SDHC - dismech genes

Normal function · from ai-gene-review (Q99643, commit 79fe13b38970) · AI-generated, not KB evidence

SDHC encodes the large cytochrome b560 transmembrane subunit of succinate dehydrogenase (SDH, Complex II), a heterotetrameric enzyme (SDHA/SDHB/SDHC/SDHD) embedded in the mitochondrial inner membrane. Together with SDHD, SDHC forms the membrane anchor domain of Complex II, contributing to the ubiquinone (CoQ) binding site and harboring the heme b (cytochrome b560) prosthetic group shared between the two membrane subunits. SDHC has three transmembrane helices and provides key residues (Ile56, Trp61, Met65, Ile69) that directly contact ubiquinone at the Q-site. The heme b is axially coordinated by His127 of SDHC and the corresponding histidine of SDHD. SDHC has no independent catalytic activity; its role is structural (membrane anchoring, heme environment, Q-site formation). Complex II uniquely links the TCA cycle and the electron transport chain by catalyzing succinate oxidation to fumarate (at SDHA) and transferring electrons to ubiquinone at the SDHC/SDHD membrane interface, but does NOT pump protons. SDHC functions as a tumor suppressor; germline loss-of-function mutations and promoter hypermethylation cause paraganglioma/ pheochromocytoma (PPGL3), gastrointestinal stromal tumors (GIST), and Carney triad, via succinate accumulation and pseudohypoxic signaling.

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

molecular function: heme binding · 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
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: PGL3

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	UD	No Known Disease Relationship 2022-03-07	no dismech entry

Mechanism modules · computed from kb/

oncometabolite_dioxygenase_inhibition via Pheochromocytoma and Paraganglioma