SDHD encodes the small cytochrome b-like membrane anchor subunit (CybS) of succinate dehydrogenase (SDH, Complex II), a heterotetrameric enzyme (SDHA/SDHB/SDHC/SDHD) embedded in the mitochondrial inner membrane. SDHD has three transmembrane helices and, together with SDHC, forms the membrane anchor domain that attaches the hydrophilic SDHA/SDHB catalytic head to the inner membrane. SDHD and SDHC together coordinate one heme b group (with His102 of SDHD serving as an axial ligand) and form the ubiquinone-binding entrance channel (involving SDHD TM2 helix and Tyr114 directly contacting ubiquinone). Complex II is unique among OXPHOS complexes in that it does NOT pump protons across the inner membrane. SDHD has no independent catalytic activity but contributes structurally to the ubiquinone binding site and electron sink function of heme b. SDHD functions as a tumor suppressor; heterozygous loss-of-function germline mutations cause hereditary paraganglioma/pheochromocytoma syndrome type 1 (PPGL1) via succinate accumulation acting as an oncometabolite. Biallelic mutations cause mitochondrial complex II deficiency type 3 (MC2DN3) with encephalomyopathy and cardiomyopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006099 tricarboxylic acid cycle | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for TCA cycle involvement. Complex II is the only membrane-bound enzyme of the TCA cycle, catalyzing the oxidation of succinate to fumarate. SDHD is essential as the membrane anchor subunit. The IBA is phylogenetically well-supported with evidence from orthologous SDH subunits across multiple species. Confirmed by the original cDNA cloning study (PMID:9533030) which established SDHD as part of the succinate-ubiquinone oxidoreductase complex. Reason: TCA cycle involvement is a core biological process for SDHD as part of Complex II. The IBA is phylogenetically sound and well-supported by biochemical evidence. 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 PMID:37098072 Human complex II is a key protein complex that links two essential energy-producing processes: the tricarboxylic acid cycle and oxidative phosphorylation file:human/SDHD/SDHD-deep-research-falcon.md The SDHD gene (chromosome 11q23.1) encodes the small cytochrome b-like membrane subunit of mitochondrial Complex II (succinate dehydrogenase; SQR), partnering with SDHC to anchor the catalytic SDHA/SDHB dimer, harbor heme b, and form the ubiquinone-binding/channel region |
| GO:0006121 mitochondrial electron transport, succinate to ubiquinone | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for the specific electron transport process from succinate to ubiquinone. SDHD forms part of the ubiquinone-binding entrance channel (via TM2 helix and Tyr114) and coordinates heme b (via His102) which serves as an electron sink facilitating ubiquinone reduction. The cryo-EM structure (PMID:37098072) directly demonstrates SDHD residues at the quinone binding site. Reason: This is a core biological process for SDHD. The SDHD subunit directly contributes to the ubiquinone-binding site and heme b coordination that enable electron transfer from succinate to ubiquinone. Phylogenetically well-supported and confirmed by structural data. 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 |
| GO:0045273 respiratory chain complex II (succinate dehydrogenase) | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for Complex II membership. SDHD is one of the four core subunits of Complex II, forming the membrane anchor together with SDHC. The IBA is strongly supported phylogenetically. The cryo-EM structure (PMID:37098072) directly demonstrates SDHD as an integral subunit of the complex. Reason: Localization to respiratory chain complex II is the most fundamental cellular component annotation for SDHD. Well-supported by IBA phylogenetic inference and confirmed by cryo-EM structure showing all four subunits. 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) 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 |
| GO:0020037 heme binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for heme binding. SDHD coordinates heme b together with SDHC at the interface between the two membrane-spanning subunits. His102 of SDHD serves as an axial binding residue for the heme b iron (PMID:37098072, UniProt FT BINDING 102). Histidine residues predicted as heme axial ligands were identified in the second transmembrane segment of each subunit in the original cloning study (PMID:9533030). Reason: Heme binding is a core molecular function of SDHD. His102 directly coordinates the heme b iron atom as an axial ligand, confirmed by the cryo-EM structure at 2.86 angstrom resolution. The heme b functions as an electron sink stabilizing semiquinone intermediates during ubiquinone reduction. Supporting Evidence: PMID:37098072 Electron paramagnetic resonance (EPR) spectra revealed the presence of redox centers 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:0048039 ubiquinone binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for ubiquinone binding. SDHD directly contributes to the ubiquinone-binding site via Tyr114, which contacts ubiquinone in the entrance pocket formed by SDHC TM1, SDHD TM2, and the SDHB C-terminus (PMID:37098072). UniProt annotates SDHD Tyr114 as a ubiquinone-binding residue (ligand shared with SDHB). Reason: Ubiquinone binding is a core molecular function of SDHD. Structural evidence from cryo-EM directly shows Tyr-SDHD114 contacting ubiquinone at the binding entrance. This is one of the key subunit-specific contributions of SDHD to the complex. 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 |
