SDHC

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006121 mitochondrial electron transport, succinate to ubiquinone	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for the biological process of electron transport from succinate to ubiquinone. This is the defining biological process for Complex II/SDH in the mitochondrial electron transport chain. SDHC, together with SDHD, forms the membrane arm where ubiquinone is ultimately reduced to ubiquinol. SDHC provides key residues (Ile56, Trp61, Met65, Ile69) that directly contact ubiquinone at the Q-site (PMID:37098072). The heme b coordinated by His127 of SDHC may serve as an electron sink during the two-electron reduction of ubiquinone (PMID:37098072). The IBA is phylogenetically supported with evidence from orthologous SDH cytochrome b560 subunits. Reason: This is a core biological process for SDHC. SDHC is essential for the terminal step of electron transfer from succinate to ubiquinone in Complex II, providing the Q-site and heme b environment. Well-supported by IBA phylogenetic inference and confirmed by the human Complex II cryo-EM structure (PMID:37098072). Supporting Evidence: PMID:37098072 UQ is also observed to bind at the entrance of the pocket formed by the transmembrane helix I of SDHC, transmembrane helix II of SDHD, and the C-terminal segment of SDHB. It interacts with Pro-SDHB197, Trp-SDHB201, Ile-SDHB246, Ile-SDHC56, Trp-SDHC61, Met-SDHC65, Ile-SDHC69, and Tyr-SDHD114 PMID:9533030 Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex in both the tricarboxylic acid cycle and the aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic organisms
GO:0045273 respiratory chain complex II (succinate dehydrogenase)	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation that SDHC is part of respiratory chain complex II. SDHC is one of the four core subunits of SDH/Complex II, serving as a membrane anchor. The cryo-EM structure of human Complex II at 2.86 angstroms (PMID:37098072) directly resolved SDHC with three transmembrane helices in the membrane domain. All four subunits (SDHA, SDHB, SDHC, SDHD) were confirmed by SDS-PAGE and mass spectrometry (PMID:37098072). Reason: SDHC is unambiguously a subunit of Complex II. This is confirmed by the cryo-EM structure (PMID:37098072), the original cDNA cloning study (PMID:9533030), and is a core structural annotation. The IBA is phylogenetically sound. Supporting Evidence: PMID:37098072 All the four subunits (SDHA, SDHB, SDHC, and SDHD) were detected by SDS-PAGE (SI Appendix, Fig. S1D) and mass spectrometry (MS) (SI Appendix, Table S1). PMID:9533030 the amino acid sequences of the large (cybL) and small (cybS) subunits of cytochrome b in human liver complex II were deduced from cDNAs isolated by homology probing
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation based on UniProt subcellular location mapping. SDHC is an integral membrane protein with three transmembrane helices that spans the mitochondrial inner membrane. This is confirmed by the cryo-EM structure (PMID:37098072) and the UniProt annotation (ECO:0000269\|PubMed:37098072). SDHC topology shows matrix-facing N-terminus, three transmembrane helices, and short intermembrane space loops. Reason: Correct localization. SDHC is an integral multi-pass protein of the mitochondrial inner membrane, confirmed by cryo-EM at 2.86 angstroms. This is a core localization annotation. Supporting Evidence: PMID:37098072 The entire hydrophobic domain contains two membrane-anchored subunits: SDHC and SDHD
GO:0006099 tricarboxylic acid cycle	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for TCA cycle involvement from combined automated methods including ortholog transfer from mouse (UniProtKB:Q9CZB0) and InterPro/UniPathway mapping. Complex II is the only membrane-bound member of the TCA cycle, catalyzing the oxidation of succinate to fumarate. SDHC contributes to this reaction by anchoring the complex in the membrane and providing the Q-site for ubiquinone reduction, which is coupled to succinate oxidation. Reason: TCA cycle involvement is a core function of SDHC as part of Complex II. The original cDNA cloning study (PMID:9533030) describes Complex II as an enzyme in both the TCA cycle and the respiratory chain. Supporting Evidence: PMID:9533030 Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex in both the tricarboxylic acid cycle and the aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic organisms
GO:0009055 electron transfer activity	IEA GO_REF:0000002	MODIFY	Summary: IEA annotation for electron transfer activity from InterPro (IPR014314, IPR018495). SDHC contributes to electron transfer within Complex II by harboring the heme b prosthetic group (axially coordinated by His127 of SDHC) and providing residues that form the ubiquinone binding pocket. The heme b serves as an electron sink that stabilizes the semiquinone radical during the two-electron reduction of ubiquinone (PMID:37098072). However, SDHC does not independently perform electron transfer; it contributes to the complex-level activity. The qualifier should ideally be 'contributes_to' rather than 'enables'. Reason: SDHC contributes to electron transfer as part of Complex II via heme b and the Q-site, but it does not independently enable electron transfer activity. The InterPro-based annotation is reasonable but the qualifier should be 'contributes_to'. Additionally, a more specific term would be preferred if available. Accept the annotation concept but flag that the qualifier in GOA is 'enables' whereas 'contributes_to' would be more appropriate for a membrane anchor subunit. Proposed replacements: electron transfer activity Supporting Evidence: PMID:37098072 the heme b is proposed to serve as an electron sink in the electron transfer pathway
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for general membrane localization from InterPro (IPR018495, IPR034804). SDHC is an integral membrane protein with three transmembrane helices. This is correct but very general; the more specific term GO:0005743 (mitochondrial inner membrane) is also annotated and provides a much more informative localization. Reason: Correct but general. SDHC is an integral membrane protein with three transmembrane helices. It is acceptable for IEA annotations to be broader than experimental annotations. The more specific GO:0005743 is also present.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword (KW-0479 Metal-binding) mapping. SDHC coordinates heme b iron via the axial ligand His127 (shared with SDHD). The heme b iron is the relevant metal ion. This annotation is correct but very general; the more specific GO:0020037 (heme binding) is also annotated via ISS. Reason: Correct but general. SDHC binds the iron atom of heme b through axial coordination at His127. The more specific child term GO:0020037 (heme binding) is also annotated. It is acceptable for IEA keyword-based annotations to use broader terms. Supporting Evidence: PMID:37098072 The two membrane-anchored proteins (SDHC and SDHD) in human CII, each with three transmembrane helices, contain only one heme b group
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: IPI annotation from a large-scale neurodegenerative disease interactome mapping study (Haenig et al. 2020) using systematic yeast two-hybrid screening. The GOA contains five separate entries for this PMID with different interactors: PRKCA (P17252), YWHAG (P61981), SETDB1 (Q15047-2), LMO3 (Q8TAP4-4), and KAT5 (Q92993). These interactions were detected in a high-throughput screen focused on neurodegenerative disease-associated proteins. SDHC is a small transmembrane mitochondrial protein with limited cytoplasmic exposure; direct physical interactions with nuclear/cytoplasmic proteins like PRKCA, YWHAG, KAT5, SETDB1, and LMO3 are of uncertain biological significance and may reflect Y2H artifacts from overexpression of fragments outside their native membrane context. Reason: The 'protein binding' term is uninformative per GO curation guidelines. Furthermore, these interactions were detected in a high-throughput Y2H screen focused on neurodegenerative disease networks. The biological relevance of interactions between a small mitochondrial inner membrane protein (SDHC) and nuclear/cytoplasmic proteins (PRKCA, YWHAG, KAT5, SETDB1, LMO3) is highly questionable. Y2H is known to produce false positives, especially for membrane proteins tested outside their native lipid environment. The core protein-protein interactions of SDHC (with SDHD, SDHB, SDHA within Complex II) are already captured by the CC annotation GO:0045273. Supporting Evidence: PMID:32814053 we report on an interactome map that focuses on neurodegenerative disease (ND), connects
GO:0005739 mitochondrion	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for mitochondrial localization via Ensembl Compara ortholog transfer from mouse (UniProtKB:Q9CZB0). SDHC has a mitochondrial transit peptide (residues 1-29, inferred by similarity) and is localized to the mitochondrial inner membrane as part of Complex II. Confirmed by the cryo-EM structure (PMID:37098072) and mass spectrometry identification in the mitochondrial proteome (PMID:34800366). Reason: Correct localization, well supported by structural evidence (PMID:37098072) and proteomics (PMID:34800366, PMID:21269460, PMID:25944712). SDHC is a well-established mitochondrial protein.
GO:0005759 mitochondrial matrix	IEA GO_REF:0000107	REMOVE	Summary: IEA annotation for mitochondrial matrix localization via Ensembl Compara ortholog transfer from mouse (UniProtKB:Q9CZB0). The GOA qualifier is 'is_active_in'. This is problematic for SDHC because SDHC is an integral transmembrane protein that spans the inner membrane, not a matrix protein. While the N-terminal domain of SDHC (residues 30-65) faces the matrix, the majority of the protein consists of three transmembrane helices spanning the membrane. Describing SDHC as 'is_active_in' the mitochondrial matrix is misleading; it is more accurately localized to the mitochondrial inner membrane (GO:0005743). Reason: SDHC is an integral multi-pass transmembrane protein of the inner mitochondrial membrane, not a matrix protein. The cryo-EM structure (PMID:37098072) clearly shows SDHC embedded in the membrane with three transmembrane helices. The N-terminal domain extends into the matrix but the protein's primary localization is the inner membrane itself, which is already annotated. Mitochondrial matrix (with qualifier 'is_active_in') is misleading for a transmembrane anchor subunit. Supporting Evidence: PMID:37098072 The entire hydrophobic domain contains two membrane-anchored subunits: SDHC and SDHD
GO:0008177 succinate dehydrogenase (quinone) activity	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for SDH quinone reductase activity via Ensembl Compara ortholog transfer from mouse (UniProtKB:Q9CZB0). GO:0008177 is defined as the overall reaction of the SDH complex (succinate + quinone -> fumarate + quinol). The qualifier 'contributes_to' is appropriate for SDHC, which does not independently catalyze this reaction but provides essential structural components: the membrane anchor, the Q-binding site (residues Ile56, Trp61, Met65, Ile69 directly contact ubiquinone), and the heme b environment (His127 as axial ligand). Without SDHC, the complex cannot reduce ubiquinone. Reason: The 'contributes_to' qualifier is correctly used here. SDHC provides essential structural contributions to the SDH quinone activity by forming part of the Q-site and harboring the heme b, but does not independently catalyze the reaction. This is consistent with the pattern used for Complex II subunit annotations in the SDHA and SDHB reviews. Supporting Evidence: PMID:37098072 UQ is also observed to bind at the entrance of the pocket formed by the transmembrane helix I of SDHC, transmembrane helix II of SDHD, and the C-terminal segment of SDHB. It interacts with Pro-SDHB197, Trp-SDHB201, Ile-SDHB246, Ile-SDHC56, Trp-SDHC61, Met-SDHC65, Ile-SDHC69, and Tyr-SDHD114 file:human/SDHC/SDHC-deep-research-falcon.md Correct gene/protein: SDHC encodes the membrane-embedded cytochrome b560 subunit of mitochondrial succinate dehydrogenase (Complex II), forming the membrane arm with SDHD. It houses the heme b and contributes to the ubiquinone-binding pocket
GO:0045273 respiratory chain complex II (succinate dehydrogenase)	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for Complex II membership via Ensembl Compara ortholog transfer from mouse (UniProtKB:Q9CZB0). Consistent with IBA, ISS, IDA, and TAS annotations for the same term. Reason: Correct and consistent with multiple lines of evidence from different sources. SDHC is unambiguously a subunit of Complex II.
