mitochondrial complex III deficiency

Summary

mitochondrial complex III deficiency (MONDO:0015448) is a disease with 11 cohort genes. The dominant Reactome pathway is Complex III assembly (11 cohort genes).

At a glance

• Cohort genes: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex III deficiency
Mondo ID	MONDO:0015448
Orphanet	1460
DOID	DOID:0111139
UMLS	C1852372
MedGen	377658
GARD	0008295
Is cancer (heuristic)	no

Also known as: isolated coenzyme Q-cytochrome C reductase deficiency · isolated CoQ-cytochrome C reductase deficiency · isolated mitochondrial respiratory chain complex III deficiency · isolated ubiquinone-cytochrome C reductase deficiency · mitochondrial respiratory chain complex III deficiency

Data availability: 11 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial respiratory chain complex deficiency › mitochondrial complex III deficiency

Related subtypes (8): mitochondrial complex V (ATP synthase) deficiency, nuclear type 1, mitochondrial complex V (ATP synthase) deficiency, nuclear type 2, mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, mitochondrial complex V (ATP synthase) deficiency, nuclear type 4B, mitochondrial complex V (ATP synthase) deficiency, nuclear type 5, mitochondrial complex IV deficiency, nuclear-type, mitochondrial complex I deficiency, SDHC-related Mitochondrial Disease

Subtypes (1): mitochondrial complex III deficiency, nuclear type

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 54 · Orphanet: 16 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CYC1	Definitive	Autosomal recessive	mitochondrial complex III deficiency nuclear type 6	3
TTC19	Definitive	Autosomal recessive	mitochondrial complex III deficiency nuclear type 2	7
BCS1L	Strong	Autosomal recessive	mitochondrial complex III deficiency nuclear type 1	16
LYRM7	Strong	Autosomal recessive	mitochondrial complex III deficiency nuclear type 8	3
UQCC2	Strong	Autosomal recessive	mitochondrial complex III deficiency nuclear type 7	3
UQCRB	Strong	Autosomal recessive	mitochondrial complex III deficiency nuclear type 3	5
UQCRC2	Strong	Autosomal recessive	mitochondrial complex III deficiency nuclear type 5	4
UQCRFS1	Strong	Autosomal recessive	mitochondrial complex III deficiency, nuclear type 10	4
UQCRQ	Strong	Autosomal recessive	mitochondrial complex III deficiency nuclear type 4	5
UQCC3	Moderate	Autosomal recessive	mitochondrial complex III deficiency nuclear type 9	2
MT-CYB	Supportive	Autosomal recessive	mitochondrial complex III deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BCS1L	Orphanet:123	Björnstad syndrome
BCS1L	Orphanet:1460	Isolated complex III deficiency
BCS1L	Orphanet:254902	Renal tubulopathy-encephalopathy-liver failure syndrome
BCS1L	Orphanet:53693	GRACILE syndrome
UQCRB	Orphanet:1460	Isolated complex III deficiency
UQCRC2	Orphanet:1460	Isolated complex III deficiency
UQCRFS1	Orphanet:1460	Isolated complex III deficiency
UQCC2	Orphanet:1460	Isolated complex III deficiency
CYC1	Orphanet:1460	Isolated complex III deficiency
TTC19	Orphanet:1460	Isolated complex III deficiency
LYRM7	Orphanet:1460	Isolated complex III deficiency
UQCRQ	Orphanet:1460	Isolated complex III deficiency
UQCC3	Orphanet:1460	Isolated complex III deficiency
MT-CYB	Orphanet:104	Leber hereditary optic neuropathy
MT-CYB	Orphanet:137675	Histiocytoid cardiomyopathy
MT-CYB	Orphanet:1460	Isolated complex III deficiency