| GO:0005740 mitochondrial envelope | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro (IPR007992 CybS) mapping to mitochondrial envelope. SDHD is an integral protein of the inner mitochondrial membrane. This term is correct but less specific than GO:0005743 (mitochondrial inner membrane) which is also annotated from multiple evidence codes. Reason: Correct localization. SDHD is embedded in the inner mitochondrial membrane, which is part of the mitochondrial envelope. The more specific GO:0005743 is also present from IDA, NAS, TAS, ISS, and IEA evidence. Acceptable for an IEA to be at this broader level. Supporting Evidence: PMID:37098072 The entire hydrophobic domain contains two membrane-anchored subunits: SDHC and SDHD |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location vocabulary mapping. SDHD is a multi-pass integral protein of the inner mitochondrial membrane with three transmembrane helices, confirmed by the cryo-EM structure (PMID:37098072) and the original cloning study (PMID:9533030). Reason: Correct localization. SDHD is an integral inner mitochondrial membrane protein. Well-supported by multiple experimental evidence sources. 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: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:Q9CXV1) and UniProt keyword/UniPathway mapping. Consistent with the IBA and IDA annotations for the same term. Reason: Correct. Duplicate of the IBA and IDA annotations for the same GO term. TCA cycle involvement is a core function of SDHD as part of Complex II. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro (IPR007992, IPR034804) mapping to the generic 'membrane' term. SDHD is a multi-pass integral membrane protein with three transmembrane helices. This term is correct but very broad; more specific terms (GO:0005743, GO:0005740) are also annotated. Reason: Correct but very general. Acceptable for an IEA to be at this broad level. The more specific GO:0005743 (mitochondrial inner membrane) is also annotated. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProt keyword (KW-0479 Metal-binding) mapping. SDHD binds iron as part of the heme b group coordinated between SDHC and SDHD. His102 of SDHD is an axial binding residue for the heme iron. This is correct but very general; the more informative GO:0020037 (heme binding) is also annotated. Reason: Correct but general. SDHD coordinates iron as part of heme b via His102. The more specific GO:0020037 (heme binding) is also annotated and provides more informative description of the actual binding function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI annotation for protein binding based on the HuRI high-throughput binary interactome study (PMID:32296183). The IntAct record indicates SDHD interacts with RHBDD2 (Q6NTF9-3), an interaction detected by yeast two-hybrid. UniProt also records this as the only documented binary interaction for SDHD outside of Complex II subunit-subunit interactions. RHBDD2 is a rhomboid-like protease with uncertain functional relevance to SDHD. Reason: 'Protein binding' is an uninformative term per GO curation guidelines. The interaction with RHBDD2 was detected in a high-throughput Y2H screen and its biological relevance to SDHD function is unclear. SDHD binds SDHC as its primary protein partner within Complex II, but this interaction is already captured by the Complex II component annotations. The generic 'protein binding' term does not inform about SDHD function. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI' |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for mitochondrion localization from combined automated methods including ortholog transfer and ARBA rules. SDHD is a mitochondrial protein as part of Complex II in the inner mitochondrial membrane. This is correct but less specific than GO:0005743 (mitochondrial inner membrane). Reason: Correct localization. SDHD resides in the mitochondrion. Acceptable for an IEA to be at this broader level when more specific terms are also annotated. