SDHD - dismech genes

Normal function · from ai-gene-review (O14521, commit 79fe13b38970) · AI-generated, not KB evidence

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.

SDHD is the small cytochrome b-like membrane anchor subunit (cybS) of succinate dehydrogenase (Complex II). Together with SDHC, it forms the membrane anchor domain that attaches the catalytic SDHA:SDHB subcomplex to the inner mitochondrial membrane. SDHD provides the His102 axial ligand to the heme b (cytochrome b560) iron atom shared between SDHC and SDHD, making heme binding (GO:0020037) its primary subunit-specific molecular function. SDHD also contributes to ubiquinone binding at the Q-site (Tyr114 directly contacts ubiquinone at the entrance pocket formed by SDHC TM1, SDHD TM2, and SDHB C-terminus). SDHD has no independent catalytic activity but contributes to the overall succinate dehydrogenase (quinone) activity (GO:0008177) of the Complex II heterotetramer. The heme b coordinated by SDHD and SDHC serves as an electron sink stabilizing semiquinone intermediates during ubiquinone reduction. Through Complex II, SDHD participates in mitochondrial electron transport from succinate to ubiquinone (GO:0006121) and the tricarboxylic acid cycle (GO:0006099). Complex II is unique among OXPHOS complexes in that it does NOT pump protons across the inner membrane.

molecular function: heme binding · contributes to molecular function: succinate dehydrogenase (quinone) activity · directly involved in: mitochondrial electron transport, succinate to ubiquinone; tricarboxylic acid cycle · locations: mitochondrial inner membrane · in complex: respiratory chain complex II (succinate dehydrogenase)

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Cowden Syndrome	susceptibility	mechanism: Reduced Succinate Dehydrogenase Activity subtype: CS3 scoped to subtype: CS3
Hereditary Pheochromocytoma-Paraganglioma Syndrome	causative
Carney-Stratakis syndrome	untyped Germline Loss-of-Function Variants	mechanism: Germline SDH complex loss of function
Pheochromocytoma and Paraganglioma	untyped Germline Loss-of-Function Mutations	mechanism: Succinate Dehydrogenase Complex Dysfunction subtype: PGL1

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
hereditary pheochromocytoma-paraganglioma MONDO:0017366	AD	Definitive 2021-06-17	Hereditary Pheochromocytoma-Paraganglioma Syndrome causative
mitochondrial disease MONDO:0044970	AR	Limited 2022-04-04	no dismech entry

Mechanism modules · computed from kb/

oncometabolite_dioxygenase_inhibition via Pheochromocytoma and Paraganglioma