membrane potential, ATP, and ROS

    PMID:26888427

    Open questions at the time
    • Did not resolve which assembly step or module NDUFC2 contributes to
    • Mechanism linking ROS to downstream inflammation not defined
  2. 2017 Medium

    Connected NDUFC2 deficiency to ultrastructural mitochondrial damage and showed the phenotype is stress-modulated and pharmacologically tractable, refining how loss manifests cellularly.

    Evidence Rat heterozygous KO fibroblasts and human PBMCs with rs11237379 variant; TEM, ROS/ATP assays; resveratrol intervention

    PMID:28973657

    Open questions at the time
    • Causal chain from complex I defect to cristae loss not mechanistically dissected
    • Resveratrol effect on ROS not tied to a defined molecular target
  3. 2019 Medium

    Placed NDUFC2-dependent mitochondrial function upstream of vascular inflammatory and atherogenic programs in human vascular cells.

    Evidence siRNA silencing in endothelial and smooth muscle cells; viability, angiogenesis, atherogenesis marker assays

    PMID:30808603

    Open questions at the time
    • Signaling intermediates between mitochondrial dysfunction and atherogenic gene expression not identified
    • In vitro only
  4. 2020 High

    Resolved the precise molecular role of NDUFC2 as required and sufficient for assembly of the ND2 module of the complex I membrane arm, and established it as a Mendelian disease gene.

    Evidence Patient fibroblasts with homozygous variants; complexome profiling; activity assays; wild-type cDNA rescue

    PMID:32969598

    Open questions at the time
    • Atomic-level role of NDUFC2 within the assembly intermediate not defined
    • Direct assembly-factor or subunit contacts not mapped
  5. 2023 Medium

    Defined a specific signaling axis (SIRT3-AMPK-AKT-MnSOD) through which NDUFC2 loss causes cardiomyocyte hypertrophy, advancing the link from bioenergetic defect to cardiac pathology.

    Evidence siRNA silencing in H9c2 and primary rat cardiomyocytes; hypertrophy and pathway analyses

    PMID:37558995

    Open questions at the time
    • Causal ordering within SIRT3-AMPK-AKT-MnSOD not fully established
    • Single lab, in vitro models
  6. 2023 Medium

    Showed NDUFC2 acts upstream of NLRP3 inflammasome activation and endothelial-mesenchymal transformation in ischemia-reperfusion injury, extending its role to inflammatory tissue remodeling.

    Evidence OGD/R model in HBMECs with NDUFC2 overexpression; NLRP3 KO tMCAO mouse; EndoMT markers and antioxidant gene RT-PCR

    PMID:37506315

    Open questions at the time
    • Direct molecular link between NDUFC2-dependent ROS and NLRP3 activation not established
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the localized ND2-module assembly defect is mechanistically transduced into the distinct downstream programs (NLRP3 inflammasome, SIRT3-AMPK-AKT-MnSOD, EndoMT) remains unresolved.
  • No structural model of NDUFC2 within the membrane arm
  • ROS-to-signaling coupling not mechanistically defined
  • Tissue-specific downstream pathway selection not explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 2
Complex memberships
complex I ND2 modulemitochondrial respiratory chain complex I