GO:0005743 mitochondrial inner membrane	NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-...	ACCEPT	Summary: NAS annotation from ComplexPortal based on review by Signes and Fernandez-Vizarra (2018) on assembly of OXPHOS complexes. SDHC is an integral multi-pass protein of the mitochondrial inner membrane, forming the membrane anchor of Complex II together with SDHD. Confirmed by cryo-EM (PMID:37098072). Reason: Correct localization. SDHC is an integral protein of the inner mitochondrial membrane with three transmembrane helices, confirmed by the cryo-EM structure (PMID:37098072). Supporting Evidence: PMID:37098072 The entire hydrophobic domain contains two membrane-anchored subunits: SDHC and SDHD
GO:0006099 tricarboxylic acid cycle	NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-...	ACCEPT	Summary: NAS annotation from ComplexPortal for TCA cycle involvement based on the OXPHOS assembly review (PMID:30030361). SDHC is a structural subunit of Complex II which catalyzes the succinate to fumarate step of the TCA cycle. Reason: Correct and consistent with IEA and TAS annotations for the same term. TCA cycle involvement is a core function of SDHC as part of Complex II. Supporting Evidence: PMID:30030361 The assembly of the five oxidative phosphorylation system (OXPHOS) complexes in the inner mitochondrial membrane is an intricate process
GO:0006121 mitochondrial electron transport, succinate to ubiquinone	NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-...	ACCEPT	Summary: NAS annotation from ComplexPortal for the specific electron transport process from succinate to ubiquinone. SDHC is essential for this process because it forms part of the ubiquinone binding site and provides the heme b environment needed for electron flow from the [3Fe-4S] cluster to ubiquinone. Consistent with the IBA annotation for the same term. Reason: Core biological process for SDHC. SDHC provides the terminal portion of the electron transfer pathway in Complex II by forming the Q-binding pocket with SDHD and SDHB. Supporting Evidence: PMID:37098072 The edge-to-edge distance between these redox-active prosthetic groups is less than 14 Å (Fig. 3), a distance range that can efficiently support the delivery of electrons between these redox centers (22)
GO:0042776 proton motive force-driven mitochondrial ATP synthesis	NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-...	REMOVE	Summary: NAS annotation from ComplexPortal suggesting SDHC is involved in proton motive force-driven mitochondrial ATP synthesis. This annotation is problematic because Complex II does NOT pump protons across the inner mitochondrial membrane. Unlike Complexes I, III, and IV which translocate protons to generate the proton motive force, Complex II transfers electrons from succinate to ubiquinone without any proton pumping. Complex II contributes to ATP synthesis only indirectly by feeding reduced ubiquinol into the Q pool, which is then oxidized by Complex III (which does pump protons). The same annotation was marked REMOVE for SDHB in the parallel review. Reason: Complex II is the only OXPHOS complex that does NOT pump protons. The proton motive force is generated by Complexes I, III, and IV. Complex II feeds electrons into the ubiquinone pool but does not directly contribute to the proton gradient. This annotation is misleading and was also marked REMOVE for SDHB. The correct process annotation for SDHC is GO:0006121 (mitochondrial electron transport, succinate to ubiquinone). Supporting Evidence: PMID:37098072 The respiratory chain (also called electron transport chain) consists of complexes I-IV. It oxidizes the reducing equivalents in nicotinamide adenine dinucleotide (NADH) and succinate using molecular oxygen and couples the translocation of protons from the mitochondrial matrix into the intermembrane space
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: HTP annotation for mitochondrial localization from a quantitative high-confidence human mitochondrial proteome study (Morgenstern et al. 2021). SDHC was identified in the mitochondrial proteome by quantitative mass spectrometry. Reason: Correct. SDHC is a well-established mitochondrial protein confirmed by proteomics and structural studies. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context [SDHC identified by quantitative mass spectrometry]
GO:0045273 respiratory chain complex II (succinate dehydrogenase)	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for Complex II membership by manual transfer from ortholog (UniProtKB:D0VWV4, bovine). Consistent with all other annotations for this term. Reason: Correct. Transfer from the well-characterized bovine SDH complex. SDHC is unambiguously a subunit of Complex II.
GO:0045273 respiratory chain complex II (succinate dehydrogenase)	IDA PMID:37098072 Structure of the human respiratory complex II.	ACCEPT	Summary: IDA annotation for Complex II membership from the cryo-EM structure study (Du et al. 2023). This study resolved the human Complex II structure at 2.86 angstroms showing all four subunits including SDHC in the membrane domain. SDHC was directly identified in the complex by cryo-EM, SDS-PAGE, and mass spectrometry. Reason: Direct experimental evidence from the human Complex II cryo-EM structure. This is the strongest evidence for SDHC's membership in Complex II. Supporting Evidence: PMID:37098072 All the four subunits (SDHA, SDHB, SDHC, and SDHD) were detected by SDS-PAGE (SI Appendix, Fig. S1D) and mass spectrometry (MS) (SI Appendix, Table S1).
GO:0045273 respiratory chain complex II (succinate dehydrogenase)	TAS PMID:9533030 Cytochrome b in human complex II (succinate-ubiquinone oxido...	ACCEPT	Summary: TAS annotation for Complex II membership from the original cDNA cloning study of SDHC and SDHD (Hirawake et al. 1997). This study cloned the cDNA for the large (cybL/SDHC) and small (cybS/SDHD) subunits of cytochrome b in human liver Complex II and determined their role as membrane-anchors. Reason: The original characterization study of SDHC establishes it as a subunit of Complex II. Supporting Evidence: PMID:9533030 the amino acid sequences of the large (cybL) and small (cybS) subunits of cytochrome b in human liver complex II were deduced from cDNAs isolated by homology probing
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-70994	ACCEPT	Summary: TAS annotation for inner mitochondrial membrane localization from Reactome pathway R-HSA-70994 (SDH complex dehydrogenates succinate). Reactome models Complex II as located in the inner mitochondrial membrane where it catalyzes the oxidation of succinate coupled to ubiquinone reduction. Reason: Correct localization, consistent with all other inner membrane annotations.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9855252	ACCEPT	Summary: TAS annotation for inner mitochondrial membrane localization from Reactome pathway R-HSA-9855252 (SDHA:SDHB binds to SDHC:SDHD). This Reactome entry models the assembly of Complex II by association of the catalytic SDHA:SDHB subcomplex with the membrane-anchored SDHC:SDHD subcomplex at the inner mitochondrial membrane. Reason: Correct localization. The Reactome assembly model places SDHC:SDHD at the inner mitochondrial membrane, consistent with experimental evidence.
GO:0005743 mitochondrial inner membrane	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for inner mitochondrial membrane localization by manual transfer from ortholog (UniProtKB:D0VWV4, bovine). Consistent with all other inner membrane annotations. Reason: Correct. Transfer from the well-characterized bovine SDH complex. SDHC is located in the inner mitochondrial membrane.
GO:0020037 heme binding	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for heme binding by manual transfer from ortholog (UniProtKB:D0VWV4, bovine). SDHC provides the axial His127 ligand to the heme b (cytochrome b560) iron atom. The heme b is shared between SDHC and SDHD, with each subunit providing one histidine as an axial ligand. The cryo-EM structure (PMID:37098072, PDB:8GS8) directly confirmed the heme b binding site in the SDHC/SDHD interface. UniProt annotates the binding site at residue 127 with evidence ECO:0000269\|PubMed:37098072. The heme b is important for protein stability and may serve as an electron sink during ubiquinone reduction. Reason: Heme binding is a core molecular function of SDHC. The His127 axial ligand coordinates the heme b iron atom, confirmed by cryo-EM structure (PMID:37098072). This is one of the few subunit-specific molecular functions of SDHC. Supporting Evidence: PMID:37098072 The two membrane-anchored proteins (SDHC and SDHD) in human CII, each with three transmembrane helices, contain only one heme b group PMID:37098072 the heme cofactor is also crucial for the heme protein to achieve its proper fold and thus become a stable, functional structure PMID:9533030 Histidine residues, which are possible heme axial ligands in cytochrome b of complex II, were found in the second transmembrane segment of each subunit
GO:0005739 mitochondrion	TAS PMID:2302193 Human complex II (succinate-ubiquinone oxidoreductase): cDNA...	ACCEPT	Summary: TAS annotation for mitochondrial localization from Kita et al. (1990). This study cloned the cDNA for the iron-sulfur subunit of human liver Complex II and established that Complex II is located in mitochondria. Note that PMID:2302193 specifically describes the Ip (SDHB) subunit, not SDHC directly, but the TAS inference to SDHC as a subunit of the same complex is reasonable since Complex II is exclusively mitochondrial. Reason: Correct localization. While the publication specifically cloned the SDHB subunit, the inference that SDHC is mitochondrial as a subunit of Complex II is well-supported. Supporting Evidence: PMID:2302193 Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex of both the tricarboxylic acid cycle and of the aerobic respiratory chains of mitochondria in eukaryotic cell and prokaryotic organisms
GO:0006099 tricarboxylic acid cycle	TAS PMID:9533030 Cytochrome b in human complex II (succinate-ubiquinone oxido...	ACCEPT	Summary: TAS annotation for TCA cycle involvement from the original cDNA cloning study (Hirawake et al. 1997). This study explicitly describes Complex II as an enzyme involved in both the TCA cycle and aerobic respiration. Reason: Correct. TCA cycle involvement is a core biological process for SDHC as part of Complex II. Consistent with IEA and NAS annotations for the same term. Supporting Evidence: PMID:9533030 Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex in both the tricarboxylic acid cycle and the aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic organisms
GO:0009060 aerobic respiration	TAS PMID:9533030 Cytochrome b in human complex II (succinate-ubiquinone oxido...	ACCEPT	Summary: TAS annotation for aerobic respiration from the original cDNA cloning study (Hirawake et al. 1997). Complex II is part of the aerobic respiratory chain, linking succinate oxidation in the TCA cycle to ubiquinone reduction in the electron transport chain. Reason: Correct. Aerobic respiration is a core biological process for SDHC as part of Complex II. Complex II participates in both the TCA cycle and the electron transport chain during aerobic respiration. Supporting Evidence: PMID:9533030 Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex in both the tricarboxylic acid cycle and the aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic organisms
GO:0016020 membrane	TAS PMID:9533030 Cytochrome b in human complex II (succinate-ubiquinone oxido...	ACCEPT	Summary: TAS annotation for general membrane localization from the original cDNA cloning study (Hirawake et al. 1997). SDHC was predicted to have three transmembrane segments, indicating its role as a membrane-anchor. This is correct but very general; the more specific term GO:0005743 (mitochondrial inner membrane) is also annotated. Reason: Correct but general. The original study predicted three transmembrane segments for SDHC, establishing its role as a membrane protein. The more specific inner membrane term is also annotated from multiple evidence sources. Supporting Evidence: PMID:9533030 From hydrophobicity analysis, both cybL and cybS appear to have three transmembrane segments, indicating their role as membrane-anchors for the enzyme complex
GO:0048039 ubiquinone binding	IDA PMID:37098072 Structure of the human respiratory complex II.	NEW	Summary: The cryo-EM structure of human Complex II (PMID:37098072) directly demonstrates that ubiquinone binds at a pocket formed jointly by SDHC, SDHD, and SDHB. Specific SDHC residues Ile56, Trp61, Met65, and Ile69 directly contact ubiquinone. This is a subunit-specific molecular function of SDHC that is not currently annotated. Reason: Ubiquinone binding is a key subunit-specific molecular function of SDHC that is missing from the current annotation set. The cryo-EM structure (PMID:37098072) provides direct structural evidence for SDHC residues contacting ubiquinone. The qualifier should be 'contributes_to' since the Q-site is shared with SDHD and SDHB. Supporting Evidence: PMID:37098072 UQ is also observed to bind at the entrance of the pocket formed by the transmembrane helix I of SDHC, transmembrane helix II of SDHD, and the C-terminal segment of SDHB. It interacts with Pro-SDHB197, Trp-SDHB201, Ile-SDHB246, Ile-SDHC56, Trp-SDHC61, Met-SDHC65, Ile-SDHC69, and Tyr-SDHD114