Cohort genes → proteins

11 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BCS1L	HGNC:1020	ENSG00000074582	Q9Y276	Mitochondrial chaperone BCS1	gencc
UQCRB	HGNC:12582	ENSG00000156467	P14927	Cytochrome b-c1 complex subunit 7	gencc
UQCRC2	HGNC:12586	ENSG00000140740	P22695	Cytochrome b-c1 complex subunit 2, mitochondrial	gencc
UQCRFS1	HGNC:12587	ENSG00000169021	P47985	Cytochrome b-c1 complex subunit Rieske, mitochondrial	gencc
UQCC2	HGNC:21237	ENSG00000137288	Q9BRT2	Ubiquinol-cytochrome c reductase complex assembly factor 2	gencc
CYC1	HGNC:2579	ENSG00000179091	P08574	Cytochrome c1, heme protein, mitochondrial	gencc
TTC19	HGNC:26006	ENSG00000011295	Q6DKK2	Tetratricopeptide repeat protein 19, mitochondrial	gencc
LYRM7	HGNC:28072	ENSG00000186687	Q5U5X0	Complex III assembly factor LYRM7	gencc
UQCRQ	HGNC:29594	ENSG00000164405	O14949	Cytochrome b-c1 complex subunit 8	gencc
UQCC3	HGNC:34399	ENSG00000204922	Q6UW78	Ubiquinol-cytochrome-c reductase complex assembly factor 3	gencc
MT-CYB	HGNC:7427	ENSG00000198727	P00156	Cytochrome b	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCS1L	Mitochondrial chaperone BCS1	Chaperone necessary for the incorporation of Rieske iron-sulfur protein UQCRFS1 into the mitochondrial respiratory chain complex III.
UQCRB	Cytochrome b-c1 complex subunit 7	Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.
UQCRC2	Cytochrome b-c1 complex subunit 2, mitochondrial	Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.
UQCRFS1	Cytochrome b-c1 complex subunit Rieske, mitochondrial	Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.
UQCC2	Ubiquinol-cytochrome c reductase complex assembly factor 2	Required for the assembly of the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex).
CYC1	Cytochrome c1, heme protein, mitochondrial	Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.
TTC19	Tetratricopeptide repeat protein 19, mitochondrial	Required for the preservation of the structural and functional integrity of mitochondrial respiratory complex III by allowing the physiological turnover of the Rieske protein UQCRFS1.
LYRM7	Complex III assembly factor LYRM7	Assembly factor required for Rieske Fe-S protein UQCRFS1 incorporation into the cytochrome b-c1 (CIII) complex.
UQCRQ	Cytochrome b-c1 complex subunit 8	Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.
UQCC3	Ubiquinol-cytochrome-c reductase complex assembly factor 3	Required for the assembly of the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex), mediating cytochrome b recruitment and probably stabilization within the complex.
MT-CYB	Cytochrome b	Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 9 · Druggable fraction: 0.18

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	9	1.5×	0.217
Protease	1	3.3×	0.394
Enzyme (other)	1	1.1×	0.616

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BCS1L	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
UQCRB	Enzyme (other)	yes	7.1.1.8	QCR7, QCR7_sf
UQCRC2	Protease	yes		Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16
UQCRFS1	Other/Unknown	no		Rieske_TM, Rieske_Fe-S_prot_C, Ubiquinol_cyt_c_Rdtase_Fe-S-su
UQCC2	Other/Unknown	no		UQCC2
CYC1	Other/Unknown	no		Cyt_c1, Cyt_c1_TM_anchor_C, Cyt_c-like_dom_sf
TTC19	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC19
LYRM7	Other/Unknown	no		Complex1_LYR_dom, Complex1_LYR_LYRM7, MZM1/LYRM7
UQCRQ	Other/Unknown	no		Cyt_bc1_su8, Cyt_bc1_su8_sf
UQCC3	Other/Unknown	no		UQCC3
MT-CYB	Other/Unknown	no		Cyt_b/b6_N, Cyt_b/b6_C, Di-haem_cyt_TM

Expression context

Cohort genes with no expression data: 0.

