SDHA

---
id: P31040
gene_symbol: SDHA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SDHA encodes the flavoprotein (Fp) subunit of succinate dehydrogenase (SDH, Complex
  II),
  a heterotetrameric enzyme (SDHA/SDHB/SDHC/SDHD) embedded in the mitochondrial inner
  membrane.
  SDHA contains a covalently bound FAD cofactor (attached at His99) and catalyzes
  the oxidation
  of succinate to fumarate as part of the TCA cycle. The electrons from succinate
  oxidation are
  transferred via FAD to the iron-sulfur clusters in SDHB and ultimately to ubiquinone
  bound
  at the SDHC/SDHD membrane interface, coupling the TCA cycle to the electron transport
  chain.
  Complex II is unique among OXPHOS complexes in that it does NOT pump protons across
  the inner
  membrane. SDHA also functions as a tumor suppressor; loss-of-function mutations
  cause
  paraganglioma/pheochromocytoma (PPGL5) via succinate accumulation and pseudohypoxic
  HIF1a
  stabilization. Biallelic mutations cause Leigh syndrome, mitochondrial complex II
  deficiency,
  and dilated cardiomyopathy.
alternative_products:
  - name: '1'
    id: P31040-1
  - name: '2'
    id: P31040-2
    sequence_note: VSP_055077
  - name: '3'
    id: P31040-3
    sequence_note: VSP_055078
existing_annotations:
# ============================================================
# IBA ANNOTATIONS (phylogenetic inference from GO_Central)
# ============================================================
  - term:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for the overall SDH quinone reductase activity. GO:0008177
        is defined as
        "the overall reaction of the entire SDH complex" (succinate + quinone -> fumarate
        + quinol).
        The IBA uses the qualifier 'enables' which is debatable for a single subunit
        of a complex enzyme.
        However, SDHA alone can catalyze the succinate -> fumarate half-reaction (the
        succinate
        dehydrogenase activity per se), and it is the catalytic subunit where the
        substrate binding
        and FAD-mediated oxidation occurs. The full quinone reduction requires all
        four subunits.
        The IMP annotation from PMID:7550341 uses 'contributes_to' which is arguably
        more precise
        for the full quinone-dependent reaction. Nevertheless, IBA annotations are
        well-curated
        phylogenetic inferences and the 'enables' qualifier is defensible since SDHA
        provides the
        primary catalytic function of the complex. The deep research review (SDHA-deep-research-falcon.md)
        confirms that the FAD cofactor is covalently linked in the SDHA subunit via
        a conserved histidine,
        essential for catalysis in characterized complex II enzymes.
      action: MODIFY
      reason: >-
        SDHA is the catalytic subunit of SDH complex containing the FAD cofactor and
        active site
        for succinate oxidation. While the full quinone reduction requires the entire
        complex,
        SDHA's role is central and catalytic. The IBA is phylogenetically sound, but
        the enables qualifier should not be accepted as-is for the whole-complex
        quinone reaction. Use an intrinsic succinate dehydrogenase activity term for
        SDHA's enabled activity and retain GO:0008177 only with contributes_to.
      proposed_replacement_terms:
        - id: GO:0000104
          label: succinate dehydrogenase activity
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            The active site for succinate-fumarate interconversion is located at the
            interface
            between the FAD-binding domain and the capping domain
        - reference_id: PMID:7550341
          supporting_text: >-
            We now report a mutation in the nuclear-encoded flavoprotein (Fp) subunit
            gene
            of the succinate dehydrogenase (SDH) in two siblings with complex II deficiency
        - reference_id: file:human/SDHA/SDHA-deep-research-falcon.md
          supporting_text: >-
            Complex II (succinate dehydrogenase, SDH) catalyzes the oxidation of succinate
            to fumarate, coupling two-electron transfer via FAD and iron-sulfur centers
            to reduce ubiquinone to ubiquinol in the inner mitochondrial membrane
  - 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 SDHA is part of respiratory chain complex II. This is
        a core structural
        annotation for SDHA as the flavoprotein subunit of the SDH/Complex II heterotetramer
        (SDHA+SDHB+SDHC+SDHD). Confirmed by cryo-EM structure (PMID:37098072).
      action: ACCEPT
      reason: >-
        SDHA is unambiguously a subunit of Complex II. The cryo-EM structure at 2.86A
        shows all
        four subunits including SDHA in the complex (PMID:37098072). This is a core
        annotation.
      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:0050660
      label: flavin adenine dinucleotide binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for FAD binding. SDHA contains a covalently bound FAD cofactor
        attached at
        His99 (Tele-8alpha-FAD histidine). This is confirmed by crystal and cryo-EM
        structures
        (PMID:32887801, PMID:37098072). Note that GO:0071949 (FAD binding) is also
        annotated
        via Reactome. GO:0050660 is the more general term. Both are appropriate; this
        IBA is correct.
      action: ACCEPT
      reason: >-
        FAD binding is a core molecular function of SDHA. The FAD cofactor is covalently
        attached
        to His99 and is essential for catalysis. Supported by multiple structural
        studies.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            The hydrophilic head of human CII consists of the flavin adenine dinucleotide
            (FAD)-binding protein (SDHA)
        - reference_id: PMID:19628817
          supporting_text: >-
            Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination
            (incorporation
            of the flavin adenine dinucleotide cofactor)
  - 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 specific 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. SDHA initiates this process by oxidizing succinate
        via FAD and
        passing electrons through the iron-sulfur centers of SDHB to ubiquinone at
        SDHC/SDHD.
      action: ACCEPT
      reason: >-
        This is a core biological process annotation for SDHA. The electron flow from
        succinate
        to ubiquinone begins at SDHA's FAD cofactor. This is the defining ETC function
        of Complex II.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            we propose that the human CII succinate- and ubiquinone-binding sites
            are likely to be
            connected by a similar chain of redox centers
  - term:
      id: GO:0009055
      label: electron transfer activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for electron transfer activity. SDHA is the initial electron
        acceptor in
        Complex II, receiving electrons from succinate via its FAD cofactor. The electrons
        then
        transfer through the [2Fe-2S] cluster of SDHB. This is a core molecular function
        annotation.
      action: ACCEPT
      reason: >-
        SDHA performs electron transfer as part of the succinate-to-ubiquinone chain.
        The FAD cofactor
        accepts electrons from succinate and transfers them to the iron-sulfur protein
        SDHB.