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000107 | MODIFY | Summary: IEA annotation for mitochondrial matrix localization from Ensembl Compara ortholog transfer (mouse Q9CXV1). The GOA qualifier is 'is_active_in'. SDHD is an integral inner membrane protein with a short N-terminal region (residues 57-63) in the matrix and the bulk of the protein spanning the membrane. The cryo-EM structure (PMID:37098072) maps SDHD topology showing matrix-facing and IMS-facing regions. This annotation is misleading because SDHD is not primarily active in the matrix; its functional role is within the membrane and at the quinone-binding site. Reason: SDHD is an integral membrane protein of the inner mitochondrial membrane. While a small N-terminal loop faces the matrix, calling SDHD 'is_active_in' the mitochondrial matrix is inaccurate. The appropriate localization for SDHD is the inner mitochondrial membrane (GO:0005743) which is already well-annotated. This IEA likely results from a blanket ortholog transfer that does not distinguish membrane-spanning from soluble subunits of the complex. Proposed replacements: mitochondrial inner membrane 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 | MODIFY | Summary: IEA annotation for SDH quinone activity from Ensembl Compara ortholog transfer (mouse Q9CXV1). The GOA qualifier is 'enables'. GO:0008177 represents the overall reaction of the SDH complex (succinate + quinone -> fumarate + quinol, EC 1.3.5.1). SDHD alone cannot catalyze this reaction; it provides the membrane anchor and contributes to the ubiquinone-binding site via Tyr114 (PMID:37098072). The qualifier should be 'contributes_to' rather than 'enables' for a non-catalytic subunit that participates in the quinone binding site. Reason: SDHD contributes to the overall SDH quinone activity by providing part of the ubiquinone-binding site (Tyr114) and anchoring the complex in the membrane, but does not enable it alone. Relation-only correction (go-annotation#6414). GO:0008177 is the whole-complex succinate:quinone reaction, which no single subunit carries out, so the GOA 'enables' relation should become 'contributes_to'. The term is kept; the intended contributes_to assertion is recorded as the paired NEW row below, pending the upstream GOA change. Proposed replacements: succinate dehydrogenase (quinone) activity 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 |
| GO:0045273 respiratory chain complex II (succinate dehydrogenase) | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation for Complex II membership from Ensembl Compara ortholog transfer (mouse Q9CXV1). Consistent with IBA, ISS, IDA, and TAS annotations for the same term. SDHD is unequivocally a core subunit of Complex II. Reason: Correct. Duplicate of multiple other annotations for this well-established Complex II membership. SDHD is one of the four core subunits. |
| GO:0005743 mitochondrial inner membrane | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | ACCEPT | Summary: NAS annotation from ComplexPortal citing the OXPHOS assembly review by Signes and Fernandez-Vizarra (2018). SDHD is an integral inner mitochondrial membrane protein with three transmembrane helices. This review covers the assembly of OXPHOS complexes I-V including Complex II. Reason: Correct localization. Inner mitochondrial membrane is the well-established localization for SDHD. Consistent with IDA and structural evidence. Supporting Evidence: PMID:30030361 The assembly of the five oxidative phosphorylation system (OXPHOS) complexes in the inner mitochondrial membrane is an intricate process |
| 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, citing the OXPHOS assembly review. Complex II uniquely functions in both the TCA cycle and the electron transport chain. Consistent with IBA and IDA annotations for the same term. Reason: Correct. TCA cycle involvement is a core function of Complex II and therefore of SDHD. Consistent with multiple other evidence lines. 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. SDHD contributes to the ubiquinone-binding site and heme b coordination that are essential for electron transfer from succinate to ubiquinone. Consistent with IBA annotation for the same term. Reason: Correct. SDHD directly contributes to electron transfer by forming part of the quinone-binding entrance and coordinating heme b. Consistent with structural evidence. Supporting Evidence: PMID:30030361 The assembly of the five oxidative phosphorylation system (OXPHOS) complexes in the inner mitochondrial membrane is an intricate process |
| GO:0042776 proton motive force-driven mitochondrial ATP synthesis | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | MARK AS OVER ANNOTATED | Summary: NAS annotation from ComplexPortal for proton motive force-driven ATP synthesis. Complex II transfers electrons from succinate to ubiquinone, contributing to the overall electron flow that drives proton pumping by Complexes I, III, and IV, which in turn drives ATP synthesis by Complex V. However, Complex II itself does NOT pump protons. This annotation attributes a downstream consequence of Complex II activity to SDHD rather than a direct function. Reason: Complex II does NOT pump protons across the inner membrane. While it does feed electrons into the ubiquinone pool, contributing indirectly to the proton motive force via Complexes III and IV, annotating SDHD with 'proton motive force-driven mitochondrial ATP synthesis' overstates the direct role. The direct contributions of SDHD are better captured by GO:0006121 (electron transport, succinate to ubiquinone) and the Complex II component annotation. Supporting Evidence: PMID:37098072 Respiratory complex II plays a crucial role in