APOO

Summary

APOO (apolipoprotein O, HGNC:28727) is a protein-coding gene on chromosome Xp22.11, encoding MICOS complex subunit MIC26 (Q9BUR5). Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane.

This gene is a member of the apolipoprotein family. Members of this protein family are involved in the transport and metabolism of lipids. The encoded protein associates with HDL, LDL and VLDL lipoproteins and is characterized by chondroitin-sulfate glycosylation. This protein may be involved in preventing lipid accumulation in the myocardium in obese and diabetic patients. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 3, 4, 5, 12 and 16.

Source: NCBI Gene 79135 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Moderate, GenCC)
• Clinical variants (ClinVar): 115 total — 1 pathogenic
• GTEx eGene: eQTL in 24 tissues, sQTL in 10 (q < 0.05)
• MANE Select transcript: NM_024122
• Notable: 115 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28727
Approved symbol	APOO
Name	apolipoprotein O
Location	Xp22.11
Locus type	gene with protein product
Status	Approved
Aliases	MGC4825, My025, Mic23, MIC26, MICOS26
Ensembl gene	ENSG00000184831
Ensembl biotype	protein_coding
OMIM	300753
Entrez	79135

Gene structure

Transcript identifiers

Ensembl transcripts: 118 — 63 protein_coding, 52 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000379226

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 2, TSL 3: 3, TSL 4: 1, TSL 5: 1

ENST00000379226, ENST00000439528, ENST00000476598, ENST00000490078, ENST00000633372, ENST00000633432, ENST00000633609, ENST00000634086, ENST00000634188, ENST00000899502, ENST00000899503, ENST00000899504, ENST00000899505, ENST00000899506, ENST00000899507, ENST00000899508, ENST00000899509, ENST00000899510, ENST00000899511, ENST00000899512, ENST00000899513, ENST00000899514, ENST00000899515, ENST00000913487, ENST00000913488, ENST00000913489, ENST00000913490, ENST00000969328, ENST00000987416, ENST00000987417, ENST00000987418, ENST00001039803, ENST00001039804, ENST00001039805, ENST00001039806, ENST00001039807, ENST00001062383, ENST00001062384, ENST00001062385, ENST00001062386, ENST00001062387, ENST00001093140, ENST00001093141, ENST00001093142, ENST00001093143, ENST00001093144, ENST00001093145, ENST00001093146, ENST00001093147, ENST00001093148, ENST00001093149, ENST00001093150, ENST00001093151, ENST00001093152, ENST00001093153, ENST00001093154, ENST00001093155, ENST00001093156, ENST00001093157, ENST00001093158, ENST00001093159, ENST00001093160, ENST00001093161, ENST00001093162, ENST00001093163, ENST00001093164, ENST00001093165, ENST00001093166, ENST00001093167, ENST00001093168, ENST00001093169, ENST00001093170, ENST00001093171, ENST00001093172, ENST00001093173, ENST00001093174, ENST00001093175, ENST00001093176, ENST00001093177, ENST00001093178, ENST00001093179, ENST00001093180, ENST00001093181, ENST00001093182, ENST00001093183, ENST00001093184, ENST00001093185, ENST00001093186, ENST00001093187, ENST00001093188, ENST00001093189, ENST00001093190, ENST00001093191, ENST00001093192, ENST00001093193, ENST00001093194, ENST00001093195, ENST00001093196, ENST00001093197, ENST00001093198, ENST00001093199, ENST00001093200, ENST00001093201, ENST00001093202, ENST00001093203, ENST00001093204, ENST00001093205, ENST00001093206, ENST00001093207, ENST00001093208, ENST00001093209, ENST00001093210, ENST00001093211, ENST00001110498, ENST00001121988, ENST00001129266, ENST00001129267, ENST00001132266

RefSeq mRNA: 1 — MANE Select: NM_024122 NM_024122

CCDS: CCDS14208

Canonical transcript exons

ENST00000379226 — 9 exons

Exon	Start	End
ENSE00001295024	23878915	23879034
ENSE00001316126	23874403	23874457
ENSE00001319822	23880845	23880952
ENSE00001884150	23833353	23833612
ENSE00001953643	23907694	23907938
ENSE00003563287	23856302	23856382
ENSE00003578073	23840313	23840377
ENSE00003653487	23858642	23858733
ENSE00003666837	23868593	23868688

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 97.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.4834 / max 135.4164, expressed in 1814 samples.

Highest expression (Bgee): decidua, heart right ventricle, ventricle myocardium, prefrontal cortex, pons.