        This is phylogenetically and biochemically well-supported.
      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)

# ============================================================
# IEA ANNOTATIONS (electronic/computational)
# ============================================================
  - 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. SDHA is a peripheral
        membrane
        protein on the matrix side of the inner mitochondrial membrane, as part of
        Complex II.
        Confirmed by cryo-EM (PMID:37098072) and UniProt subcellular location annotation.
      action: ACCEPT
      reason: >-
        Correct localization. SDHA is the matrix-facing subunit of Complex II which
        is anchored
        in the inner mitochondrial membrane via SDHC and SDHD. The IEA mapping is
        accurate and
        consistent with experimental data including the cryo-EM structure.
      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. SDHA catalyzes step 6 of the TCA
        cycle: the
        oxidation of succinate to fumarate. This is one of the two core biological
        processes
        of Complex II (the other being ETC).
      action: ACCEPT
      reason: >-
        TCA cycle involvement is a core function of SDHA. The succinate to fumarate
        reaction
        is a canonical step of the TCA cycle. Widely supported by literature.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            Human complex II is a key protein complex that links two essential energy-producing
            processes: the tricarboxylic acid cycle and oxidative phosphorylation
  - term:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for the same SDH quinone activity as the IBA above, inferred
        from
        combined automated methods (UniProt keyword, InterPro, EC number). Redundant
        with the
        IBA and IMP annotations but consistent.
      action: MODIFY
      reason: >-
        Consistent with Complex II function, but not acceptable as an enables
        annotation for SDHA alone. The quinone-dependent reaction is performed by
        the intact heterotetramer; SDHA's enabled activity is the succinate
        dehydrogenase half-reaction.
      proposed_replacement_terms:
        - id: GO:0000104
          label: succinate dehydrogenase activity
  - term:
      id: GO:0016491
      label: oxidoreductase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for general oxidoreductase activity. SDHA catalyzes the oxidation
        of
        succinate (EC 1.3.5.1), making it an oxidoreductase. This is a correct but
        very broad
        parent term. The more specific child terms (GO:0008177, GO:0016627) are also
        annotated.
      action: ACCEPT
      reason: >-
        Correct but general. It is acceptable for IEA annotations to be broader than
        experimental
        annotations. The more specific GO:0008177 is also present.
  - term:
      id: GO:0016627
      label: oxidoreductase activity, acting on the CH-CH group of donors
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IEA annotation from InterPro mapping. SDHA oxidizes succinate to fumarate,
        converting
        a CH-CH single bond to a C=C double bond. This is an accurate intermediate-level
        classification of the catalytic activity.
      action: ACCEPT
      reason: >-
        Correct classification. Succinate oxidation to fumarate involves removal of
        two hydrogens
        from the CH2-CH2 group to form the trans double bond of fumarate. This InterPro-based
        IEA is accurate.
  - term:
      id: GO:0022900
      label: electron transport chain
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IEA annotation for general electron transport chain involvement from InterPro.
        This is
        broader than GO:0006121 (mitochondrial electron transport, succinate to ubiquinone)
        which is the more specific IBA annotation. Both are correct.
      action: ACCEPT
      reason: >-
        Correct but more general than the IBA annotation GO:0006121. Complex II is
        part of the
        electron transport chain. Acceptable for IEA to use the broader term.
  - term:
      id: GO:0050660
      label: flavin adenine dinucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IEA annotation for FAD binding from InterPro. Redundant with the IBA annotation
        for
        the same term. Both are correct.
      action: ACCEPT
      reason: >-
        Correct and consistent with the IBA annotation. FAD is covalently bound to
        SDHA at His99.

# ============================================================
# IPI ANNOTATIONS (protein-protein interaction)
# ============================================================
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17353931
    review:
      summary: >-
        IPI annotation from large-scale mass spectrometry protein-protein interaction
        study
        (Ewing et al. 2007). The WITH/FROM field indicates interaction with HLA-B
        (P01889).
        This is from a high-throughput screen and the biological significance of an
        SDHA-HLA-B
        interaction is unclear. Likely a non-specific or indirect detection.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput protein-protein interaction data. The SDHA-HLA-B interaction
        has no
        known biological relevance and is likely an artifact of overexpression-based
        mass
        spectrometry. Furthermore, 'protein binding' is uninformative as a GO term.
        Keep as
        non-core.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19628817
    review:
      summary: >-
        IPI annotation for interaction between SDHA and SDHAF2/SDH5 (Q9NX18). Hao
        et al. (2009)
        showed that SDH5/SDHAF2 is required for flavination of succinate dehydrogenase.
        The
        interaction between SDHA and SDHAF2 is essential for covalent FAD attachment.
        This is a biologically meaningful interaction confirmed by UniProt (INTERACTION
        section)
        and multiple studies.
      action: KEEP_AS_NON_CORE
      reason: >-
        The SDHA-SDHAF2 interaction is biologically meaningful (required for FAD cofactor
        insertion), but 'protein binding' is too vague. The interaction is better
        captured by
        the functional context (SDHAF2 is a complex II assembly factor). Keep as non-core
        since
        the underlying biology is valid even though the GO term is uninformative.
      supported_by:
        - reference_id: PMID:19628817
          supporting_text: >-
            Both yeast and human Sdh5 interact with the catalytic subunit of the succinate
            dehydrogenase (SDH) complex ... Sdh5 is required for SDH-dependent respiration
            and for Sdh1 flavination
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19688755
    review:
      summary: >-
        IPI annotation for interaction with SDHB (P21912) from LC-MS/MS analysis of
        blue native
        PAGE-separated complexes. This confirms the well-established SDHA-SDHB interaction
        as
        part of Complex II assembly.
      action: KEEP_AS_NON_CORE
      reason: >-
        The SDHA-SDHB interaction is a core biochemical feature of Complex II, but
        this is already
        captured by the CC annotation GO:0045273 (part_of respiratory chain complex
        II). The
        'protein binding' annotation is uninformative. Keep as non-core.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24606901
    review:
      summary: >-
        IPI annotation for interaction with SDHB (P21912) from a study on cochaperone
        binding
        to LYR motifs for iron-sulfur cluster delivery. This relates to Complex II
        assembly.
      action: KEEP_AS_NON_CORE
      reason: >-
        Another SDHA-SDHB interaction detected in the context of iron-sulfur cluster
        delivery.