Core Functions

SDHC is the large cytochrome b560 transmembrane subunit of succinate dehydrogenase (Complex II). Together with SDHD, it forms the membrane anchor domain that anchors the catalytic SDHA:SDHB subcomplex in the inner mitochondrial membrane. SDHC provides the His127 axial ligand to the heme b (cytochrome b560) iron atom shared between SDHC and SDHD, making heme binding (GO:0020037) its primary subunit-specific molecular function. SDHC also contributes to ubiquinone binding at the Q-site (residues Ile56, Trp61, Met65, Ile69 directly contact ubiquinone) and to the overall succinate dehydrogenase (quinone) activity (GO:0008177) of the Complex II heterotetramer. The heme b is proposed to serve as an electron sink during the two-electron reduction of ubiquinone. Through Complex II, SDHC participates in mitochondrial electron transport from succinate to ubiquinone (GO:0006121) and the tricarboxylic acid cycle (GO:0006099).

Molecular Function:

heme binding

Directly Involved In:

mitochondrial electron transport, succinate to ubiquinone tricarboxylic acid cycle

Cellular Locations:

mitochondrial inner membrane

In Complex:

respiratory chain complex II (succinate dehydrogenase)

Supporting Evidence:

PMID:37098072
The two membrane-anchored proteins (SDHC and SDHD) in human CII, each with three transmembrane helices, contain only one heme b group
PMID:37098072
UQ is also observed to bind at the entrance of the pocket formed by the transmembrane helix I of SDHC, transmembrane helix II of SDHD, and the C-terminal segment of SDHB. It interacts with Pro-SDHB197, Trp-SDHB201, Ile-SDHB246, Ile-SDHC56, Trp-SDHC61, Met-SDHC65, Ile-SDHC69, and Tyr-SDHD114
PMID:9533030
Histidine residues, which are possible heme axial ligands in cytochrome b of complex II, were found in the second transmembrane segment of each subunit

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

file:human/SDHC/SDHC-deep-research-falcon.md

Falcon deep research synthesis for human SDHC

PMID:2302193

Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of iron sulfur (Ip) subunit of liver mitochondria.

Established Complex II as a mitochondrial enzyme involved in the TCA cycle and aerobic respiratory chain. Cloned the iron-sulfur (Ip/SDHB) subunit.

"Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex of both the tricarboxylic acid cycle and of the aerobic respiratory chains of mitochondria in eukaryotic cell and prokaryotic organisms"

PMID:9533030

Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23.

Original cDNA cloning of SDHC (cybL, 140 mature amino acids) and SDHD (cybS, 103 amino acids) from human liver. Predicted three transmembrane segments for each subunit. Identified histidine residues as potential heme axial ligands. Mapped SDHC to chromosome 1q21 and SDHD to 11q23.

"the amino acid sequences of the large (cybL) and small (cybS) subunits of cytochrome b in human liver complex II were deduced from cDNAs isolated by homology probing with mixed primers for the polymerase chain reaction. The mature cybL and cybS contain 140 and 103 amino acids, respectively"

PMID:30030361

Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.

Review of OXPHOS complex assembly. Complex II assembly involves the SDHA:SDHB catalytic subcomplex associating with the SDHC:SDHD membrane anchor in the inner mitochondrial membrane.

"The assembly of the five oxidative phosphorylation system (OXPHOS) complexes in the inner mitochondrial membrane is an intricate process"

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

Large-scale Y2H interactome mapping for neurodegenerative disease. Detected interactions between SDHC and several nuclear/cytoplasmic proteins (PRKCA, YWHAG, KAT5, SETDB1, LMO3) of uncertain biological significance for a mitochondrial membrane protein.

"we report on an interactome map that focuses on neurodegenerative disease (ND), connects"

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

Quantitative proteomics confirmed SDHC as a component of the high-confidence human mitochondrial proteome.

"Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context [SDHC identified by quantitative mass spectrometry]"

PMID:37098072

Structure of the human respiratory complex II.

Determined cryo-EM structure of human Complex II at 2.86 angstroms. SDHC resolved with three transmembrane helices, one heme b group (shared with SDHD), and ubiquinone bound at the pocket formed by transmembrane helix I of SDHC, helix II of SDHD, and the C-terminal segment of SDHB. SDHC residues Ile56, Trp61, Met65, Ile69 directly contact ubiquinone. His127 of SDHC provides an axial ligand to heme b iron. The heme b is proposed to serve as an electron sink during the two-electron reduction of ubiquinone.

"The two membrane-anchored proteins (SDHC and SDHD) in human CII, each with three transmembrane helices, contain only one heme b group"

Reactome:R-HSA-70994

SDH complex dehydrogenates succinate

Reactome:R-HSA-9855252

SDHA:SDHB binds to SDHC:SDHD

Deep Research

Falcon

(SDHC-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 26 citations 2026-02-11T08:55:23.580998

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan (concise)
- Verify target identity and nomenclature (SDHC, UniProt Q99643) and distinguish from similarly named genes. (Completed.)
- Summarize key concepts: Complex II function; SDHC’s specific role; localization; pathways; structural/mechanistic insights.
- Compile recent (2023–2024) developments: disease associations; guidelines and consensus statements for SDHx; translational implementations.
- Provide expert viewpoints and quantitative data where available; include URLs and publication dates.

Comprehensive research report: SDHC (Human; UniProt Q99643)

Identity verification and basic definition
- Correct gene/protein: SDHC encodes the membrane-embedded cytochrome b560 subunit of mitochondrial succinate dehydrogenase (Complex II), forming the membrane arm with SDHD. It houses the heme b (cytochrome b560) and contributes to the ubiquinone-binding pocket (the Q-pool site). SDHC’s role as a lipophilic anchoring subunit and cytochrome b560 carrier is explicitly described in recent peer‑reviewed sources, confirming alignment with the UniProt description and cytochrome b560 family membership (Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (chatoff2025metaboliceffectsof pages 1-3, chatoff2025metaboliceffectsof pages 4-6).

