Gene Ontology annotation through association of InterPro records with GO terms.
Annotation inferences using phylogenetic trees
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PANTHER phylogenetic propagation across the cytochrome c1 family assigns CYC1 to respiratory chain complex III (GO:0045275) and to mitochondrial electron transport, ubiquinol to cytochrome c (GO:0006122), consistent with the conserved subunit identity from fungal to mammalian bc1 complexes.
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
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Compara orthology transfers mouse-derived annotations to human CYC1, including respiratory chain complex III (GO:0045275) and mitochondrion (GO:0005739) which are correct, and response to glucagon (GO:0033762) from rat which is not supported by any direct human evidence and likely reflects a transcriptional/abundance correlate in glucagon-stimulated tissues rather than a CYC1 function.
Automatic assignment of GO terms using logical inference, based on on inter-ontology links.
Electronic Gene Ontology annotations created by ARBA machine learning models
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ARBA rule-based annotation assigns CYC1 the broad cellular component term membrane (GO:0016020). More specific evidence (IDA, TAS, IEA) supports mitochondrial inner membrane (GO:0005743) as the correct compartment.
Combined Automated Annotation using Multiple IEA Methods.
Huntingtin interacting proteins are genetic modifiers of neurodegeneration.
Defining the membrane proteome of NK cells.
Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes.
Proteomic characterization of the human sperm nucleus.
Structural organization of the human mitochondrial cytochrome c1 gene.
Architecture of the human interactome defines protein communities and disease networks.
Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
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Cryo-EM structure of the human megacomplex I2III2IV2 places CYC1 as a catalytic subunit of dimeric Complex III at the mitochondrial inner membrane, with heme c1 positioned for electron transfer to soluble cytochrome c.
"Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2)."
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
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IntAct interactome screen captures CYC1 with polyQ disease proteins (HTT, ATXN1, ATXN3-3); likely co-aggregation/contamination, not a physiological CYC1 binding function.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
Mutations in CYC1, encoding cytochrome c1 subunit of respiratory chain complex III, cause insulin-responsive hyperglycemia.
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Homozygous p.Trp96Cys and p.Leu215Phe variants cause isolated complex III deficiency with insulin-responsive hyperglycemia and recurrent metabolic crises; cytochrome c1 is reduced in patient muscle and fibroblasts, and wild-type CYC1 rescues complex III activity in patient cells, giving direct functional evidence that CYC1 is required for complex III enzymatic activity. The per-tissue CIII/citrate-synthase ratios (~4% liver, 24% muscle, 25% fibroblasts) are reported in the full text, which is not in the cache; the quoted abstract supports the reduction and the rescue but not those figures.
"Cytochrome c1 is present at reduced levels in the skeletal muscle and skin fibroblasts of affected individuals. ... exogenous expression of wild-type CYC1 rescues complex III activity,"
Pathological variants in nuclear genes causing mitochondrial complex III deficiency: an update.
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2024 review consolidates known nuclear genes for complex III deficiency and lists CYC1 (OMIM 615453) as a core subunit gene with four reported cases/families and variants p.Trp96Cys, p.Leu215Phe, and p.Arg317Trp.
"Originally, two unrelated patients carrying disease‐associated variants in CYC1 were reported (NM_001916.5:c.288G > T, NP_001907.3:p.Trp96Cys and NM_001916.5:c.643C > T, NP_001907.3:p.Leu215Phe)"
The functional significance of mitochondrial respiratory chain supercomplexes.
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Expert 2023 review of respiratory supercomplexes; emphasizes complex III's obligate homodimer architecture and the Q-cycle role in linking ubiquinol oxidation to cytochrome c reduction.
"CIII couples electron transfer from QH2 to cytochrome c (Cytc) with the shuttling of H+ into the IMS via a mechanism called Q‐cycle (Mitchell, 1975; Osyczka et al, 2005)."
The flexible chain: regulation of structure and activity of ETC complexes defines rate of ATP synthesis and sites of superoxide generation.
Defective complex III mitochondrial respiratory chain due to a novel variant in CYC1 gene masquerades acute demyelinating syndrome or Leber hereditary optic neuropathy.
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Case report of a homozygous p.Arg317Trp CYC1 variant presenting with complex III deficiency mimicking acute demyelinating syndrome or Leber hereditary optic neuropathy, expanding the clinical spectrum of CYC1-related disease.
"We report on a 10-year-old girl born to consanguineous Iranian parents presenting with recurrent visual loss episodes and optic nerve contrast enhancement in brain imaging reminiscent of an acquired demyelination syndrome (i.e. optic neuritis or multiple sclerosis), who was ultimately confirmed to have a novel homozygous missense variant of unknown significance, c.949C > T; p.(Arg317Trp) in the CYC1 gene,"
IMMP2L enhances the structure and function of mitochondrial GPD2 dehydrogenase.
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In Immp2l knockout mice, the inner mitochondrial membrane peptidase IMMP2L is required to cleave the transit peptide of cytochrome c1 (Cyc1); uncleaved Cyc1 accumulates and AlphaFold2-Multimer modeling predicts altered Cyc1-Cyb contacts, with respiration reduced ~27% in MEFs and ~31% for succinate-driven kidney respiration.
"is devoid of all Immp2l peptidase activity, as confirmed by its failure to cleave and remove the signal transit peptides from Cyc1 and Gpd2 [3]. ... In this analysis, Alpha-Fold2-Multimer predicted 56 ‘new’ molecular interactions between the ‘uncleaved’ signal transit peptide of Cyc1 and Cyb in mice (Figure 7D)."
Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
Electron transfer from ubiquinol to cytochrome c of complex III
Unknown peptidase cleaves UQCRFS1 subunit
TTC19 clears UQCRFS1 fragments from Complex III
Deep research report on P08574 (openai o3-deep-research-2025-06-26)
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Detailed narrative review of CYC1 cytochrome c1 function, structure, maturation by HCCS, role in the Q-cycle as the electron donor to soluble cytochrome c, supercomplex organization, and clinical relevance (MC3DN6, insulin-responsive hyperglycemia).
Deep research report on P08574 (falcon Edison Scientific Literature)
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Comprehensive 2024-2025 update on CYC1 function (electron-transfer subunit of complex III), topology (IMM, single C-proximal TM, heme domain in IMS), maturation (HCCS heme attachment, IMMP2L cleavage), and disease (MC3DN6 with p.Trp96Cys, p.Leu215Phe, p.Arg317Trp).