        Biologically relevant to Complex II assembly but 'protein binding' is uninformative.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26496610
    review:
      summary: >-
        IPI annotation for interaction with SDHAF2 (Q9NX18) from a quantitative interactome
        study
        (Hein et al. 2015). Confirms the SDHA-SDHAF2 assembly factor interaction.
      action: KEEP_AS_NON_CORE
      reason: >-
        Confirms the SDHA-SDHAF2 interaction in an independent quantitative study.
        Biologically
        relevant but 'protein binding' remains uninformative as a GO term.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26618866
    review:
      summary: >-
        IPI annotation for interaction with CFTR (P13569) from a study on deltaF508-CFTR
        interactome remodelling. The biological significance of SDHA-CFTR interaction
        is
        questionable -- this is likely a non-specific detection in a large-scale study.
      action: KEEP_AS_NON_CORE
      reason: >-
        The SDHA-CFTR interaction is of unclear biological significance. CFTR is an
        ABC
        transporter involved in chloride conductance, and its interaction with a mitochondrial
        enzyme is likely indirect or an artifact. Keep as non-core.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26749241
    review:
      summary: >-
        IPI annotation for interaction with SDHB (P21912) from a study on SDHAF1 mutations
        impairing Fe-S cluster transfer to SDHB. Relevant to Complex II assembly.
      action: KEEP_AS_NON_CORE
      reason: >-
        SDHA-SDHB interaction confirmed in the context of Fe-S cluster assembly. Biologically
        meaningful but 'protein binding' is uninformative. Already captured by CC
        annotation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28330616
    review:
      summary: >-
        IPI annotation for interaction with PTPN3 (P26045) from systematic analysis
        of human
        protein phosphatase interactions. The biological relevance of an SDHA-PTPN3
        interaction
        is unclear. PTPN3 is a tyrosine phosphatase. SDHA is known to be phosphorylated
        at
        Tyr-215 by SRC, so a phosphatase interaction could be biologically relevant
        but is
        not well characterized.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput phosphatase interaction study. While SDHA is phosphorylated
        at Y215,
        the specific relevance of PTPN3 interaction is not established.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: >-
        IPI annotation for interaction with SDHB (P21912) from architecture of the
        human
        interactome study (Huttlin et al. 2017). Confirms SDHA-SDHB subunit interaction.
      action: KEEP_AS_NON_CORE
      reason: >-
        Another confirmation of the SDHA-SDHB interaction. Already well established
        and
        captured by the CC annotation for Complex II membership.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: >-
        IPI annotation for interaction with SDHAF2 (Q9NX18) from the same architecture
        of
        the human interactome study (Huttlin et al. 2017). This is the second GOA
        entry for
        this PMID, detecting the SDHA-SDHAF2 assembly factor interaction.
      action: KEEP_AS_NON_CORE
      reason: >-
        Confirms the SDHA-SDHAF2 interaction. SDHAF2 is the assembly factor required
        for
        FAD insertion into SDHA. Biologically meaningful but 'protein binding' is
        uninformative.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29128334
    review:
      summary: >-
        IPI annotation for interaction with HLA-B (P01889) from mitochondrial protein
        interaction
        map linked to neurodegeneration. Same interactor as PMID:17353931. The biological
        significance of SDHA-HLA-B interaction remains unclear.
      action: KEEP_AS_NON_CORE
      reason: >-
        Second independent detection of SDHA-HLA-B interaction, but the biological
        relevance
        remains unclear. HLA-B is an MHC class I molecule, not expected to functionally
        interact
        with a mitochondrial matrix enzyme.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29924966
    review:
      summary: >-
        IPI annotation for interaction with CFTR (P13569) from a proteomic variant
        approach study.
        Second SDHA-CFTR interaction, of unclear biological significance.
      action: KEEP_AS_NON_CORE
      reason: >-
        SDHA-CFTR interaction detected by proteomics. Unclear biological significance.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31324722
    review:
      summary: >-
        IPI annotation for interaction with CFTR (P13569) from study on calpain 1
        and
        Phe508del-CFTR. Third SDHA-CFTR interaction detection. Multiple detections
        suggest
        a real physical interaction but its functional significance for SDHA is unclear.
      action: KEEP_AS_NON_CORE
      reason: >-
        Third detection of SDHA-CFTR interaction. While multiple detections suggest
        a real
        interaction, the functional significance for SDHA function is unclear.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        IPI annotation for interaction with SDHB (P21912) from dual proteome-scale
        network
        study (Huttlin et al. 2021). Confirms the known Complex II SDHA-SDHB subunit
        interaction.
      action: KEEP_AS_NON_CORE
      reason: >-
        Confirms the SDHA-SDHB interaction. Well established and captured by CC annotation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        IPI annotation for interaction with SDHAF2 (Q9NX18) from dual proteome-scale
        network
        study (Huttlin et al. 2021). This is the second GOA entry for this PMID, confirming
        the SDHA-SDHAF2 assembly factor interaction.
      action: KEEP_AS_NON_CORE
      reason: >-
        Confirms the SDHA-SDHAF2 interaction. Well established.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35156780
    review:
      summary: >-
        IPI annotation for interaction with CFTR (P13569) from membrane two-hybrid
        screening.
        Fourth SDHA-CFTR interaction detection.
      action: KEEP_AS_NON_CORE
      reason: >-
        Yet another SDHA-CFTR detection. While robust, CFTR interaction is not relevant
        to
        the core function of SDHA.

# ============================================================
# LOCALIZATION ANNOTATIONS
# ============================================================
  - 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.
        SDHA has a mitochondrial transit peptide (residues 1-42) and is localized
        to the
        mitochondrial matrix as part of Complex II.
      action: ACCEPT
      reason: >-
        Correct localization, well supported by multiple lines of evidence including
        the transit peptide and IDA evidence.
  - 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.
        SDHA faces the matrix side of the inner membrane as a peripheral membrane
        protein.
      action: ACCEPT
      reason: >-
        Correct. SDHA is on the matrix side of the inner mitochondrial membrane, confirmed
        by cryo-EM structure (PMID:37098072) showing SDHA in the hydrophilic head
        of Complex II
        facing the matrix.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            The hydrophilic head of human CII consists of the flavin adenine dinucleotide
            (FAD)-binding protein (SDHA) and the iron-sulfur protein (SDHB)
  - 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.