Key concepts and current understanding
- Primary enzymatic function (Complex II): Succinate dehydrogenase (Complex II) uniquely links the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) by catalyzing succinate oxidation to fumarate (at SDHA, with covalently bound FAD) and transferring electrons via SDHB’s three Fe–S clusters to reduce ubiquinone (CoQ) to ubiquinol in the membrane arm (SDHC/SDHD). Complex II does not directly pump protons but supports the proton motive force via the reduced CoQ pool (Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (chatoff2025metaboliceffectsof pages 4-6).
- SDHC’s specific mechanistic role: SDHC, together with SDHD, anchors the enzyme to the inner mitochondrial membrane and provides the heme b (cytochrome b560) environment and quinone-binding site needed for ubiquinone reduction. Multiple recent reviews affirm SDHC’s membrane anchoring and cytochrome b560 identity and involvement in the quinone site (Antioxidants, 2025-01; URL: https://doi.org/10.3390/antiox14010076; Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (osz2025mutationsofthe pages 2-4, chatoff2025metaboliceffectsof pages 1-3).
- Subcellular localization: Complex II is an inner mitochondrial membrane (IMM) complex; SDHC and SDHD are the transmembrane subunits of the IMM arm (Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (chatoff2025metaboliceffectsof pages 4-6).
- Pathways: SDHC functions in both the TCA cycle (through SDH activity linking succinate→fumarate) and the ETC (electron transfer to the CoQ pool), thus integrating central carbon metabolism with oxidative phosphorylation (Cell Biology & Toxicology, 2025-04; URL: https://doi.org/10.1007/s10565-025-10022-w) (wang2025sdhdefectivecancers pages 1-3).

Structural and mechanistic insights (Q sites, heme, subunit interplay)
- Quinone sites: The ubiquinone-binding pocket of Complex II resides in the membrane arm formed by SDHC and SDHD; this “Q-pool active site” accommodates ubiquinone/ubiquinol interconversion during catalysis (Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (chatoff2025metaboliceffectsof pages 1-3).
- Heme b (cytochrome b560): SDHC is recognized as the cytochrome b560 subunit, and alternative splicing that removes an SDHC heme-binding region reduces SDH activity, emphasizing the functional importance of cytochrome b/heme in electron transfer within the membrane arm (Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (chatoff2025metaboliceffectsof pages 3-4).
- SDHC–SDHD interaction and electron flow: Electrons from FADH2 (SDHA) traverse SDHB’s Fe–S clusters to the quinone-binding pocket where SDHC/SDHD stabilize and reduce CoQ, forming ubiquinol that fuels Complex III; recent comparative cell-model work confirms membrane-arm participation in ubiquinone handling and that loss of SDHC disrupts SDH activity with succinate accumulation (Cancer & Metabolism, 2024-12; URL: https://doi.org/10.1186/s40170-024-00369-9) (khazal2024similardeficienciesdifferent pages 12-14).

Recent developments and latest research (2023–2024 priority)
- Disease associations and mechanisms: Contemporary reviews and models reaffirm that germline or somatic SDHx defects—including in SDHC—drive PPGL, GIST, pituitary tumors, and rare RCC, via succinate accumulation that inhibits α‑ketoglutarate–dependent dioxygenases, stabilizing HIFα (pseudohypoxia) and inducing broad histone/DNA hypermethylation programs (Cancer & Metabolism, 2024-12; URL: https://doi.org/10.1186/s40170-024-00369-9) (khazal2024similardeficienciesdifferent pages 12-14), and (Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (chatoff2025metaboliceffectsof pages 8-9).
- SDHC promoter hypermethylation (“epimutations”): Recognized as a recurrent cause of SDH-deficient GIST and PPGL; modern reviews and scoping papers cite SDHC promoter hypermethylation in Carney triad and related contexts, with decreased SDHC mRNA expression (Frontiers in Immunology, 2023-03; URL: https://doi.org/10.3389/fimmu.2023.1093974; Human Molecular Genetics, 2020-10; URL: https://doi.org/10.1093/hmg/ddaa201) (chatoff2025metaboliceffectsof pages 4-6). Recent synthesis also highlights SDHC “epimutant” cases and alternative splicing impacting the heme region (Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (chatoff2025metaboliceffectsof pages 3-4, chatoff2025metaboliceffectsof pages 1-3).
- PPGL guidelines and consensus in the SDHx era: Recent expert statements prioritize gene-guided surveillance and multidisciplinary care. While a 2024 international consensus focuses on SDHB carriers, it situates practices within broader SDHx management frameworks used by Endocrine Society and allied groups (Nature Reviews Endocrinology, 2024-12; URL: https://doi.org/10.1038/s41574-023-00926-0) (wang2025sdhdefectivecancers pages 1-3). Additional 2024 reviews emphasize high yield of multigene panels for PPGL predisposition genes including SDHC and the need for longitudinal penetrance data (Endocrine Oncology, 2024-01; URL: https://doi.org/10.1530/eo-24-0029) (wang2025sdhdefectivecancers pages 1-3).
- SDH-deficient GIST and clinical genomics: 2024 analyses document practical value of next-generation sequencing and highlight the diversity of non‑KIT/PDGFRA drivers; SDH-deficient subsets remain a key molecular category with distinct management implications (Cancers, 2024-04; URL: https://doi.org/10.3390/cancers16091707) (no direct mechanistic SDHC data but supports clinical implementation) (wang2025sdhdefectivecancers pages 1-3).

Current applications and real-world implementations
- Immunohistochemistry (IHC): Bi-allelic inactivation of any SDH subunit (including SDHC) typically results in loss of SDHB protein detectable by IHC, which is widely used as a screening marker to identify SDH-deficient tumors across sites; this practical diagnostic principle is reiterated in recent literature syntheses (Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (chatoff2025metaboliceffectsof pages 3-4).
- Genetic testing and sequencing panels: Routine multigene testing for PPGL/GIST now includes SDHC alongside other SDHx genes; 2024 clinical exome panel reports and reviews illustrate real-world pipelines for patient work‑up and family management (Experimental and Therapeutic Medicine, 2024-12; URL: https://doi.org/10.3892/etm.2024.12784; Endocrine Oncology, 2024-01; URL: https://doi.org/10.1530/eo-24-0029) (wang2025sdhdefectivecancers pages 1-3).
- Methylation profiling and metabolomics: Recognition of SDHC promoter hypermethylation supports methylation-based assays; metabolomics confirms succinate accumulation and is used to classify SDH-deficient PPGLs and to support variant interpretation (Hormone and Metabolic Research, 2019-07; URL: https://doi.org/10.1055/a-0926-3790) (wang2025sdhdefectivecancers pages 1-3).
- Imaging and targeted therapies: SDH-deficient tumors often overexpress angiogenic programs; anti-angiogenic agents such as sunitinib demonstrate activity in SDH-deficient settings; contemporary reviews and models link pseudohypoxia to these responses (Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (chatoff2025metaboliceffectsof pages 8-9).

Expert opinions and analyses
- Consensus and guideline perspectives favor gene-informed surveillance schedules and modalities, with emphasis on high-risk SDHx carriers. While SDHB carries higher metastatic risk overall, SDHC carriers remain clinically important and require structured surveillance programs advised by expert groups (Nature Reviews Endocrinology, 2024-12; URL: https://doi.org/10.1038/s41574-023-00926-0; Endocrine Oncology, 2024-01; URL: https://doi.org/10.1530/eo-24-0029) (wang2025sdhdefectivecancers pages 1-3).
- Mechanistic consensus: Contemporary overviews converge that SDHC’s disruption compromises the membrane arm’s quinone chemistry and redox routing, causing succinate accumulation and αKG-dioxygenase inhibition (pseudohypoxia and hypermethylation), central to SDH-deficient tumorigenesis (Cancer & Metabolism, 2024-12; URL: https://doi.org/10.1186/s40170-024-00369-9; Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (khazal2024similardeficienciesdifferent pages 12-14, chatoff2025metaboliceffectsof pages 8-9).

Relevant statistics and quantitative data from recent studies
- SDH-deficient GIST proportion: Approximately 7–8% of GIST diagnoses are SDH-deficient; within these, SDHA is most frequently mutated, followed by SDHB, with additional cases due to SDHC mechanisms including promoter hypermethylation; a strong female and pediatric enrichment is noted in SDH‑deficient GIST (Journal of Cellular Physiology, 2025-07; URL: https://doi.org/10.1002/jcp.70066) (chatoff2025metaboliceffectsof pages 3-4).
- Epidemiology of PPGL: Modern systematic review estimates overall PPGL incidence ~0.6 per 100,000 per year in studies after 2010, reflecting increased detection and screening—contextualizing the growing yield of SDHx testing in practice (Journal of the Endocrine Society, 2022-07; URL: https://doi.org/10.1210/jendso/bvac105) (wang2025sdhdefectivecancers pages 1-3).
- Diagnostic genomics yield in PPGL: 2024 multi‑institution experiences show substantial identification of SDHx pathogenic/likely pathogenic variants using multigene panels and incidental findings in hereditary clinics, supporting widespread adoption in clinical workflows (Endocrine Oncology, 2024-01; URL: https://doi.org/10.1530/eo-24-0029) (wang2025sdhdefectivecancers pages 1-3).

Notes on ambiguity check
- The gene symbol SDHC is sometimes used in non‑human contexts, but the sources evaluated here explicitly reference mammalian/human Complex II subunits and SDHC’s role as cytochrome b560. No contradictory gene/protein with the same symbol was identified in 2023–2024 sources consulted. The functional/structural attributes match the UniProt Q99643 entry (cytochrome b560 family; IMM localization; quinone site participation) (chatoff2025metaboliceffectsof pages 1-3, chatoff2025metaboliceffectsof pages 4-6).

