NDUFS4 Gene

HGNC Family	Mitochondrial respiratory chain complexes
Name	NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase)
Description	This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNDUFS4 is a critical accessory subunit of mitochondrial complex I that is indispensable for proper assembly and full catalytic activity of the enzyme. Several studies have shown that mutations in NDUFS4—including nonsense, frameshift, and splice‐site alterations—disrupt the incorporation of nuclear‐encoded subunits, compromising the assembly and stability of complex I and ultimately causing severe mitochondrial dysfunction and Leigh syndrome. Patient mitochondria and corresponding model systems have revealed that loss or defective processing of NDUFS4 destabilizes the holoenzyme, interferes with the integration of adjacent subunits (such as NDUFA12) and prompts compensatory increases in specific assembly factors, thereby impeding normal respiratory function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPost‐translational modifications play a pivotal role in regulating the function of NDUFS4. For example, the endoplasmic reticulum–mitochondria bridging protein BAP31 facilitates the translocation of NDUFS4 from the cytosol into mitochondria, while cAMP/PKA‐mediated phosphorylation at a specific serine/threonine consensus sequence in its C-terminal region promotes mitochondrial import and prevents its retrograde diffusion to the cytosol. Disruption of these phosphorylation sites—either by direct mutation or by interference with the signaling cascade—impairs the assembly and activation of complex I, and in some models even precludes the replacement of oxidatively damaged subunits."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to these protein‐level regulatory events, the expression of NDUFS4 is tightly controlled at the transcript level via alternative splicing and nonsense-mediated mRNA decay. Aberrant regulation of NDUFS4 transcripts—as observed in patient fibroblasts and various knockout mouse models—further compromises complex I assembly, leading to distinctive metabolic and neurological phenotypes. Experimental models have not only underscored the importance of precise NDUFS4 expression for mitochondrial homeostasis but have also provided novel insights into therapeutic strategies to overcome defects in complex I biogenesis and function. These findings extend from molecular studies of transcript regulation to investigations in animal and cellular reprogramming systems, emphasizing the broad impact of NDUFS4 dysfunction in mitochondrial diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael Lazarou, Matthew McKenzie, Akira Ohtake, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Analysis of the assembly profiles for mitochondrial- and nuclear-DNA-encoded subunits into complex I."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00074-07"}], "href": "https://doi.org/10.1128/MCB.00074-07"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17438127"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17438127"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Arcangela Iuso, Salvatore Scacco, Claudia Piccoli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dysfunctions of cellular oxidative metabolism in patients with mutations in the NDUFS1 and NDUFS4 genes of complex I."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M513387200"}], "href": "https://doi.org/10.1074/jbc.M513387200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16478720"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16478720"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Salvatore Scacco, Vittoria Petruzzella, Sandy Budde, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Activation of the cAMP cascade in human fibroblast cultures rescues the activity of oxidatively damaged complex I."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2011.11.030"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2011.11.030"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22198267"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22198267"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Megan E Breuer, Peter H G M Willems, Jan A M Smeitink, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cellular and animal models for mitochondrial complex I deficiency: a focus on the NDUFS4 subunit."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "IUBMB Life (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/iub.1127"}], "href": "https://doi.org/10.1002/iub.1127"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23378164"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23378164"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Merel J W Adjobo-Hermans, Ria de Haas, Peter H G M Willems, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "-/-"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " mice and Leigh syndrome patients: A stabilizing role for NDUFAF2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Bioenerg (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbabio.2020.148213"}], "href": "https://doi.org/10.1016/j.bbabio.2020.148213"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32335026"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32335026"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Vittoria Petruzzella, Damiano Panelli, Alessandra Torraco, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2023.12.020"}], "href": "https://doi.org/10.1016/j.neuron.2023.12.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38266647"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38266647"}]}]}]}
Synonyms	CI-18, CI-18 kDa, AQDQ, CI-AQDQ
Proteins	NDUS4_HUMAN
NCBI Gene ID	4724
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

NDUFS4 has 7,063 functional associations with biological entities spanning 9 categories (molecular profile, organism, disease, phenotype or trait, functional term, phrase or reference, chemical, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 133 datasets.

Click the + buttons to view associations for NDUFS4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

NDUFS4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of NDUFS4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of NDUFS4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of NDUFS4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of NDUFS4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of NDUFS4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of NDUFS4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of NDUFS4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of NDUFS4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of NDUFS4 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of NDUFS4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of NDUFS4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with NDUFS4 protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of NDUFS4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of NDUFS4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of NDUFS4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations	phenotypes associated with NDUFS4 gene from the curated ClinVar Gene-Phenotype Associations dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with NDUFS4 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing NDUFS4 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of NDUFS4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing NDUFS4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing NDUFS4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing NDUFS4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing NDUFS4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with NDUFS4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with NDUFS4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	CORUM Protein Complexes	protein complexs containing NDUFS4 protein from the CORUM Protein Complexes dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of NDUFS4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with NDUFS4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with NDUFS4 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with NDUFS4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of NDUFS4 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by NDUFS4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores	diseases involving NDUFS4 gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving NDUFS4 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with NDUFS4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with NDUFS4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with NDUFS4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with NDUFS4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for NDUFS4 protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at NDUFS4 gene from the ENCODE Histone Modification Site Profiles dataset.