        Redundant with IBA and other annotations for the same term.
      action: ACCEPT
      reason: >-
        Correct and consistent with IBA, ISS, IDA, and TAS annotations for this term.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        IDA annotation for mitochondrial localization from HPA immunofluorescence
        data.
        Direct experimental evidence of SDHA mitochondrial localization.
      action: ACCEPT
      reason: >-
        Direct experimental evidence of mitochondrial localization by immunofluorescence.
  - term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-71403
    review:
      summary: >-
        TAS annotation from Reactome TCA cycle pathway. SDHA participates in the TCA
        cycle
        by catalyzing the succinate to fumarate step.
      action: ACCEPT
      reason: >-
        Core function annotation. Consistent with IEA and NAS annotations for the
        same term.
        SDHA is a canonical TCA cycle enzyme.
  - 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. SDHA is part of Complex II which is embedded
        in the
        inner mitochondrial membrane.
      action: ACCEPT
      reason: >-
        Correct localization. Complex II spans the inner membrane via SDHC/SDHD subunits,
        with
        SDHA on the matrix side as a peripheral membrane protein.
  - 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. Redundant with
        other
        TCA cycle annotations but consistent.
      action: ACCEPT
      reason: >-
        Correct and consistent with other TCA cycle annotations from Reactome and
        IEA sources.
  - 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 ETC process. Consistent
        with the
        IBA annotation for the same term.
      action: ACCEPT
      reason: >-
        Correct. This is a core biological process for SDHA/Complex II.
  - 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 SDHA 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).
        Annotating SDHA with this term conflates electron donation to the Q pool with
        proton
        translocation.
      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 should be removed. The correct process annotation for SDHA
        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
        # [Note: This passage describes the overall respiratory chain but the proton translocation
        # is performed by CI, CIII, CIV -- not CII. CII transfers electrons but does not pump protons.]
  - term:
      id: GO:0071949
      label: FAD binding
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9854672
    review:
      summary: >-
        TAS annotation from Reactome for FAD binding. The Reactome entry R-HSA-9854672
        describes the covalent attachment of FAD to SDHA. GO:0071949 (FAD binding)
        specifically
        refers to binding the oxidized form of FAD, which is appropriate for SDHA.
      action: ACCEPT
      reason: >-
        Correct. SDHA covalently binds FAD at His99. This is the more specific FAD
        binding term
        compared to GO:0050660, and both are appropriate. Reactome accurately captures
        this step
        of Complex II maturation.
  - 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). SDHA was identified
        in the
        mitochondrial proteome.
      action: ACCEPT
      reason: >-
        Correct. SDHA is a well-established mitochondrial protein confirmed by proteomics.
  - 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 bovine ortholog
        (Q0QF01). Consistent with all other annotations for this term.
      action: ACCEPT
      reason: >-
        Correct. Transfer from the well-characterized bovine SDH complex.

# ============================================================
# KEY EXPERIMENTAL ANNOTATIONS
# ============================================================
  - term:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    evidence_type: IMP
    original_reference_id: PMID:7550341
    qualifier: contributes_to
    review:
      summary: >-
        IMP annotation with 'contributes_to' qualifier from the landmark Bourgeron
        et al. (1995)
        study. This study identified the first nuclear gene mutation causing mitochondrial
        respiratory chain deficiency -- an Arg554Trp mutation in SDHA causing Leigh
        syndrome
        with complex II deficiency. The 'contributes_to' qualifier is appropriate
        for GO:0008177
        since the GO term definition states "This term represents the overall reaction
        of the
        entire SDH complex." The full quinone reduction reaction requires all four
        subunits
        (SDHA provides succinate oxidation/FAD reduction, SDHB provides Fe-S electron
        relay,
        and SDHC/SDHD provide the quinone binding site). SDHA alone cannot complete
        the quinone
        reduction half of the reaction.
      action: ACCEPT
      reason: >-
        The 'contributes_to' qualifier is arguably more precise than 'enables' for
        GO:0008177
        since the GO definition explicitly states it represents the overall reaction
        of the
        entire complex. SDHA provides the succinate dehydrogenase half-reaction (via
        FAD) but
        quinone reduction requires the membrane-anchored subunits. The contributes_to
        qualifier is correct for this complex-level activity; the intrinsic SDHA
        activity is covered separately by the proposed GO:0000104 annotation.
      supported_by:
        - reference_id: PMID:7550341
          supporting_text: >-
            We now report a mutation in the nuclear-encoded flavoprotein (Fp) subunit
            gene of the
            succinate dehydrogenase (SDH) in two siblings with complex II deficiency
            presenting
            as Leigh syndrome
  - 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 2.86A showing all four
        subunits.
        SDHA was directly identified in the complex by cryo-EM, SDS-PAGE, and mass
        spectrometry.
      action: ACCEPT
      reason: >-
        Direct experimental evidence from cryo-EM structure of human Complex II showing
        SDHA
        as a subunit.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            We observed all four subunits in a monomeric assembly (Fig. 1A). This
            arrangement
            is similar to that in W. succinogenes QFR
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-70994
    review:
      summary: >-
        TAS annotation from Reactome for mitochondrial matrix localization. The Reactome
        entry
        describes the SDH complex dehydrogenation of succinate, placing SDHA in the
        matrix.
      action: ACCEPT
      reason: >-
        Correct. SDHA is on the matrix face of Complex II.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9854672
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with the FAD attachment
        to SDHA
        reaction which occurs in the matrix.
      action: ACCEPT
      reason: >-
        Correct. FAD attachment to SDHA occurs in the mitochondrial matrix.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9854961
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with SDHAF4 binding
        to FAD-SDHA.
      action: ACCEPT
      reason: >-
        Correct. SDHAF4 binding to FAD-SDHA occurs in the mitochondrial matrix during
        Complex II
        assembly.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9855212
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with SDHA binding to
        SDHB.
      action: ACCEPT
      reason: >-
        Correct. SDHA-SDHB subcomplex formation occurs in the matrix.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9855252
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with SDHA:SDHB binding
        to SDHC:SDHD.
      action: ACCEPT
      reason: >-
        Correct. The final assembly step of Complex II involves SDHA:SDHB joining
        SDHC:SDHD
        at the membrane.
  - term:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    evidence_type: IMP
    original_reference_id: PMID:24781757
    review:
      summary: >-
        IMP annotation from Renkema et al. (2015) who characterized SDHA mutations
        causing
        multisystem mitochondrial disease. They showed that the c.565T>G mutation
        severely
        affects enzyme activity and confirmed pathogenicity by lentiviral complementation.