Conclusion
Human SDHC (UniProt Q99643) is the cytochrome b560 transmembrane subunit of mitochondrial Complex II that anchors the complex in the inner mitochondrial membrane, harbors heme b, and contributes to the ubiquinone (Q) site where CoQ is reduced to CoQH2. Through Complex II activity, SDHC participates in succinate oxidation (succinate→fumarate) and electron transfer to the CoQ pool, integrating the TCA cycle with the ETC. Recent clinical/translational literature (2023–2024) underscores SDHC’s role in SDH‑deficient tumor biology (PPGL, GIST), including well‑documented SDHC promoter hypermethylation; real‑world implementations include SDHB‑IHC screening, multigene NGS panels that include SDHC, and emerging methylation/metabolomic assays. These practices are reinforced by current expert reviews and consensus statements advocating gene‑informed surveillance and management for SDHx‑related neoplasia (chatoff2025metaboliceffectsof pages 1-3, wang2025sdhdefectivecancers pages 1-3, chatoff2025metaboliceffectsof pages 4-6, chatoff2025metaboliceffectsof pages 3-4, osz2025mutationsofthe pages 2-4, chatoff2025metaboliceffectsof pages 8-9, khazal2024similardeficienciesdifferent pages 12-14).

References

(chatoff2025metaboliceffectsof pages 1-3): Adam Chatoff, Daniel S. Kantner, Nathaniel W. Snyder, and Lori Rink. Metabolic effects of succinate dehydrogenase loss in cancer. Journal of cellular physiology, 240 7:e70066, Jul 2025. URL: https://doi.org/10.1002/jcp.70066, doi:10.1002/jcp.70066. This article has 0 citations and is from a peer-reviewed journal.
(chatoff2025metaboliceffectsof pages 4-6): Adam Chatoff, Daniel S. Kantner, Nathaniel W. Snyder, and Lori Rink. Metabolic effects of succinate dehydrogenase loss in cancer. Journal of cellular physiology, 240 7:e70066, Jul 2025. URL: https://doi.org/10.1002/jcp.70066, doi:10.1002/jcp.70066. This article has 0 citations and is from a peer-reviewed journal.
(osz2025mutationsofthe pages 2-4): Fanni Ősz, Aamir Nazir, Krisztina Takács-Vellai, and Zsolt Farkas. Mutations of the electron transport chain affect lifespan and ros levels in c. elegans. Antioxidants, 14:76, Jan 2025. URL: https://doi.org/10.3390/antiox14010076, doi:10.3390/antiox14010076. This article has 8 citations and is from a poor quality or predatory journal.
(wang2025sdhdefectivecancers pages 1-3): Jiaer Wang, Tao Yuan, Bo Yang, Qiaojun He, and Hong Zhu. Sdh defective cancers: molecular mechanisms and treatment strategies. Cell Biology and Toxicology, Apr 2025. URL: https://doi.org/10.1007/s10565-025-10022-w, doi:10.1007/s10565-025-10022-w. This article has 12 citations and is from a peer-reviewed journal.
(chatoff2025metaboliceffectsof pages 3-4): Adam Chatoff, Daniel S. Kantner, Nathaniel W. Snyder, and Lori Rink. Metabolic effects of succinate dehydrogenase loss in cancer. Journal of cellular physiology, 240 7:e70066, Jul 2025. URL: https://doi.org/10.1002/jcp.70066, doi:10.1002/jcp.70066. This article has 0 citations and is from a peer-reviewed journal.
(khazal2024similardeficienciesdifferent pages 12-14): Fatimah J. Al Khazal, Sanjana Mahadev Bhat, Yuxiang Zhu, Cristina M. de Araujo Correia, Sherry X. Zhou, Brandon A. Wilbanks, Clifford D. Folmes, Gary C. Sieck, Judith Favier, and L. James Maher. Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma. Cancer & Metabolism, Dec 2024. URL: https://doi.org/10.1186/s40170-024-00369-9, doi:10.1186/s40170-024-00369-9. This article has 6 citations and is from a peer-reviewed journal.
(chatoff2025metaboliceffectsof pages 8-9): Adam Chatoff, Daniel S. Kantner, Nathaniel W. Snyder, and Lori Rink. Metabolic effects of succinate dehydrogenase loss in cancer. Journal of cellular physiology, 240 7:e70066, Jul 2025. URL: https://doi.org/10.1002/jcp.70066, doi:10.1002/jcp.70066. This article has 0 citations and is from a peer-reviewed journal.

Citations

chatoff2025metaboliceffectsof pages 4-6
wang2025sdhdefectivecancers pages 1-3
chatoff2025metaboliceffectsof pages 1-3
chatoff2025metaboliceffectsof pages 3-4
khazal2024similardeficienciesdifferent pages 12-14
chatoff2025metaboliceffectsof pages 8-9
osz2025mutationsofthe pages 2-4
quinone
https://doi.org/10.1002/jcp.70066
https://doi.org/10.3390/antiox14010076;
https://doi.org/10.1007/s10565-025-10022-w
https://doi.org/10.1186/s40170-024-00369-9
https://doi.org/10.3389/fimmu.2023.1093974;
https://doi.org/10.1093/hmg/ddaa201
https://doi.org/10.1038/s41574-023-00926-0
https://doi.org/10.1530/eo-24-0029
https://doi.org/10.3390/cancers16091707
https://doi.org/10.3892/etm.2024.12784;
https://doi.org/10.1055/a-0926-3790
https://doi.org/10.1038/s41574-023-00926-0;
https://doi.org/10.1186/s40170-024-00369-9;
https://doi.org/10.1210/jendso/bvac105
https://doi.org/10.1002/jcp.70066,
https://doi.org/10.3390/antiox14010076,
https://doi.org/10.1007/s10565-025-10022-w,
https://doi.org/10.1186/s40170-024-00369-9,