the two primary key metabolic pathways for generating ATP: the Krebs cycle (also known as tricarboxylic acid, TCA) and the OXPHOS pathway [Complex II does not directly pump protons but contributes electrons to the ubiquinone pool] |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: HTP annotation for mitochondrion localization from the high-confidence human mitochondrial proteome study by Morgenstern et al. (2021). SDHD was detected as part of the high-confidence mitochondrial proteome by quantitative mass spectrometry. Consistent with all other localization evidence. Reason: Correct. Mitochondrial localization of SDHD is confirmed by high-throughput proteomics and consistent with all other evidence. Broader than GO:0005743 but acceptable for HTP evidence. Supporting Evidence: PMID:34800366 We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP) |
| GO:0045273 respiratory chain complex II (succinate dehydrogenase) | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for Complex II membership transferred from ortholog (UniProtKB:A5GZW8, A. suum SDHD). Consistent with IBA, IDA, TAS, and IEA annotations for the same term. Reason: Correct. Consistent with multiple other evidence lines. Complex II membership is the core component annotation for SDHD. |
| 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 based on the cryo-EM structure of human Complex II (Du et al., 2023). The structure was determined at 2.86 angstrom resolution by cryo-EM showing all four subunits (SDHA, SDHB, SDHC, SDHD) in a monomeric assembly. SDHD was identified by mass spectrometry and its structure was resolved in the complex showing three transmembrane helices. Reason: Strong experimental evidence from the definitive human Complex II structure. This is the highest-quality direct evidence for SDHD as a Complex II subunit. 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) 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: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 based on the original cDNA cloning study by Hirawake et al. (1997). This study cloned the cDNA for the small (cybS/SDHD) subunit of cytochrome b in human liver Complex II and mapped the gene to chromosome 11q23. Reason: Correct. The original cloning study establishing SDHD as a Complex II subunit. Consistent with all subsequent structural and biochemical evidence. 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 |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-70994 | ACCEPT | Summary: TAS annotation from Reactome pathway R-HSA-70994 (SDH complex dehydrogenates succinate). SDHD is placed in the inner mitochondrial membrane as part of the SDH complex in this Reactome reaction. Reason: Correct localization. Consistent with all other evidence for SDHD in the inner mitochondrial membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9855252 | ACCEPT | Summary: TAS annotation from Reactome pathway R-HSA-9855252 (SDHA:SDHB binds to SDHC:SDHD). This Reactome reaction describes the assembly of the SDHA/SDHB catalytic dimer with the SDHC/SDHD membrane anchor in the inner mitochondrial membrane. Reason: Correct localization. The assembly of SDHC:SDHD with SDHA:SDHB occurs at the inner mitochondrial membrane. Consistent with all other evidence. |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for inner mitochondrial membrane localization transferred from ortholog (UniProtKB:A5GZW8, A. suum SDHD). Consistent with IDA, NAS, TAS, and IEA annotations for the same term. Reason: Correct. Consistent with multiple other evidence lines for inner mitochondrial membrane localization. |
| GO:0020037 heme binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for heme binding transferred from ortholog (UniProtKB:A5GZW8, A. suum SDHD). Consistent with the IBA annotation for the same term. SDHD coordinates heme b via His102 as an axial ligand, confirmed by the human cryo-EM structure (PMID:37098072). Reason: Correct. Heme binding is a core molecular function of SDHD. The ISS transfer is validated by the human cryo-EM structure showing heme b coordination. Supporting Evidence: PMID:37098072 Electron paramagnetic resonance (EPR) spectra revealed the presence of redox centers |
| GO:0048039 ubiquinone binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for ubiquinone binding transferred from ortholog (UniProtKB:A5GZW8, A. suum SDHD). Consistent with the IBA annotation for the same term. SDHD Tyr114 directly contacts ubiquinone in the binding pocket as shown by the cryo-EM structure (PMID:37098072). Reason: Correct. Ubiquinone binding is a core molecular function of SDHD. The ISS transfer is validated by the human cryo-EM structure. 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 |