        This annotation uses 'enables' qualifier (no explicit 'contributes_to' in
        GOA TSV line).
      action: MODIFY
      reason: >-
        Valid IMP evidence showing that SDHA mutations directly impair SDH enzyme
        activity.
        The study demonstrates that specific SDHA mutations cause isolated complex
        II deficiency through impaired catalysis, but the enabled MF should be the
        intrinsic succinate dehydrogenase activity rather than the whole-complex
        quinone activity unless the qualifier is contributes_to.
      proposed_replacement_terms:
        - id: GO:0000104
          label: succinate dehydrogenase activity
      supported_by:
        - reference_id: PMID:24781757
          supporting_text: >-
            For the third new mutation, c.565T>G, we show that it severely affects
            enzyme activity.
            Its pathogenicity was confirmed by lentiviral complementation experiments
            on the
            fibroblasts of patients carrying this mutation
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23747254
    review:
      summary: >-
        IPI annotation for interaction with TRAP1 (Q12931) from Sciacovelli et al.
        (2013).
        This study showed that the mitochondrial chaperone TRAP1 binds to and inhibits
        SDH
        complex (specifically SDHA), leading to succinate accumulation and pseudohypoxic
        HIF1a stabilization in tumors. This is a functionally significant interaction
        demonstrated
        by co-immunoprecipitation, BN-PAGE, and crosslinking experiments.
      action: KEEP_AS_NON_CORE
      reason: >-
        The SDHA-TRAP1 interaction is biologically significant (TRAP1 inhibits SDH
        activity
        to promote the Warburg effect in tumors), but 'protein binding' remains uninformative.
        The interaction is regulatory rather than a core molecular function of SDHA.
      supported_by:
        - reference_id: PMID:23747254
          supporting_text: >-
            TRAP1 binds to and inhibits succinate dehydrogenase (SDH), the complex
            II of the
            respiratory chain. The respiratory downregulation elicited by TRAP1 interaction
            with SDH promotes tumorigenesis by priming the succinate-dependent stabilization
            of the proneoplastic transcription factor HIF1a
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation for inner membrane localization by transfer from bovine ortholog
        (Q0QF01).
        Consistent with other annotations and cryo-EM evidence.
      action: ACCEPT
      reason: >-
        Correct. Transfer from well-characterized bovine SDH complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15961414
    review:
      summary: >-
        IPI annotation for interaction with frataxin (Q16595) from Gonzalez-Cabo et
        al. (2005).
        This study showed physical interaction between human frataxin and human succinate
        dehydrogenase complex subunits, suggesting a role for frataxin in the mitochondrial
        electron transport chain. Frataxin is involved in iron-sulfur cluster biogenesis.
      action: KEEP_AS_NON_CORE
      reason: >-
        The SDHA-frataxin interaction is biologically interesting given frataxin's
        role in
        Fe-S cluster biogenesis and Friedreich ataxia pathogenesis. However, 'protein
        binding'
        is uninformative and this represents a regulatory/assembly interaction rather
        than a
        core SDHA function.
      supported_by:
        - reference_id: PMID:15961414
          supporting_text: >-
            We also demonstrate a physical interaction between human frataxin and
            human succinate
            dehydrogenase complex subunits, suggesting also a key role of frataxin
            in the
            mitochondrial electron transport chain in humans
  - term:
      id: GO:0006105
      label: succinate metabolic process
    evidence_type: IDA
    original_reference_id: PMID:7550341
    review:
      summary: >-
        IDA annotation for succinate metabolic process from Bourgeron et al. (1995).
        SDHA
        catalyzes the oxidation of succinate to fumarate, which is central to succinate
        metabolism. This is correct but less specific than the TCA cycle annotation.
      action: ACCEPT
      reason: >-
        Correct. SDHA directly metabolizes succinate as part of its catalytic function.
        This is a reasonable biological process annotation complementing the TCA cycle
        and ETC annotations.
  - term:
      id: GO:0007399
      label: nervous system development
    evidence_type: IMP
    original_reference_id: PMID:16361598
    review:
      summary: >-
        IMP annotation for nervous system development from Horvath et al. (2006).
        This study
        described a child with Leigh syndrome caused by compound heterozygous SDHA
        mutations
        (W119X and A83V), presenting with severe progressive neurodegenerative disorder
        causing
        epilepsy, psychomotor retardation, and tetraspasticity starting at age five
        months.
        The IMP logic is that SDHA mutations cause a neurodevelopmental phenotype,
        therefore
        SDHA is involved in nervous system development. However, this is a classic
        case of
        over-annotation. SDHA is a housekeeping metabolic enzyme. The nervous system
        is particularly
        sensitive to mitochondrial dysfunction due to its high energy demands, but
        SDHA is not
        specifically involved in nervous system development. The neurological phenotype
        is a
        secondary consequence of impaired cellular energy production, not a direct
        developmental
        role for SDHA in neural patterning or differentiation.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        This is a clear over-annotation. SDHA mutations cause Leigh syndrome with
        neurological
        features because the nervous system is especially vulnerable to mitochondrial
        energy
        deficits, not because SDHA has a specific role in neural development. The
        nervous system
        phenotype is a secondary consequence of impaired oxidative phosphorylation.
        By this logic,
        any essential metabolic gene causing disease with neurological symptoms would
        be annotated
        with 'nervous system development', which is not informative.
      supported_by:
        - reference_id: PMID:16361598
          supporting_text: >-
            The clinical symptoms started at age five months and led to a severe progressive
            neurodegenerative disorder causing epilepsy, psychomotor retardation,
            and
            tetraspasticity. Biochemical measurement of skeletal muscle showed a severe
            decrease in mitochondrial complex II
  - term:
      id: GO:0022904
      label: respiratory electron transport chain
    evidence_type: IDA
    original_reference_id: PMID:7550341
    review:
      summary: >-
        IDA annotation for respiratory electron transport chain from Bourgeron et
        al. (1995).