📄 View Raw YAML

---
id: Q99643
gene_symbol: SDHC
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: SDHC encodes the large cytochrome b560 transmembrane subunit of succinate
  dehydrogenase (SDH, Complex II), a heterotetrameric enzyme (SDHA/SDHB/SDHC/SDHD)
  embedded in the mitochondrial inner membrane. Together with SDHD, SDHC forms the
  membrane anchor domain of Complex II, contributing to the ubiquinone (CoQ) binding
  site and harboring the heme b (cytochrome b560) prosthetic group shared between
  the two membrane subunits. SDHC has three transmembrane helices and provides key
  residues (Ile56, Trp61, Met65, Ile69) that directly contact ubiquinone at the Q-site.
  The heme b is axially coordinated by His127 of SDHC and the corresponding histidine
  of SDHD. SDHC has no independent catalytic activity; its role is structural (membrane
  anchoring, heme environment, Q-site formation). Complex II uniquely links the TCA
  cycle and the electron transport chain by catalyzing succinate oxidation to fumarate
  (at SDHA) and transferring electrons to ubiquinone at the SDHC/SDHD membrane interface,
  but does NOT pump protons. SDHC functions as a tumor suppressor; germline loss-of-function
  mutations and promoter hypermethylation cause paraganglioma/ pheochromocytoma (PPGL3),
  gastrointestinal stromal tumors (GIST), and Carney triad, via succinate accumulation
  and pseudohypoxic signaling.
alternative_products:
  - name: '1'
    id: Q99643-1
  - name: '2'
    id: Q99643-2
    sequence_note: VSP_041383
  - name: 3 (CII-3b)
    id: Q99643-3
    sequence_note: VSP_041382
  - name: '4'
    id: Q99643-4
    sequence_note: VSP_041382, VSP_041383
  - name: '5'
    id: Q99643-5
    sequence_note: VSP_041381
existing_annotations:
  - term:
      id: GO:0006121
      label: mitochondrial electron transport, succinate to ubiquinone
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation for the biological process of electron transport from
        succinate to ubiquinone. This is the defining biological process for Complex
        II/SDH in the mitochondrial electron transport chain. SDHC, together with
        SDHD, forms the membrane arm where ubiquinone is ultimately reduced to ubiquinol.
        SDHC provides key residues (Ile56, Trp61, Met65, Ile69) that directly contact
        ubiquinone at the Q-site (PMID:37098072). The heme b coordinated by His127
        of SDHC may serve as an electron sink during the two-electron reduction of
        ubiquinone (PMID:37098072). The IBA is phylogenetically supported with evidence
        from orthologous SDH cytochrome b560 subunits.
      action: ACCEPT
      reason: This is a core biological process for SDHC. SDHC is essential for the
        terminal step of electron transfer from succinate to ubiquinone in Complex
        II, providing the Q-site and heme b environment. Well-supported by IBA phylogenetic
        inference and confirmed by the human Complex II cryo-EM structure (PMID:37098072).
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: UQ is also observed to bind at the entrance of the pocket
            formed by the transmembrane helix I of SDHC, transmembrane helix II of
            SDHD, and the C-terminal segment of SDHB. It interacts with Pro-SDHB197,
            Trp-SDHB201, Ile-SDHB246, Ile-SDHC56, Trp-SDHC61, Met-SDHC65, Ile-SDHC69,
            and Tyr-SDHD114
        - reference_id: PMID:9533030
          supporting_text: Complex II (succinate-ubiquinone oxidoreductase) is an
            important enzyme complex in both the tricarboxylic acid cycle and the
            aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic
            organisms
  - term:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation that SDHC is part of respiratory chain complex II. SDHC
        is one of the four core subunits of SDH/Complex II, serving as a membrane
        anchor. The cryo-EM structure of human Complex II at 2.86 angstroms (PMID:37098072)
        directly resolved SDHC with three transmembrane helices in the membrane domain.
        All four subunits (SDHA, SDHB, SDHC, SDHD) were confirmed by SDS-PAGE and
        mass spectrometry (PMID:37098072).
      action: ACCEPT
      reason: SDHC is unambiguously a subunit of Complex II. This is confirmed by
        the cryo-EM structure (PMID:37098072), the original cDNA cloning study (PMID:9533030),
        and is a core structural annotation. The IBA is phylogenetically sound.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: All the four subunits (SDHA, SDHB, SDHC, and SDHD) were
            detected by SDS-PAGE (SI Appendix, Fig. S1D) and mass spectrometry (MS)
            (SI Appendix, Table S1).
        - reference_id: PMID:9533030
          supporting_text: the amino acid sequences of the large (cybL) and small
            (cybS) subunits of cytochrome b in human liver complex II were deduced
            from cDNAs isolated by homology probing
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation based on UniProt subcellular location mapping. SDHC
        is an integral membrane protein with three transmembrane helices that spans
        the mitochondrial inner membrane. This is confirmed by the cryo-EM structure
        (PMID:37098072) and the UniProt annotation (ECO:0000269|PubMed:37098072).
        SDHC topology shows matrix-facing N-terminus, three transmembrane helices,
        and short intermembrane space loops.
      action: ACCEPT
      reason: Correct localization. SDHC is an integral multi-pass protein of the
        mitochondrial inner membrane, confirmed by cryo-EM at 2.86 angstroms. This
        is a core localization annotation.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: 'The entire hydrophobic domain contains two membrane-anchored
            subunits: SDHC and SDHD'
  - term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation for TCA cycle involvement from combined automated methods
        including ortholog transfer from mouse (UniProtKB:Q9CZB0) and InterPro/UniPathway
        mapping. Complex II is the only membrane-bound member of the TCA cycle, catalyzing
        the oxidation of succinate to fumarate. SDHC contributes to this reaction
        by anchoring the complex in the membrane and providing the Q-site for ubiquinone
        reduction, which is coupled to succinate oxidation.
      action: ACCEPT
      reason: TCA cycle involvement is a core function of SDHC as part of Complex
        II. The original cDNA cloning study (PMID:9533030) describes Complex II as
        an enzyme in both the TCA cycle and the respiratory chain.
      supported_by:
        - reference_id: PMID:9533030
          supporting_text: Complex II (succinate-ubiquinone oxidoreductase) is an
            important enzyme complex in both the tricarboxylic acid cycle and the
            aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic
            organisms
  - term:
      id: GO:0009055
      label: electron transfer activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation for electron transfer activity from InterPro (IPR014314,
        IPR018495). SDHC contributes to electron transfer within Complex II by harboring
        the heme b prosthetic group (axially coordinated by His127 of SDHC) and providing
        residues that form the ubiquinone binding pocket. The heme b serves as an
        electron sink that stabilizes the semiquinone radical during the two-electron
        reduction of ubiquinone (PMID:37098072). However, SDHC does not independently
        perform electron transfer; it contributes to the complex-level activity. The
        qualifier should ideally be 'contributes_to' rather than 'enables'.
      action: MODIFY
      reason: SDHC contributes to electron transfer as part of Complex II via heme
        b and the Q-site, but it does not independently enable electron transfer activity.
        The InterPro-based annotation is reasonable but the qualifier should be 'contributes_to'.
        Additionally, a more specific term would be preferred if available. Accept
        the annotation concept but flag that the qualifier in GOA is 'enables' whereas
        'contributes_to' would be more appropriate for a membrane anchor subunit.
      proposed_replacement_terms:
        - id: GO:0009055
          label: electron transfer activity
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: the heme b is proposed to serve as an electron sink in
            the electron transfer pathway
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation for general membrane localization from InterPro (IPR018495,
        IPR034804). SDHC is an integral membrane protein with three transmembrane
        helices. This is correct but very general; the more specific term GO:0005743
        (mitochondrial inner membrane) is also annotated and provides a much more
        informative localization.
      action: ACCEPT
      reason: Correct but general. SDHC is an integral membrane protein with three
        transmembrane helices. It is acceptable for IEA annotations to be broader
        than experimental annotations. The more specific GO:0005743 is also present.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation from UniProt keyword (KW-0479 Metal-binding) mapping.
        SDHC coordinates heme b iron via the axial ligand His127 (shared with SDHD).
        The heme b iron is the relevant metal ion. This annotation is correct but
        very general; the more specific GO:0020037 (heme binding) is also annotated
        via ISS.
      action: ACCEPT
      reason: Correct but general. SDHC binds the iron atom of heme b through axial
        coordination at His127. The more specific child term GO:0020037 (heme binding)
        is also annotated. It is acceptable for IEA keyword-based annotations to use
        broader terms.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: The two membrane-anchored proteins (SDHC and SDHD) in human
            CII, each with three transmembrane helices, contain only one heme b group
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: 'IPI annotation from a large-scale neurodegenerative disease interactome
        mapping study (Haenig et al. 2020) using systematic yeast two-hybrid screening.
        The GOA contains five separate entries for this PMID with different interactors:
        PRKCA (P17252), YWHAG (P61981), SETDB1 (Q15047-2), LMO3 (Q8TAP4-4), and KAT5
        (Q92993). These interactions were detected in a high-throughput screen focused
        on neurodegenerative disease-associated proteins. SDHC is a small transmembrane
        mitochondrial protein with limited cytoplasmic exposure; direct physical interactions
        with nuclear/cytoplasmic proteins like PRKCA, YWHAG, KAT5, SETDB1, and LMO3
        are of uncertain biological significance and may reflect Y2H artifacts from
        overexpression of fragments outside their native membrane context.'
      action: MARK_AS_OVER_ANNOTATED
      reason: The 'protein binding' term is uninformative per GO curation guidelines.
        Furthermore, these interactions were detected in a high-throughput Y2H screen
        focused on neurodegenerative disease networks. The biological relevance of
        interactions between a small mitochondrial inner membrane protein (SDHC) and
        nuclear/cytoplasmic proteins (PRKCA, YWHAG, KAT5, SETDB1, LMO3) is highly
        questionable. Y2H is known to produce false positives, especially for membrane
        proteins tested outside their native lipid environment. The core protein-protein
        interactions of SDHC (with SDHD, SDHB, SDHA within Complex II) are already
        captured by the CC annotation GO:0045273.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: we report on an interactome map that focuses on neurodegenerative
            disease (ND), connects
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: IEA annotation for mitochondrial localization via Ensembl Compara ortholog
        transfer from mouse (UniProtKB:Q9CZB0). SDHC has a mitochondrial transit peptide
        (residues 1-29, inferred by similarity) and is localized to the mitochondrial
        inner membrane as part of Complex II. Confirmed by the cryo-EM structure (PMID:37098072)
        and mass spectrometry identification in the mitochondrial proteome (PMID:34800366).
      action: ACCEPT
      reason: Correct localization, well supported by structural evidence (PMID:37098072)
        and proteomics (PMID:34800366, PMID:21269460, PMID:25944712). SDHC is a well-established
        mitochondrial protein.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: IEA annotation for mitochondrial matrix localization via Ensembl Compara
        ortholog transfer from mouse (UniProtKB:Q9CZB0). The GOA qualifier is 'is_active_in'.
        This is problematic for SDHC because SDHC is an integral transmembrane protein
        that spans the inner membrane, not a matrix protein. While the N-terminal
        domain of SDHC (residues 30-65) faces the matrix, the majority of the protein
        consists of three transmembrane helices spanning the membrane. Describing