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Ndufc2 disruption altered complex I assembly and activity, reduced mitochondrial membrane potential and ATP levels, and increased reactive oxygen species production and inflammation both in vitro and in vivo, establishing Ndufc2 as required for mitochondrial complex I function. Ndufc2 knock-out rat model (in vivo) and in vitro cellular studies; microarray expression analysis; functional assays for complex I activity, membrane potential, ATP, and ROS Journal of the American Heart Association High 26888427
2017 Ndufc2 deficiency causes marked mitochondrial dysfunction with increased ROS, loss of internal cristae, and ultrastructural impairment of mitochondrial morphology in rat heterozygous knock-out fibroblasts and human PBMCs homozygous for the rs11237379 variant; stress stimuli (high-NaCl, LPS) exacerbate the damage, and resveratrol counteracts ROS generation. In vitro fibroblasts from Ndufc2 heterozygous KO rats; human PBMCs; transmission electron microscopy for ultrastructural analysis; ROS/ATP assays; pharmacological intervention with resveratrol Human molecular genetics Medium 28973657
2020 Bi-allelic loss-of-function variants in NDUFC2 cause severe defects in complex I activity, subunit expression, and assembly, with complexome profiling revealing aberrant assembly intermediates indicative of stalled biogenesis specifically in the ND2 module of the membrane arm; lentiviral rescue with wild-type NDUFC2 cDNA restored complex I assembly, confirming the causal role of NDUFC2 in membrane arm assembly. Patient fibroblasts with homozygous NDUFC2 variants; biochemical complex I activity assays; complexome profiling; lentiviral transduction with wild-type NDUFC2 cDNA rescue EMBO molecular medicine High 32969598
2019 NDUFC2 silencing in human endothelial and vascular smooth muscle cells affected cell viability and angiogenesis and stimulated expression of markers of atherogenesis and plaque rupture, placing NDUFC2-dependent mitochondrial function upstream of vascular inflammatory signaling. siRNA-mediated NDUFC2 silencing in human vascular cells; cell viability assays; angiogenesis assays; expression analysis of atherogenesis markers International journal of cardiology Medium 30808603
2023 Ndufc2 silencing in H9c2 and primary rat cardiomyocytes caused cardiomyocyte hypertrophy through mitochondrial dysfunction, identifying SIRT3-AMPK-AKT-MnSOD as the major underlying signaling pathway. siRNA-mediated Ndufc2 silencing in H9c2 and primary cardiomyocytes; hypertrophy assays; pathway analysis of SIRT3, AMPK, AKT, and MnSOD signaling Molecular medicine (Cambridge, Mass.) Medium 37558995
2023 NDUFC2 overexpression suppressed NLRP3 inflammasome activation and endothelial-mesenchymal transformation (EndoMT) in human brain microvascular endothelial cells subjected to OGD/R, and rescued SOD1 and CAT mRNA expression, placing NDUFC2 upstream of NLRP3 activation in ischemia-reperfusion injury. In vitro OGD/R model in HBMECs; NDUFC2 overexpression; NLRP3 KO mouse tMCAO model; markers of EndoMT (α-SMA, CD31); RT-PCR for SOD1 and CAT Neuroreport Medium 37506315

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease. Journal of the American Heart Association 45 26888427
2019 High-Throughput RNA Sequencing Reveals NDUFC2-AS lncRNA Promotes Adipogenic Differentiation in Chinese Buffalo (Bubalus bubalis L). Genes 25 31500202
2020 Bi-allelic pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of complex I. EMBO molecular medicine 24 32969598
2017 In vitro characterization of mitochondrial function and structure in rat and human cells with a deficiency of the NADH: ubiquinone oxidoreductase Ndufc2 subunit. Human molecular genetics 24 28973657
2019 The reduction of NDUFC2 expression is associated with mitochondrial impairment in circulating mononuclear cells of patients with acute coronary syndrome. International journal of cardiology 20 30808603
2015 Expression profiling of SCN8A and NDUFC2 genes in colorectal carcinoma. Experimental oncology 15 25804238
2023 Polymorphic variants at NDUFC2, encoding a mitochondrial complex I subunit, associate with cardiac hypertrophy in human hypertension. Molecular medicine (Cambridge, Mass.) 8 37558995
2024 Targeting the HLC-1, LC-2/ad, and PC-14 lung cancer cell lines by the silver nanoparticles green-formulated by Descurainia sophia leaf extract. Molecular and cellular probes 6 39675531
2022 Impact of a NDUFC2 Variant on the Occurrence of Acute Coronary Syndromes. Frontiers in cardiovascular medicine 4 35711349
2023 NDUFC2 deficiency exacerbates endothelial mesenchymal transformation during ischemia-reperfusion via NLRP3. Neuroreport 2 37506315

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