        The study showed that SDHA mutation causes complex II deficiency, directly
        demonstrating
        SDHA's role in the respiratory electron transport chain. This is broader than
        GO:0006121
        but still accurate.
      action: ACCEPT
      reason: >-
        Correct. SDHA is part of Complex II which is a component of the respiratory
        electron
        transport chain. The Bourgeron et al. study directly demonstrated that SDHA
        mutation
        leads to respiratory chain deficiency.
      supported_by:
        - reference_id: PMID:7550341
          supporting_text: >-
            We now report a mutation in the nuclear-encoded flavoprotein (Fp) subunit
            gene
            of the succinate dehydrogenase (SDH) in two siblings with complex II deficiency
            presenting as Leigh syndrome
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:16826196
    review:
      summary: >-
        IDA annotation for mitochondrial localization from Huang et al. (2007). This
        study
        was about Complex I and IFN-beta/RA-induced cell death. The connection to
        SDHA
        mitochondrial localization is indirect -- the study mentions upregulation
        of MRC
        complex subunits but is primarily about Complex I (GRIM-19, NDUFS3). SDHA
        mitochondrial localization is well-established from other sources regardless.
      action: ACCEPT
      reason: >-
        Mitochondrial localization of SDHA is beyond question, even though this particular
        reference is not the strongest evidence for SDHA specifically.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:7550341
    review:
      summary: >-
        IDA annotation for mitochondrial localization from Bourgeron et al. (1995).
        The study
        demonstrated mitochondrial respiratory chain deficiency from SDHA mutation,
        placing
        SDHA in the mitochondrion.
      action: ACCEPT
      reason: >-
        Correct mitochondrial localization, supported by the original study showing
        that SDHA
        mutation causes mitochondrial respiratory chain deficiency.
  - term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    evidence_type: TAS
    original_reference_id: PMID:7550341
    review:
      summary: >-
        TAS annotation for TCA cycle from Bourgeron et al. (1995). The study refers
        to SDH
        as part of the TCA cycle/respiratory chain.
      action: ACCEPT
      reason: >-
        Correct. The succinate to fumarate reaction is a canonical TCA cycle step.
  - term:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    evidence_type: TAS
    original_reference_id: PMID:7550341
    review:
      summary: >-
        TAS annotation for Complex II membership from Bourgeron et al. (1995). The
        study
        directly discusses Complex II deficiency from SDHA mutation.
      action: ACCEPT
      reason: >-
        Correct. SDHA is the flavoprotein subunit of Complex II.

# ============================================================
# NEW ANNOTATIONS (missing from current set)
# ============================================================
  - term:
      id: GO:0000104
      label: succinate dehydrogenase activity
    evidence_type: IDA
    original_reference_id: PMID:7550341
    review:
      summary: >-
        GO:0000104 (succinate dehydrogenase activity) is defined as "Catalysis of
        the reaction:
        succinate + acceptor = fumarate + reduced acceptor." This is a more appropriate
        molecular
        function term for SDHA than GO:0008177 (quinone-specific) when annotating
        the subunit
        alone, because SDHA catalyzes the succinate to fumarate reaction via its FAD
        cofactor
        regardless of the downstream electron acceptor. The Bourgeron et al. study
        demonstrated
        that mutation of SDHA impairs succinate dehydrogenase activity. This annotation
        should
        use the 'enables' qualifier since SDHA alone (with its FAD cofactor) is sufficient
        to
        catalyze succinate oxidation.
      action: NEW
      reason: >-
        GO:0000104 more precisely captures SDHA's intrinsic catalytic function (succinate
        oxidation with a generic acceptor) as opposed to GO:0008177 which specifies
        the
        quinone-dependent overall complex reaction. SDHA alone can oxidize succinate
        to
        fumarate; the FAD cofactor serves as the immediate electron acceptor. This
        term
        fills a gap where the current annotations only capture the complex-level activity.
        Note: GO:0160308 (succinate dehydrogenase (FAD) activity; RHEA:30343) is a more
        specific child term that explicitly names FAD as the acceptor (FAD + succinate + H+
        = fumarate + FADH2). This may be more precise for SDHA since FAD is the actual
        cofactor. However, GO:0160308 is under consideration for obsolescence. If retained,
        it would be the preferred term over GO:0000104. The three SDH activity terms form
        a specificity series: GO:0000104 (generic acceptor, RHEA:16357) > GO:0160308
        (FAD, RHEA:30343) and GO:0008177 (quinone, EC:1.3.5.1, RHEA:40523).
      supported_by:
        - reference_id: PMID:7550341
          supporting_text: >-
            The deleterious effect of the Arg to Trp substitution on the catalytic
            activity
            of SDH was observed in a SDH- yeast strain transformed with mutant Fp
            cDNA
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: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:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    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: PMID:15961414
    title: Frataxin interacts functionally with mitochondrial electron transport chain
      proteins.
    findings:
      - statement: >-
          Frataxin physically interacts with succinate dehydrogenase complex subunits
          SDHA
          and SDHB in both yeast and humans, suggesting a role for frataxin in the
          mitochondrial
          electron transport chain.
        supporting_text: >-
          We also demonstrate a physical interaction between human frataxin and human
          succinate
          dehydrogenase complex subunits, suggesting also a key role of frataxin in
          the
          mitochondrial electron transport chain in humans
  - id: PMID:16361598
    title: Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of
      succinate dehydrogenase (SDHA).
    findings:
      - statement: >-
          Compound heterozygous SDHA mutations (W119X nonsense in exon 4 and A83V
          missense in
          exon 3) cause Leigh syndrome with severe complex II deficiency demonstrated
          by
          biochemical measurement in skeletal muscle.
        supporting_text: >-
          Biochemical measurement of skeletal muscle showed a severe decrease in mitochondrial
          complex II. Sequencing of SDHA revealed compound heterozygosity for a nonsense
          mutation in exon 4 (W119X) and a missense mutation in exon 3 (A83V), both
          absent
          in normal controls.
        reference_section_type: ABSTRACT
        full_text_unavailable: true
      - statement: >-
          Genetic heterogeneity exists for isolated complex II deficiency; six additional
          patients with Leigh or Leigh-like syndrome and complex II deficiency did
          not harbor
          SDHA mutations.
        supporting_text: >-
          In six additional patients--five with Leigh or Leigh-like syndrome and one
          with
          neuropathy and ataxia associated with isolated deficiency of complex II--mutations
          in SDHA were not detected, indicating genetic heterogeneity.
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:16826196
    title: 'Coupling mitochondrial respiratory chain to cell death: an essential role
      of mitochondrial complex I in the interferon-beta and retinoic acid-induced
      cancer cell death.'
    findings:
      - statement: >-
          IFN-beta/RA upregulates expression of mitochondrial respiratory chain complex
          subunits.