| GO:0009055 electron transfer activity | TAS PMID:9533030 Cytochrome b in human complex II (succinate-ubiquinone oxido... | ACCEPT | Summary: TAS annotation for electron transfer activity based on the original cloning study (Hirawake et al., 1997). SDHD contributes to electron transfer by coordinating heme b (electron sink) and forming the ubiquinone-binding site where the terminal electron transfer step occurs. However, SDHD itself does not harbor iron-sulfur clusters or FAD; the primary electron transfer function resides in SDHB. The heme b coordinated by SDHD/SDHC serves as an electron sink that stabilizes semiquinone intermediates rather than being a primary electron carrier. Reason: SDHD contributes to electron transfer through heme b coordination and ubiquinone binding. While SDHB is the primary electron relay subunit, SDHD provides essential structural elements for the terminal electron transfer step. The heme b acts as an electron sink with edge-to-edge distances of about 6.6 angstroms to both ubiquinone and the [3Fe-4S] cluster, within efficient electron transfer range. Supporting Evidence: PMID:37098072 The edge-to-edge distance between these redox-active prosthetic groups is less than 14 Γ
(Fig. 3), a distance range that can efficiently support the delivery of electrons between these redox centers (22) |
| GO:0005743 mitochondrial inner membrane | IDA PMID:9533030 Cytochrome b in human complex II (succinate-ubiquinone oxido... | ACCEPT | Summary: IDA annotation for inner mitochondrial membrane localization based on the original cloning study (Hirawake et al., 1997). The study characterized SDHD as a hydrophobic membrane anchor subunit of Complex II with three predicted transmembrane segments, indicating its location in the inner mitochondrial membrane. UniProt annotates this as confirmed experimental localization. Reason: Strong experimental evidence from the original cloning and characterization study. SDHD is an integral multi-pass protein of the inner mitochondrial membrane. 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:0006099 tricarboxylic acid cycle | IDA PMID:9533030 Cytochrome b in human complex II (succinate-ubiquinone oxido... | ACCEPT | Summary: IDA annotation for TCA cycle involvement based on the original cloning study. The study established SDHD as a subunit of Complex II (succinate-ubiquinone oxidoreductase), which is an important enzyme of the tricarboxylic acid cycle. Reason: Correct. The original study directly states the role of Complex II in the TCA cycle, and SDHD was identified as a core subunit of this complex. 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:0005739 mitochondrion | TAS PMID:2302193 Human complex II (succinate-ubiquinone oxidoreductase): cDNA... | ACCEPT | Summary: TAS annotation for mitochondrion localization citing Kita et al. (1990), which cloned the iron-sulfur subunit (SDHB/Ip) of human liver mitochondrial Complex II. While this paper primarily concerns SDHB, it establishes the mitochondrial localization of Complex II. SDHD is a subunit of the same complex. Reason: Correct localization. SDHD is a mitochondrial protein as part of Complex II. The reference is to a Complex II study that established its mitochondrial context. 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:0005740 mitochondrial envelope | TAS PMID:9533030 Cytochrome b in human complex II (succinate-ubiquinone oxido... | ACCEPT | Summary: TAS annotation for mitochondrial envelope localization from the original SDHD cloning study (Hirawake et al., 1997). SDHD is a membrane-spanning subunit of Complex II in the inner mitochondrial membrane. This is correct but less specific than GO:0005743 (mitochondrial inner membrane), which is also annotated. Reason: Correct but less specific than GO:0005743. Acceptable to retain as the original study supports this localization. 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:0008177 succinate dehydrogenase (quinone) activity | IDA PMID:37098072 Structure of the human respiratory complex II. | NEW | Summary: Intended replacement for the GOA 'enables' GO:0008177 row (IEA GO_REF:0000107), recording the go-annotation#6414 decision that each Complex II subunit contributes_to the whole-complex succinate:quinone oxidoreductase activity. Purified human Complex II containing all four subunits, including SDHD, was assayed directly for succinate-coupled ubiquinone reduction (PMID:37098072). Reason: SDHD supplies a heme b axial ligand (His102) and part of the ubiquinone pocket (Tyr114), so it does part of the work of the reaction but cannot catalyse it alone; contributes_to is the correct relation. Recorded here pending the upstream GOA qualifier change. Supporting Evidence: PMID:37098072 The succinate-quinone oxidoreductase enzymatic activity of human CII was determined by performing a succinate-2,6-dichlorophenolindophenol (DCIP, Sigma) assay in the presence of ubiquinone-1 (UQ1, Sigma) 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 |
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Download this section (compressed HTML)Q: How do PPGL1-causing SDHD missense variants β particularly E69K and D92G mapped onto the cryo-EM structure (PMID:37098072) β disrupt heme b coordination (His102), ubiquinone binding (Tyr114), or the SDHC/SDHD membrane-anchor interface? Distinguishing these mechanisms would refine the annotation of which molecular function (succinate-ubiquinone oxidoreductase activity vs. heme binding) is most relevant for "contributes_to" capture at the SDHD level.