        SDHC as 'is_active_in' the mitochondrial matrix is misleading; it is more
        accurately localized to the mitochondrial inner membrane (GO:0005743).
      action: REMOVE
      reason: SDHC is an integral multi-pass transmembrane protein of the inner mitochondrial
        membrane, not a matrix protein. The cryo-EM structure (PMID:37098072) clearly
        shows SDHC embedded in the membrane with three transmembrane helices. The
        N-terminal domain extends into the matrix but the protein's primary localization
        is the inner membrane itself, which is already annotated. Mitochondrial matrix
        (with qualifier 'is_active_in') is misleading for a transmembrane anchor subunit.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: 'The entire hydrophobic domain contains two membrane-anchored
            subunits: SDHC and SDHD'
  - term:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: contributes_to
    review:
      summary: "IEA annotation for SDH quinone reductase activity via Ensembl Compara\
        \ ortholog transfer from mouse (UniProtKB:Q9CZB0). GO:0008177 is defined as\
        \ the overall reaction of the SDH complex (succinate + quinone -> fumarate\
        \ + quinol). The qualifier 'contributes_to' is appropriate for SDHC, which\
        \ does not independently catalyze this reaction but provides essential structural\
        \ components: the membrane anchor, the Q-binding site (residues Ile56, Trp61,\
        \ Met65, Ile69 directly contact ubiquinone), and the heme b environment (His127\
        \ as axial ligand). Without SDHC, the complex cannot reduce ubiquinone."
      action: ACCEPT
      reason: The 'contributes_to' qualifier is correctly used here. SDHC provides
        essential structural contributions to the SDH quinone activity by forming
        part of the Q-site and harboring the heme b, but does not independently catalyze
        the reaction. This is consistent with the pattern used for Complex II subunit
        annotations in the SDHA and SDHB reviews.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: UQ is also observed to bind at the entrance of the pocket
            formed by the transmembrane helix I of SDHC, transmembrane helix II of
            SDHD, and the C-terminal segment of SDHB. It interacts with Pro-SDHB197,
            Trp-SDHB201, Ile-SDHB246, Ile-SDHC56, Trp-SDHC61, Met-SDHC65, Ile-SDHC69,
            and Tyr-SDHD114
        - reference_id: file:human/SDHC/SDHC-deep-research-falcon.md
          supporting_text: 'Correct gene/protein: SDHC encodes the membrane-embedded
            cytochrome b560 subunit of mitochondrial succinate dehydrogenase (Complex
            II), forming the membrane arm with SDHD. It houses the heme b and contributes
            to the ubiquinone-binding pocket'
  - term:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: IEA annotation for Complex II membership via Ensembl Compara ortholog
        transfer from mouse (UniProtKB:Q9CZB0). Consistent with IBA, ISS, IDA, and
        TAS annotations for the same term.
      action: ACCEPT
      reason: Correct and consistent with multiple lines of evidence from different
        sources. SDHC is unambiguously a subunit of Complex II.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: NAS
    original_reference_id: PMID:30030361
    review:
      summary: NAS annotation from ComplexPortal based on review by Signes and Fernandez-Vizarra
        (2018) on assembly of OXPHOS complexes. SDHC is an integral multi-pass protein
        of the mitochondrial inner membrane, forming the membrane anchor of Complex
        II together with SDHD. Confirmed by cryo-EM (PMID:37098072).
      action: ACCEPT
      reason: Correct localization. SDHC is an integral protein of the inner mitochondrial
        membrane with three transmembrane helices, confirmed by the cryo-EM structure
        (PMID:37098072).
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: 'The entire hydrophobic domain contains two membrane-anchored
            subunits: SDHC and SDHD'
  - term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    evidence_type: NAS
    original_reference_id: PMID:30030361
    review:
      summary: NAS annotation from ComplexPortal for TCA cycle involvement based on
        the OXPHOS assembly review (PMID:30030361). SDHC is a structural subunit of
        Complex II which catalyzes the succinate to fumarate step of the TCA cycle.
      action: ACCEPT
      reason: Correct and consistent with IEA and TAS annotations for the same term.
        TCA cycle involvement is a core function of SDHC as part of Complex II.
      supported_by:
        - reference_id: PMID:30030361
          supporting_text: The assembly of the five oxidative phosphorylation system
            (OXPHOS) complexes in the inner mitochondrial membrane is an intricate
            process
  - term:
      id: GO:0006121
      label: mitochondrial electron transport, succinate to ubiquinone
    evidence_type: NAS
    original_reference_id: PMID:30030361
    review:
      summary: NAS annotation from ComplexPortal for the specific electron transport
        process from succinate to ubiquinone. SDHC is essential for this process because
        it forms part of the ubiquinone binding site and provides the heme b environment
        needed for electron flow from the [3Fe-4S] cluster to ubiquinone. Consistent
        with the IBA annotation for the same term.
      action: ACCEPT
      reason: Core biological process for SDHC. SDHC provides the terminal portion
        of the electron transfer pathway in Complex II by forming the Q-binding pocket
        with SDHD and SDHB.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: The edge-to-edge distance between these redox-active prosthetic
            groups is less than 14 Å (Fig. 3), a distance range that can efficiently
            support the delivery of electrons between these redox centers (22)
  - term:
      id: GO:0042776
      label: proton motive force-driven mitochondrial ATP synthesis
    evidence_type: NAS
    original_reference_id: PMID:30030361
    review:
      summary: NAS annotation from ComplexPortal suggesting SDHC is involved in proton
        motive force-driven mitochondrial ATP synthesis. This annotation is problematic
        because Complex II does NOT pump protons across the inner mitochondrial membrane.
        Unlike Complexes I, III, and IV which translocate protons to generate the
        proton motive force, Complex II transfers electrons from succinate to ubiquinone
        without any proton pumping. Complex II contributes to ATP synthesis only indirectly
        by feeding reduced ubiquinol into the Q pool, which is then oxidized by Complex
        III (which does pump protons). The same annotation was marked REMOVE for SDHB
        in the parallel review.
      action: REMOVE
      reason: Complex II is the only OXPHOS complex that does NOT pump protons. The
        proton motive force is generated by Complexes I, III, and IV. Complex II feeds
        electrons into the ubiquinone pool but does not directly contribute to the
        proton gradient. This annotation is misleading and was also marked REMOVE
        for SDHB. The correct process annotation for SDHC is GO:0006121 (mitochondrial
        electron transport, succinate to ubiquinone).
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: The respiratory chain (also called electron transport chain)
            consists of complexes I-IV. It oxidizes the reducing equivalents in nicotinamide
            adenine dinucleotide (NADH) and succinate using molecular oxygen and couples
            the translocation of protons from the mitochondrial matrix into the intermembrane
            space
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: HTP annotation for mitochondrial localization from a quantitative high-confidence
        human mitochondrial proteome study (Morgenstern et al. 2021). SDHC was identified
        in the mitochondrial proteome by quantitative mass spectrometry.
      action: ACCEPT
      reason: Correct. SDHC is a well-established mitochondrial protein confirmed
        by proteomics and structural studies.
      supported_by:
        - reference_id: PMID:34800366
          supporting_text: Quantitative high-confidence human mitochondrial proteome
            and its dynamics in cellular context [SDHC identified by quantitative
            mass spectrometry]
  - term:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation for Complex II membership by manual transfer from ortholog
        (UniProtKB:D0VWV4, bovine). Consistent with all other annotations for this
        term.
      action: ACCEPT
      reason: Correct. Transfer from the well-characterized bovine SDH complex. SDHC
        is unambiguously a subunit of Complex II.
  - term:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    evidence_type: IDA
    original_reference_id: PMID:37098072
    review:
      summary: IDA annotation for Complex II membership from the cryo-EM structure
        study (Du et al. 2023). This study resolved the human Complex II structure
        at 2.86 angstroms showing all four subunits including SDHC in the membrane
        domain. SDHC was directly identified in the complex by cryo-EM, SDS-PAGE,
        and mass spectrometry.
      action: ACCEPT
      reason: Direct experimental evidence from the human Complex II cryo-EM structure.
        This is the strongest evidence for SDHC's membership in Complex II.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: All the four subunits (SDHA, SDHB, SDHC, and SDHD) were
            detected by SDS-PAGE (SI Appendix, Fig. S1D) and mass spectrometry (MS)
            (SI Appendix, Table S1).
  - term:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    evidence_type: TAS
    original_reference_id: PMID:9533030
    review:
      summary: TAS annotation for Complex II membership from the original cDNA cloning
        study of SDHC and SDHD (Hirawake et al. 1997). This study cloned the cDNA
        for the large (cybL/SDHC) and small (cybS/SDHD) subunits of cytochrome b in
        human liver Complex II and determined their role as membrane-anchors.
      action: ACCEPT
      reason: The original characterization study of SDHC establishes it as a subunit
        of Complex II.
      supported_by:
        - reference_id: PMID:9533030
          supporting_text: the amino acid sequences of the large (cybL) and small
            (cybS) subunits of cytochrome b in human liver complex II were deduced
            from cDNAs isolated by homology probing
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-70994
    review:
      summary: TAS annotation for inner mitochondrial membrane localization from Reactome
        pathway R-HSA-70994 (SDH complex dehydrogenates succinate). Reactome models
        Complex II as located in the inner mitochondrial membrane where it catalyzes
        the oxidation of succinate coupled to ubiquinone reduction.
      action: ACCEPT
      reason: Correct localization, consistent with all other inner membrane annotations.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9855252
    review:
      summary: TAS annotation for inner mitochondrial membrane localization from Reactome
        pathway R-HSA-9855252 (SDHA:SDHB binds to SDHC:SDHD). This Reactome entry
        models the assembly of Complex II by association of the catalytic SDHA:SDHB
        subcomplex with the membrane-anchored SDHC:SDHD subcomplex at the inner mitochondrial
        membrane.
      action: ACCEPT
      reason: Correct localization. The Reactome assembly model places SDHC:SDHD at
        the inner mitochondrial membrane, consistent with experimental evidence.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation for inner mitochondrial membrane localization by manual
        transfer from ortholog (UniProtKB:D0VWV4, bovine). Consistent with all other
        inner membrane annotations.
      action: ACCEPT
      reason: Correct. Transfer from the well-characterized bovine SDH complex. SDHC
        is located in the inner mitochondrial membrane.
  - term:
      id: GO:0020037
      label: heme binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation for heme binding by manual transfer from ortholog (UniProtKB:D0VWV4,
        bovine). SDHC provides the axial His127 ligand to the heme b (cytochrome b560)
        iron atom. The heme b is shared between SDHC and SDHD, with each subunit providing
        one histidine as an axial ligand. The cryo-EM structure (PMID:37098072, PDB:8GS8)
        directly confirmed the heme b binding site in the SDHC/SDHD interface. UniProt
        annotates the binding site at residue 127 with evidence ECO:0000269|PubMed:37098072.
        The heme b is important for protein stability and may serve as an electron
        sink during ubiquinone reduction.
      action: ACCEPT
      reason: Heme binding is a core molecular function of SDHC. The His127 axial
        ligand coordinates the heme b iron atom, confirmed by cryo-EM structure (PMID:37098072).