          Study is primarily about Complex I (GRIM-19, NDUFS3); SDHA relevance is
          indirect,
          as the study demonstrates that MRC upregulation drives ROS-mediated cancer
          cell death.
        supporting_text: >-
          We found that IFN-beta/RA upregulates the expression of MRC complex subunits.
          Mitochondrial-nuclear translocation of these subunits was not observed,
          but
          overproduction of reactive oxygen species (ROS), which causes loss of mitochondrial
          function, was detected upon IFN-beta/RA treatment.
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:17353931
    title: Large-scale mapping of human protein-protein interactions by mass spectrometry.
    findings: []
  - id: PMID:19628817
    title: SDH5, a gene required for flavination of succinate dehydrogenase, is mutated
      in paraganglioma.
    findings:
      - statement: >-
          SDH5/SDHAF2 physically interacts with the catalytic subunit of the SDH complex
          (Sdh1 in yeast, SDHA in humans) and is required for covalent flavination,
          i.e.
          incorporation of the FAD cofactor into the flavoprotein subunit.
        supporting_text: >-
          Both yeast and human Sdh5 interact with the catalytic subunit of the succinate
          dehydrogenase (SDH) complex, a component of both the electron transport
          chain and
          the tricarboxylic acid cycle. Sdh5 is required for SDH-dependent respiration
          and
          for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor).
        reference_section_type: ABSTRACT
        full_text_unavailable: true
      - statement: >-
          Germline loss-of-function mutations in human SDH5/SDHAF2 segregate with
          hereditary
          paraganglioma, linking SDHA flavination assembly to tumor suppression.
        supporting_text: >-
          Germline loss-of-function mutations in the human SDH5 gene, located on chromosome
          11q13.1, segregate with disease in a family with hereditary paraganglioma,
          a
          neuroendocrine tumor previously linked to mutations in genes encoding SDH
          subunits.
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:19688755
    title: LC-MS/MS as an alternative for SDS-PAGE in blue native analysis of protein
      complexes.
    findings: []
  - id: PMID:23747254
    title: The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting
      succinate dehydrogenase.
    findings:
      - statement: >-
          TRAP1 physically interacts with SDH complex II, confirmed by co-immunoprecipitation,
          BN-PAGE, and chemical crosslinking. Two distinct TRAP1/SDH complexes are
          formed
          in mitochondria.
        supporting_text: We confirmed the interaction between TRAP1 and complex II/SDH
          through further approaches, including (1) immunoprecipitation, finding coimmunoprecipitation
          (coIP) of TRAP1 with SDH and vice versa (Figure 3C), and (2) mitochondrial
          protein crosslinking with dimethyl 3,3′-dithiobis-propionimidate (DTBP),
          a homobifunctional compound that reacts with the primary amines of two interacting
          proteins at an average distance of about 8 Å (Giorgio et al., 2009), followed
          by TRAP1 immunoprecipitation in order to determine whether TRAP1 and SDH
          are closely associated. We found that two TRAP1/SDH complexes are formed
          in mitochondria (Figure 3D).
        reference_section_type: RESULTS
        full_text_unavailable: false
      - statement: >-
          TRAP1 knockdown increases SQR enzymatic activity without affecting complex
          II protein
          levels. TRAP1 re-expression restores inhibition, and the Hsp90 inhibitor
          17-AAG
          reverses TRAP1-mediated SDH inhibition, demonstrating the inhibition is
          reversible.
        supporting_text: >-
          We found that SQR enzymatic activity was increased in mitochondria from
          shTRAP1
          cells relative to those derived from control cells (Figures 4A, S2A, and
          S2B).
          TRAP1 did not affect either the cytochrome oxidase enzymatic activity of
          complex IV
          (Figure S2C) or complex II protein levels (Figure S2D) or mitochondrial
          mass
          (Figure S2E).
        reference_section_type: RESULTS
        full_text_unavailable: false
      - statement: >-
          TRAP1-mediated SDH inhibition causes intracellular succinate accumulation
          and
          pseudohypoxic HIF1a stabilization (independent of oxygen deprivation),
          establishing a mechanism for the Warburg effect in tumors via SDH regulation.
        supporting_text: We observe that TRAP1-mediated inhibition of SDH limits the
          maximal rate of respiration and leads to succinate accumulation followed
          by HIF1α, but not HIF2α, stabilization. Remarkably, the membrane-permeable
          succinate analog dimethyl succinate could both elicit HIF1α stabilization
          and rescue the tumorigenic phenotype of shTRAP1 cells, highlighting the
          mechanistic connection between TRAP1-dependent succinate accumulation and
          HIF1α-dependent tumor formation.
        reference_section_type: DISCUSSION
        full_text_unavailable: false
      - statement: >-
          The SDH inhibitor 3-nitropropionic acid (3-NP) inactivates SDH by covalent
          binding
          with an Arg residue in the catalytic core of SDHA, confirming SDHA as the
          site of
          catalytic activity in Complex II.
        supporting_text: >-
          A low concentration of the ETC complex II inhibitors 3-nitropropionic acid
          (3-NP),
          which inactivates SDH after covalent binding with an Arg residue in the
          catalytic
          core of SDHA (Huang et al., 2006), or thenoyltrifluoroacetone (TTFA), which
          blocks
          electron transfer from succinate to coenzyme Q at the quinone-binding site
          in
          subunits B and D (Huang et al., 2006), inhibited OCR in shTRAP1 cells but
          were
          inactive in the presence of TRAP1 (Figures S4B and S4C), paralleling the
          downmodulation of the SQR activity induced by 3-NP only in TRAP1-expressing
          mitochondria (Figure 5E).
        reference_section_type: RESULTS
        full_text_unavailable: false
  - id: PMID:24606901
    title: Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster
      delivery.
    findings: []
  - id: PMID:24781757
    title: 'SDHA mutations causing a multisystem mitochondrial disease: novel mutations
      and genetic overlap with hereditary tumors.'
    findings:
      - statement: >-
          Novel SDHA mutations causing isolated complex II deficiency with Leigh syndrome
          and leukodystrophy. Mutation c.565T>G severely affects enzyme activity,
          confirmed
          by lentiviral complementation. Genetic overlap between mitochondrial disease
          and
          hereditary tumor mutations in SDHA.