11 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	11
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	5
heart left ventricle	3
heart right ventricle	2
body of tongue	2
mucosa of transverse colon	2
cardiac ventricle	2
body of pancreas	1
metanephros cortex	1
renal medulla	1
vena cava	1
skeletal muscle tissue of rectus abdominis	1
gastrocnemius	1
right atrium auricular region	1
ileal mucosa	1
jejunal mucosa	1
upper leg skin	1
deltoid	1
left ventricle myocardium	1
vastus lateralis	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCS1L	279	ubiquitous	marker	body of pancreas, metanephros cortex, apex of heart
UQCRB	304	ubiquitous	marker	heart right ventricle, vena cava, renal medulla
UQCRC2	303	ubiquitous	marker	heart right ventricle, body of tongue, skeletal muscle tissue of rectus abdominis
UQCRFS1	134	ubiquitous	marker	gastrocnemius, heart left ventricle, mucosa of transverse colon
UQCC2	251	ubiquitous	marker	apex of heart, right atrium auricular region, heart left ventricle
CYC1	284	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
TTC19	291	ubiquitous	marker	jejunal mucosa, ileal mucosa, upper leg skin
LYRM7	254	ubiquitous	marker	left ventricle myocardium, vastus lateralis, deltoid
UQCRQ	295	ubiquitous	marker	apex of heart, body of tongue, cardiac ventricle
UQCC3	246	ubiquitous	marker	endothelial cell, upper arm skin, mucosa of transverse colon
MT-CYB	134	ubiquitous	marker	apex of heart, pituitary gland, zone of skin

Protein interactions among cohort

Intra-cohort edges: 41.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UQCRC2	4,507
UQCRFS1	4,001
BCS1L	3,789
MT-CYB	3,317
CYC1	3,199
UQCRB	2,538
TTC19	2,381
UQCRQ	2,366
LYRM7	1,740
UQCC2	1,016

Intra-cohort edges

A	B	Sources
BCS1L	CYC1	string_interaction
BCS1L	LYRM7	string_interaction
BCS1L	TTC19	string_interaction
BCS1L	UQCC2	string_interaction
BCS1L	UQCC3	string_interaction
BCS1L	UQCRB	string_interaction
BCS1L	UQCRFS1	string_interaction
BCS1L	UQCRQ	string_interaction
CYC1	MT-CYB	string_interaction
CYC1	UQCC3	string_interaction
CYC1	UQCRB	biogrid_interaction, intact, string_interaction
CYC1	UQCRC2	string_interaction
CYC1	UQCRFS1	biogrid_interaction, string_interaction
CYC1	UQCRQ	intact, string_interaction
LYRM7	TTC19	string_interaction
LYRM7	UQCC2	string_interaction
LYRM7	UQCC3	string_interaction
LYRM7	UQCRFS1	biogrid_interaction, intact, string_interaction
MT-CYB	UQCC2	string_interaction
MT-CYB	UQCRB	intact, string_interaction
MT-CYB	UQCRC2	intact, string_interaction
MT-CYB	UQCRFS1	intact, string_interaction
MT-CYB	UQCRQ	intact, string_interaction
TTC19	UQCC2	string_interaction
TTC19	UQCC3	string_interaction
TTC19	UQCRB	string_interaction
TTC19	UQCRC2	string_interaction
TTC19	UQCRFS1	string_interaction
TTC19	UQCRQ	string_interaction
UQCC2	UQCC3	string_interaction
UQCC2	UQCRB	string_interaction
UQCC2	UQCRQ	string_interaction
UQCC3	UQCRB	string_interaction
UQCC3	UQCRC2	string_interaction
UQCC3	UQCRQ	intact, string_interaction
UQCRB	UQCRC2	biogrid_interaction, intact, string_interaction
UQCRB	UQCRFS1	string_interaction
UQCRB	UQCRQ	biogrid_interaction, intact, string_interaction
UQCRC2	UQCRFS1	string_interaction
UQCRC2	UQCRQ	biogrid_interaction, intact, string_interaction
UQCRFS1	UQCRQ	intact, string_interaction