        This is one of the few subunit-specific molecular functions of SDHC.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: The two membrane-anchored proteins (SDHC and SDHD) in human
            CII, each with three transmembrane helices, contain only one heme b group
        - reference_id: PMID:37098072
          supporting_text: the heme cofactor is also crucial for the heme protein
            to achieve its proper fold and thus become a stable, functional structure
        - reference_id: PMID:9533030
          supporting_text: Histidine residues, which are possible heme axial ligands
            in cytochrome b of complex II, were found in the second transmembrane
            segment of each subunit
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: TAS
    original_reference_id: PMID:2302193
    review:
      summary: TAS annotation for mitochondrial localization from Kita et al. (1990).
        This study cloned the cDNA for the iron-sulfur subunit of human liver Complex
        II and established that Complex II is located in mitochondria. Note that PMID:2302193
        specifically describes the Ip (SDHB) subunit, not SDHC directly, but the TAS
        inference to SDHC as a subunit of the same complex is reasonable since Complex
        II is exclusively mitochondrial.
      action: ACCEPT
      reason: Correct localization. While the publication specifically cloned the
        SDHB subunit, the inference that SDHC is mitochondrial as a subunit of Complex
        II is well-supported.
      supported_by:
        - reference_id: PMID:2302193
          supporting_text: Complex II (succinate-ubiquinone oxidoreductase) is an
            important enzyme complex of both the tricarboxylic acid cycle and of the
            aerobic respiratory chains of mitochondria in eukaryotic cell and prokaryotic
            organisms
  - term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    evidence_type: TAS
    original_reference_id: PMID:9533030
    review:
      summary: TAS annotation for TCA cycle involvement from the original cDNA cloning
        study (Hirawake et al. 1997). This study explicitly describes Complex II as
        an enzyme involved in both the TCA cycle and aerobic respiration.
      action: ACCEPT
      reason: Correct. TCA cycle involvement is a core biological process for SDHC
        as part of Complex II. Consistent with IEA and NAS annotations for the same
        term.
      supported_by:
        - reference_id: PMID:9533030
          supporting_text: Complex II (succinate-ubiquinone oxidoreductase) is an
            important enzyme complex in both the tricarboxylic acid cycle and the
            aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic
            organisms
  - term:
      id: GO:0009060
      label: aerobic respiration
    evidence_type: TAS
    original_reference_id: PMID:9533030
    review:
      summary: TAS annotation for aerobic respiration from the original cDNA cloning
        study (Hirawake et al. 1997). Complex II is part of the aerobic respiratory
        chain, linking succinate oxidation in the TCA cycle to ubiquinone reduction
        in the electron transport chain.
      action: ACCEPT
      reason: Correct. Aerobic respiration is a core biological process for SDHC as
        part of Complex II. Complex II participates in both the TCA cycle and the
        electron transport chain during aerobic respiration.
      supported_by:
        - reference_id: PMID:9533030
          supporting_text: Complex II (succinate-ubiquinone oxidoreductase) is an
            important enzyme complex in both the tricarboxylic acid cycle and the
            aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic
            organisms
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: TAS
    original_reference_id: PMID:9533030
    review:
      summary: TAS annotation for general membrane localization from the original
        cDNA cloning study (Hirawake et al. 1997). SDHC was predicted to have three
        transmembrane segments, indicating its role as a membrane-anchor. This is
        correct but very general; the more specific term GO:0005743 (mitochondrial
        inner membrane) is also annotated.
      action: ACCEPT
      reason: Correct but general. The original study predicted three transmembrane
        segments for SDHC, establishing its role as a membrane protein. The more specific
        inner membrane term is also annotated from multiple evidence sources.
      supported_by:
        - reference_id: PMID:9533030
          supporting_text: From hydrophobicity analysis, both cybL and cybS appear
            to have three transmembrane segments, indicating their role as membrane-anchors
            for the enzyme complex
  - term:
      id: GO:0048039
      label: ubiquinone binding
    evidence_type: IDA
    original_reference_id: PMID:37098072
    review:
      summary: The cryo-EM structure of human Complex II (PMID:37098072) directly
        demonstrates that ubiquinone binds at a pocket formed jointly by SDHC, SDHD,
        and SDHB. Specific SDHC residues Ile56, Trp61, Met65, and Ile69 directly contact
        ubiquinone. This is a subunit-specific molecular function of SDHC that is
        not currently annotated.
      action: NEW
      reason: Ubiquinone binding is a key subunit-specific molecular function of SDHC
        that is missing from the current annotation set. The cryo-EM structure (PMID:37098072)
        provides direct structural evidence for SDHC residues contacting ubiquinone.
        The qualifier should be 'contributes_to' since the Q-site is shared with SDHD
        and SDHB.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: UQ is also observed to bind at the entrance of the pocket
            formed by the transmembrane helix I of SDHC, transmembrane helix II of
            SDHD, and the C-terminal segment of SDHB. It interacts with Pro-SDHB197,
            Trp-SDHB201, Ile-SDHB246, Ile-SDHC56, Trp-SDHC61, Met-SDHC65, Ile-SDHC69,
            and Tyr-SDHD114
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with GO
      terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to
      orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
      vocabulary mapping, accompanied by conservative changes to GO terms applied
      by UniProt
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data
      to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: file:human/SDHC/SDHC-deep-research-falcon.md
    title: Falcon deep research synthesis for human SDHC
    findings: []
  - id: PMID:2302193
    title: 'Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of
      iron sulfur (Ip) subunit of liver mitochondria.'
    findings:
      - statement: Established Complex II as a mitochondrial enzyme involved in the
          TCA cycle and aerobic respiratory chain. Cloned the iron-sulfur (Ip/SDHB)
          subunit.
        supporting_text: Complex II (succinate-ubiquinone oxidoreductase) is an important
          enzyme complex of both the tricarboxylic acid cycle and of the aerobic respiratory
          chains of mitochondria in eukaryotic cell and prokaryotic organisms
  - id: PMID:9533030
    title: 'Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase):
      cDNA cloning of the components in liver mitochondria and chromosome assignment
      of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23.'
    findings:
      - statement: Original cDNA cloning of SDHC (cybL, 140 mature amino acids) and
          SDHD (cybS, 103 amino acids) from human liver. Predicted three transmembrane
          segments for each subunit. Identified histidine residues as potential heme
          axial ligands. Mapped SDHC to chromosome 1q21 and SDHD to 11q23.
        supporting_text: the amino acid sequences of the large (cybL) and small (cybS)
          subunits of cytochrome b in human liver complex II were deduced from cDNAs
          isolated by homology probing with mixed primers for the polymerase chain
          reaction. The mature cybL and cybS contain 140 and 103 amino acids, respectively
  - id: PMID:30030361
    title: Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
    findings:
      - statement: Review of OXPHOS complex assembly. Complex II assembly involves
          the SDHA:SDHB catalytic subcomplex associating with the SDHC:SDHD membrane
          anchor in the inner mitochondrial membrane.
        supporting_text: The assembly of the five oxidative phosphorylation system
          (OXPHOS) complexes in the inner mitochondrial membrane is an intricate process
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
      and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings:
      - statement: Large-scale Y2H interactome mapping for neurodegenerative disease.
          Detected interactions between SDHC and several nuclear/cytoplasmic proteins
          (PRKCA, YWHAG, KAT5, SETDB1, LMO3) of uncertain biological significance
          for a mitochondrial membrane protein.
        supporting_text: we report on an interactome map that focuses on neurodegenerative
          disease (ND), connects
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome and its dynamics
      in cellular context.
    findings:
      - statement: Quantitative proteomics confirmed SDHC as a component of the high-confidence
          human mitochondrial proteome.
        supporting_text: Quantitative high-confidence human mitochondrial proteome
          and its dynamics in cellular context [SDHC identified by quantitative mass
          spectrometry]
  - id: PMID:37098072
    title: Structure of the human respiratory complex II.
    findings:
      - statement: Determined cryo-EM structure of human Complex II at 2.86 angstroms.
          SDHC resolved with three transmembrane helices, one heme b group (shared
          with SDHD), and ubiquinone bound at the pocket formed by transmembrane helix
          I of SDHC, helix II of SDHD, and the C-terminal segment of SDHB. SDHC residues
          Ile56, Trp61, Met65, Ile69 directly contact ubiquinone. His127 of SDHC provides
          an axial ligand to heme b iron. The heme b is proposed to serve as an electron
          sink during the two-electron reduction of ubiquinone.
        supporting_text: The two membrane-anchored proteins (SDHC and SDHD) in human
          CII, each with three transmembrane helices, contain only one heme b group
  - id: Reactome:R-HSA-70994
    title: SDH complex dehydrogenates succinate
    findings: []
  - id: Reactome:R-HSA-9855252
    title: SDHA:SDHB binds to SDHC:SDHD
    findings: []
core_functions:
  - molecular_function:
      id: GO:0020037
      label: heme binding
    contributes_to_molecular_function:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    directly_involved_in:
      - id: GO:0006121
        label: mitochondrial electron transport, succinate to ubiquinone
      - id: GO:0006099
        label: tricarboxylic acid cycle
    locations:
      - id: GO:0005743
        label: mitochondrial inner membrane
    in_complex:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    description: SDHC is the large cytochrome b560 transmembrane subunit of succinate
      dehydrogenase (Complex II). Together with SDHD, it forms the membrane anchor
      domain that anchors the catalytic SDHA:SDHB subcomplex in the inner mitochondrial
      membrane. SDHC provides the His127 axial ligand to the heme b (cytochrome b560)
      iron atom shared between SDHC and SDHD, making heme binding (GO:0020037) its
      primary subunit-specific molecular function. SDHC also contributes to ubiquinone
      binding at the Q-site (residues Ile56, Trp61, Met65, Ile69 directly contact
      ubiquinone) and to the overall succinate dehydrogenase (quinone) activity (GO:0008177)
      of the Complex II heterotetramer. The heme b is proposed to serve as an electron
      sink during the two-electron reduction of ubiquinone. Through Complex II, SDHC
      participates in mitochondrial electron transport from succinate to ubiquinone
      (GO:0006121) and the tricarboxylic acid cycle (GO:0006099).
    supported_by:
      - reference_id: PMID:37098072
        supporting_text: The two membrane-anchored proteins (SDHC and SDHD) in human
          CII, each with three transmembrane helices, contain only one heme b group
      - reference_id: PMID:37098072
        supporting_text: UQ is also observed to bind at the entrance of the pocket
          formed by the transmembrane helix I of SDHC, transmembrane helix II of SDHD,
          and the C-terminal segment of SDHB. It interacts with Pro-SDHB197, Trp-SDHB201,
          Ile-SDHB246, Ile-SDHC56, Trp-SDHC61, Met-SDHC65, Ile-SDHC69, and Tyr-SDHD114
      - reference_id: PMID:9533030
        supporting_text: Histidine residues, which are possible heme axial ligands
          in cytochrome b of complex II, were found in the second transmembrane segment
          of each subunit

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

Citations

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