Q: Why does heterozygous SDHD loss-of-function follow a maternal-imprinting pattern in PPGL1 (paragangliomas typically arise after paternal transmission of a mutant allele), and how does residual SDHD expression from the maternal allele in chromaffin tissues escape silencing? Resolving the tissue-specific epigenetic mechanism would underpin a more accurate process annotation around tumor suppression in chromaffin / paraganglion lineages.
Q: How does succinate accumulation from biallelic SDHD-null tumors specifically inhibit Ξ±-ketoglutarate-dependent dioxygenases (TET, JmjC, PHDs) at pathophysiological intratumoral concentrations, and which of these substrates drive the pseudohypoxia/hypermethylation phenotype most directly? This would support adding more specific BP / regulation terms for the oncometabolite signalling axis.
Experiment: Cryo-EM and site-directed mutagenesis of human Complex II reconstituted with SDHD E69K, D92G, H102A, Y114A variants. Quantify succinate-dependent ubiquinone reduction, heme b spectroscopy (UV-vis, EPR), CII holoenzyme assembly by BN-PAGE, and intracellular succinate accumulation in matched HEK293 knock-in cell lines.
Hypothesis: E69K and D92G destabilize the SDHC/SDHD membrane-anchor interface and indirectly perturb heme b coordination, whereas H102A and Y114A directly uncouple succinate oxidation from ubiquinone reduction; only the latter two class of mutations should abolish electron transfer without affecting holoenzyme assembly.
Type: structural biology / enzyme kinetics
Experiment: Allele-specific expression analysis of SDHD mRNA in chromaffin tissue and paraganglion-derived organoids from paternal vs. maternal SDHD-mutation carriers, combined with WGBS and ATAC-seq of the SDHD locus and surrounding imprinted control region. Validate parent-of-origin silencing with single-nucleus RNA-seq.
Hypothesis: Chromaffin and paraganglion cell lineages selectively silence the maternal SDHD allele through a tissue-restricted imprinting mechanism, leaving cells with only paternal SDHD expression and explaining the dependency on paternal transmission of mutations for PPGL1 manifestation.
Type: epigenetics / single-cell genomics
Experiment: Targeted metabolomics measuring intratumoral succinate and Ξ±-KG concentrations in PPGL1 SDHD-deficient tumors vs. SDHB / SDHA / non-SDH counterparts, paired with biochemical inhibition assays of TET2, KDM6A, FIH-1, and PHD2 across the observed succinate ranges. Use isogenic HEK293 SDHD-KO lines complemented with WT vs. patient variants to confirm causality of specific dioxygenase inhibition.
Hypothesis: Intratumoral succinate in SDHD-deficient PPGL reaches concentrations sufficient to selectively inhibit PHD2 and TET2 over a broader panel of Ξ±-KG-dependent dioxygenases, driving the HIF-1Ξ± stabilization and DNA hypermethylation that define the cluster-1 PPGL phenotype.
Type: cancer metabolomics / biochemistry
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