Structural data

PDB: 6 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UQCRB	P14927	5
UQCRC2	P22695	5
UQCRFS1	P47985	5
CYC1	P08574	5
UQCRQ	O14949	5
MT-CYB	P00156	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LYRM7	Q5U5X0	91.70
UQCC2	Q9BRT2	88.94
BCS1L	Q9Y276	87.10
TTC19	Q6DKK2	80.28
UQCC3	Q6UW78	74.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 11 evidence-associated genes (11 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Complex III assembly	11	439.2×	6e-30	BCS1L, UQCRB, UQCRC2, UQCRFS1, UQCC2, CYC1, TTC19, LYRM7 (+3 more)
Respiratory electron transport	8	69.2×	8e-14	BCS1L, UQCRB, UQCRC2, UQCRFS1, CYC1, LYRM7, UQCRQ, MT-CYB
Mitochondrial protein import	2	30.5×	0.005	BCS1L, CYC1
Mitochondrial protein degradation	2	20.8×	0.008	UQCRC2, UQCRQ
Aerobic respiration and respiratory electron transport	2	16.1×	0.010	BCS1L, LYRM7
Protein localization	1	17.3×	0.075	BCS1L
Mitochondrial translation termination	1	10.0×	0.109	MT-CYB
Metabolism	2	2.1×	0.244	BCS1L, LYRM7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial electron transport, ubiquinol to cytochrome c	7	824.9×	3e-19	UQCRB, UQCRC2, UQCRFS1, CYC1, UQCRQ, UQCC3, MT-CYB
mitochondrial respiratory chain complex III assembly	6	656.6×	9e-16	BCS1L, UQCRFS1, UQCC2, TTC19, LYRM7, UQCC3
cellular respiration	6	235.7×	6e-13	UQCRB, UQCRC2, CYC1, LYRM7, UQCRQ, MT-CYB
response to glucagon	2	306.4×	2e-04	CYC1, MT-CYB
oxidative phosphorylation	2	255.3×	2e-04	UQCRB, UQCRC2
subthalamus development	1	1532.0×	0.003	UQCRQ
pons development	1	1532.0×	0.003	UQCRQ
response to D-galactosamine	1	1532.0×	0.003	MT-CYB
aerobic respiration	2	45.1×	0.004	UQCRB, UQCRC2
response to cobalamin	1	766.0×	0.005	MT-CYB
electron transport coupled proton transport	1	383.0×	0.009	MT-CYB
protein insertion into mitochondrial inner membrane from matrix	1	306.4×	0.011	BCS1L
regulation of skeletal muscle cell differentiation	1	255.3×	0.012	UQCC2
response to mercury ion	1	218.9×	0.013	MT-CYB
pyramidal neuron development	1	191.5×	0.014	UQCRQ
cerebellar Purkinje cell layer development	1	139.3×	0.017	UQCRQ
response to copper ion	1	139.3×	0.017	MT-CYB
thalamus development	1	127.7×	0.017	UQCRQ
regulation of oxidative phosphorylation	1	109.4×	0.018	UQCC2
response to hyperoxia	1	102.1×	0.018	MT-CYB
positive regulation of mitochondrial translation	1	102.1×	0.018	UQCC2
hypothalamus development	1	95.8×	0.018	UQCRQ
cristae formation	1	95.8×	0.018	UQCC3
ATP biosynthetic process	1	90.1×	0.018	UQCC3
respiratory electron transport chain	1	76.6×	0.021	UQCRFS1
response to cadmium ion	1	66.6×	0.023	MT-CYB
mitochondrial respiratory chain complex IV assembly	1	56.7×	0.025	BCS1L
midbrain development	1	54.7×	0.025	UQCRQ
animal organ regeneration	1	54.7×	0.025	MT-CYB
mitochondrial respiratory chain complex I assembly	1	37.4×	0.035	BCS1L

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 10

Druggability breadth: 3 of 11 evidence-associated genes (27%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CYC1	GILTERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYC1	1	4
BCS1L	0	0
UQCRB	0	0
UQCRC2	0	0
UQCRFS1	0	0
UQCC2	0	0
TTC19	0	0
LYRM7	0	0
UQCRQ	0	0
UQCC3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GILTERITINIB	4	CYC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
UQCRB	9	Binding:9
CYC1	2	Binding:2
UQCRC2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UQCRB	7.1.1.8	quinol-cytochrome-c reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
GILTERITINIB	4	CYC1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYC1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	UQCRB, UQCRC2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	8	BCS1L, UQCRFS1, UQCC2, TTC19, LYRM7, UQCRQ, UQCC3, MT-CYB

Undrugged target profiles

10 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
UQCRB	9	CYC1
UQCRFS1	0	CYC1
MT-CYB	0	CYC1
BCS1L	0	—
UQCRC2	1	—
UQCC2	0	—
TTC19	0	—
LYRM7	0	—
UQCRQ	0	—
UQCC3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.