  - id: PMID:26496610
    title: A human interactome in three quantitative dimensions organized by stoichiometries
      and abundances.
    findings: []
  - id: PMID:26618866
    title: ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.
    findings: []
  - id: PMID:26749241
    title: Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB.
    findings: []
  - id: PMID:28330616
    title: Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics.
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and disease
      networks.
    findings: []
  - id: PMID:29128334
    title: A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration
      Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling.
    findings: []
  - id: PMID:29924966
    title: A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited
      and Somatic Disease.
    findings: []
  - id: PMID:30030361
    title: Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
    findings:
      - statement: >-
          Review of OXPHOS complex assembly. Complex II (SDH) comprises SDHA, SDHB,
          SDHC, SDHD.
          Assembly involves FAD insertion into SDHA by SDHAF2, followed by SDHA-SDHB
          dimerization
          and insertion into the membrane via SDHC-SDHD.
  - id: PMID:31324722
    title: Inhibition of calpain 1 restores plasma membrane stability to pharmacologically
      rescued Phe508del-CFTR variant.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the human
      interactome.
    findings: []
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome and its dynamics
      in cellular context.
    findings: []
  - id: PMID:35156780
    title: CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput
      screening system.
    findings: []
  - id: PMID:37098072
    title: Structure of the human respiratory complex II.
    findings:
      - statement: >-
          Cryo-EM structure of human Complex II at 2.86A resolution showing all four
          subunits
          (SDHA, SDHB, SDHC, SDHD) with FAD, three Fe-S clusters, heme b, and ubiquinone.
          SDHA contains four subdomains: FAD-binding, capping, helical, and C-terminal
          domains.
          The active site for succinate-fumarate interconversion is at the interface
          of the
          FAD-binding and capping domains. Electron transfer pathway from FAD through
          Fe-S
          clusters to ubiquinone is proposed.
  - id: PMID:7550341
    title: Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial
      respiratory chain deficiency.
    findings:
      - statement: >-
          First identification of a nuclear gene mutation causing mitochondrial respiratory
          chain
          deficiency. Homozygous Arg554Trp mutation in SDHA causes Leigh syndrome
          with complex II
          deficiency in two siblings born to consanguineous parents.
        supporting_text: >-
          We now report a mutation in the nuclear-encoded flavoprotein (Fp) subunit
          gene of the
          succinate dehydrogenase (SDH) in two siblings with complex II deficiency
          presenting as
          Leigh syndrome. Both patients were homozygous for an Arg554Trp substitution
          in the Fp
          subunit. Their parents (first cousins) were heterozygous for the mutation
          that occurred
          in a conserved domain of the protein and was absent from 120 controls.
        reference_section_type: ABSTRACT
        full_text_unavailable: true
      - statement: >-
          The deleterious effect of the Arg554Trp mutation on SDH catalytic activity
          was
          demonstrated in a yeast complementation assay using an SDH-deficient strain
          transformed with mutant Fp cDNA.
        supporting_text: >-
          The deleterious effect of the Arg to Trp substitution on the catalytic activity
          of SDH
          was observed in a SDH- yeast strain transformed with mutant Fp cDNA.
        reference_section_type: ABSTRACT
        full_text_unavailable: true
      - statement: >-
          The Fp subunit gene is duplicated in the human genome at chromosomes 3q29
          and 5p15,
          with only the chromosome 5 copy expressed.
        supporting_text: >-
          The Fp subunit gene is duplicated in the human genome (3q29; 5p15), with
          only the gene
          on chromosome 5 expressed in human-hamster somatic cell hybrids. This is
          the first
          report of a nuclear gene mutation causing a mitochondrial respiratory chain
          deficiency
          in humans.
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: Reactome:R-HSA-70994
    title: SDH complex dehydrogenates succinate
    findings: []
  - id: Reactome:R-HSA-71403
    title: Citric acid cycle (TCA cycle)
    findings: []
  - id: Reactome:R-HSA-9854672
    title: FAD attaches to SDHA
    findings: []
  - id: Reactome:R-HSA-9854961
    title: SDHAF4 binds to FAD-SDHA
    findings: []
  - id: Reactome:R-HSA-9855212
    title: SDHA binds to SDHB
    findings: []
  - id: Reactome:R-HSA-9855252
    title: SDHA:SDHB binds to SDHC:SDHD
    findings: []
  - id: file:human/SDHA/SDHA-deep-research-falcon.md
    title: Deep research review of SDHA gene function (Falcon provider)
    findings:
      - statement: >-
          SDHA encodes the covalently flavinylated FAD-containing flavoprotein subunit
          of
          mitochondrial complex II. Its catalytic role in succinate oxidation and
          electron
          transfer to ubiquinone is conserved. SDHx genes including SDHA contribute
          to
          paraganglioma/pheochromocytoma (PPGL) genetics.
        supporting_text: >-
          Complex II (succinate dehydrogenase, SDH) catalyzes the oxidation of succinate
          to fumarate, coupling two-electron transfer via FAD and iron-sulfur centers
          to
          reduce ubiquinone to ubiquinol in the inner mitochondrial membrane
core_functions:
  - molecular_function:
      id: GO:0000104
      label: succinate dehydrogenase activity
    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:0005759
        label: mitochondrial matrix
    in_complex:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    description: >-
      SDHA is the catalytic flavoprotein subunit of succinate dehydrogenase (Complex
      II).
      It contains a covalently bound FAD cofactor at His99 and catalyzes the oxidation
      of
      succinate to fumarate as part of the TCA cycle (GO:0006099). The electrons are
      transferred
      via FAD through SDHB iron-sulfur centers to ubiquinone, coupling the TCA cycle
      to the
      electron transport chain (GO:0006121). SDHA enables succinate dehydrogenase
      activity (GO:0000104)
      and contributes to the overall succinate dehydrogenase quinone activity (GO:0008177)
      of
      the Complex II heterotetramer. The complex resides in the inner mitochondrial
      membrane
      with SDHA facing the matrix.
    supported_by:
      - reference_id: PMID:37098072
        supporting_text: >-
          Human complex II is a key protein complex that links two essential energy-producing
          processes: the tricarboxylic acid cycle and oxidative phosphorylation
      - reference_id: PMID:7550341
        supporting_text: >-
          We now report a mutation in the nuclear-encoded flavoprotein (Fp) subunit
          gene
          of the succinate dehydrogenase (SDH) in two siblings with complex II deficiency