Genetic regulation across tissues (GTEx eQTL / sQTL)

APOO is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 24 tissues and its splicing (sQTL) in 10 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 34 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Tibial	eqtl	2.5e-10	-0.23	X:23918680:C:T
Skin Sun Exposed Lower leg	eqtl	4.2e-09	-0.17	X:23918680:C:T
Nerve Tibial	eqtl	7.1e-09	-0.12	X:23863284:G:A
Muscle Skeletal	sqtl	2.2e-08	-0.34	X:23863137:C:T
Skin Not Sun Exposed Suprapubic	eqtl	3.2e-08	-0.21	X:23948969:A:G
Whole Blood	eqtl	3.9e-08	+0.23	X:23845521:C:T
Cells Cultured fibroblasts	sqtl	2.7e-07	-0.36	X:23863137:C:T
Adipose Visceral Omentum	eqtl	6.3e-06	-0.19	X:23907717:A:T
Liver	eqtl	2.0e-05	+0.37	X:23815035:C:T
Cells EBV-transformed lymphocytes	sqtl	8.1e-05	-0.49	X:23863137:C:T
Pituitary	sqtl	3.0e-04	+1.75	X:23856404:T:C
Artery Aorta	eqtl	5.8e-04	-0.20	X:23907717:A:T
Cells Cultured fibroblasts	eqtl	6.4e-04	-0.09	X:23889951:G:A
Adipose Subcutaneous	eqtl	8.3e-04	-0.13	X:23960396:G:T
Brain Nucleus accumbens basal ganglia	sqtl	3.0e-03	+0.43	X:24236111:C:T
Colon Sigmoid	eqtl	4.5e-03	-0.18	X:23907717:A:T
Prostate	eqtl	4.9e-03	-0.21	X:23880560:G:A
Testis	eqtl	5.1e-03	-0.69	X:23055582:T:G
Skin Sun Exposed Lower leg	sqtl	6.7e-03	-0.25	X:23863137:C:T
Skin Not Sun Exposed Suprapubic	sqtl	7.2e-03	-0.27	X:23863137:C:T

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
198736	11.7180	1772
198733	7.4162	1688
198735	1.5965	879
198729	0.3192	118
198734	0.1835	92
198732	0.1123	33
198730	0.0739	43
198731	0.0637	22

Top tissues by expression

showing 100 of 283 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	97.93	gold quality
heart right ventricle	UBERON:0002080	97.61	gold quality
left ventricle myocardium	UBERON:0006566	96.98	gold quality
prefrontal cortex	UBERON:0000451	96.12	gold quality
pons	UBERON:0000988	95.67	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.38	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.32	gold quality
triceps brachii	UBERON:0001509	95.26	gold quality
anterior cingulate cortex	UBERON:0009835	95.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.23	gold quality
cardiac ventricle	UBERON:0002082	95.22	gold quality
heart left ventricle	UBERON:0002084	95.22	gold quality
cingulate cortex	UBERON:0003027	95.22	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.17	gold quality
myocardium	UBERON:0002349	95.08	gold quality
diaphragm	UBERON:0001103	95.02	gold quality
frontal cortex	UBERON:0001870	94.96	gold quality
vastus lateralis	UBERON:0001379	94.89	gold quality
biceps brachii	UBERON:0001507	94.86	gold quality
neocortex	UBERON:0001950	94.84	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.57	gold quality
right frontal lobe	UBERON:0002810	94.52	gold quality
apex of heart	UBERON:0002098	94.47	gold quality
cortical plate	UBERON:0005343	94.44	gold quality
ventricular zone	UBERON:0003053	94.43	gold quality
cerebral cortex	UBERON:0000956	94.32	gold quality
bronchial epithelial cell	CL:0002328	94.30	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.27	gold quality
quadriceps femoris	UBERON:0001377	94.20	gold quality
epithelium of bronchus	UBERON:0002031	94.09	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.05	gold quality
hypothalamus	UBERON:0001898	93.78	gold quality
orbitofrontal cortex	UBERON:0004167	93.77	gold quality
right atrium auricular region	UBERON:0006631	93.77	gold quality
amygdala	UBERON:0001876	93.73	gold quality
cardiac atrium	UBERON:0002081	93.72	gold quality
telencephalon	UBERON:0001893	93.71	gold quality
bronchus	UBERON:0002185	93.68	gold quality
superior frontal gyrus	UBERON:0002661	93.64	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.63	gold quality
ganglionic eminence	UBERON:0004023	93.62	gold quality
forebrain	UBERON:0001890	93.52	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.49	gold quality
postcentral gyrus	UBERON:0002581	93.43	gold quality
Ammon’s horn	UBERON:0001954	93.40	gold quality
substantia nigra	UBERON:0002038	93.35	gold quality
nucleus accumbens	UBERON:0001882	93.24	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.24	gold quality
caudate nucleus	UBERON:0001873	93.22	gold quality
heart	UBERON:0000948	93.17	gold quality
brain	UBERON:0000955	93.16	gold quality
skeletal muscle tissue	UBERON:0001134	93.01	gold quality
midbrain	UBERON:0001891	92.96	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.91	gold quality
parietal lobe	UBERON:0001872	92.82	gold quality
putamen	UBERON:0001874	92.82	gold quality
adult mammalian kidney	UBERON:0000082	92.81	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.79	gold quality
substantia nigra pars compacta	UBERON:0001965	92.62	gold quality
muscle tissue	UBERON:0002385	92.62	gold quality
gluteal muscle	UBERON:0002000	92.60	gold quality
spinal cord	UBERON:0002240	92.60	gold quality
temporal lobe	UBERON:0001871	92.59	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.31	gold quality
adenohypophysis	UBERON:0002196	92.22	gold quality
muscle organ	UBERON:0001630	92.16	gold quality
oocyte	CL:0000023	92.00	gold quality
deltoid	UBERON:0001476	91.95	gold quality
cerebellar cortex	UBERON:0002129	91.91	gold quality
pituitary gland	UBERON:0000007	91.81	gold quality
cerebellar hemisphere	UBERON:0002245	91.77	gold quality
superior vestibular nucleus	UBERON:0007227	91.67	gold quality
cerebellum	UBERON:0002037	91.63	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.63	gold quality
gastrocnemius	UBERON:0001388	91.56	gold quality
muscle of leg	UBERON:0001383	91.51	gold quality
middle temporal gyrus	UBERON:0002771	91.49	gold quality
adult organism	UBERON:0007023	91.39	gold quality
lateral globus pallidus	UBERON:0002476	91.33	gold quality
islet of Langerhans	UBERON:0000006	91.28	gold quality
entorhinal cortex	UBERON:0002728	91.21	gold quality
primary visual cortex	UBERON:0002436	91.17	gold quality
right adrenal gland	UBERON:0001233	91.07	gold quality
occipital lobe	UBERON:0002021	90.79	gold quality
right adrenal gland cortex	UBERON:0035827	90.74	gold quality
CA1 field of hippocampus	UBERON:0003881	90.44	gold quality
pigmented layer of retina	UBERON:0001782	90.42	gold quality
mucosa of transverse colon	UBERON:0004991	90.42	gold quality
dorsal root ganglion	UBERON:0000044	90.39	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.32	gold quality
nasal cavity epithelium	UBERON:0005384	90.31	gold quality
epithelium of nasopharynx	UBERON:0001951	90.23	gold quality
tongue squamous epithelium	UBERON:0006919	90.01	silver quality
dorsal plus ventral thalamus	UBERON:0001897	89.86	silver quality
adrenal tissue	UBERON:0018303	89.59	gold quality
metanephros cortex	UBERON:0010533	89.54	gold quality
cerebellar vermis	UBERON:0004720	89.43	gold quality
olfactory bulb	UBERON:0002264	89.40	silver quality
embryo	UBERON:0000922	89.35	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.44

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Frontal cortex	tissue	113.3
Caudate putamen	tissue	101.9
Tongue	tissue	68.2
Heart muscle	tissue	58.6	high
Parathyroid gland	tissue	58.1	medium
Choroid plexus	tissue	52.7
Retina	tissue	48.9
Kidney	tissue	43.3	medium
Skeletal muscle	tissue	43.1	medium
Superior colliculi	tissue	36.6
Cerebral cortex	tissue	35.2	high
Somatosensory cortex	tissue	35.2
Occipital cortex	tissue	33.8
Thalamus	tissue	33.2
Pons	tissue	31.8
Locus coeruleus	tissue	30.6
Retrosplenial and cingulate cortex	tissue	30.2
Medulla oblongata	tissue	30.1
Putamen	tissue	30.0
Spinal cord	tissue	29.9
Postcentral gyrus	tissue	29.7
Motor cortex	tissue	29.4
Hippocampal formation	tissue	29.2
Prefrontal cortex	tissue	28.4
Midbrain	tissue	28.4
Pituitary gland	tissue	28.1
Temporal cortex	tissue	28.0
Entorhinal cortex	tissue	27.9
Basal ganglia	tissue	27.8	medium
Substantia nigra	tissue	27.8
Olfactory bulb	tissue	27.6
Hippocampus	tissue	27.4	medium
Ventral forebrain	tissue	27.2
Retrosplenial cortex	tissue	26.4
Cerebellum	tissue	25.7	high
Septum	tissue	25.4
Insular cortex	tissue	24.7
Amygdala	tissue	23.5
Periaqueductal gray	tissue	23.3
Nucleus accumbens	tissue	22.3
Hypothalamus	tissue	21.6
Fallopian tube	tissue	19.5	medium
Thyroid gland	tissue	19.0	high
Salivary gland	tissue	18.5	high
Epididymis	tissue	18.5	high
Adrenal gland	tissue	18.1	medium
Rectum	tissue	17.6	high
Liver	tissue	17.0	medium
Corpus callosum	tissue	17.0
Stomach 1	tissue	16.2	high
Colon	tissue	16.2	low
Testis	tissue	15.7	high
Seminal vesicle	tissue	14.1	high
Duodenum	tissue	13.6	high
Pancreas	tissue	13.3	medium
Thymus	tissue	13.0
Prostate	tissue	12.8	medium
Breast	tissue	12.5	medium
Cervix	tissue	12.3	high
Small intestine	tissue	11.3	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Spinal trigeminal nucleus, interpolar (33.6), Mammillary body (32.8), Cerebellar nuclei (31.8), Medial vestibular nucleus (31.6), Hippocampus, CA1 (31.0).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting APOO by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 41 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-3675-3P	99.09	67.70	968

Functional genomics

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000379226 — one region, missense o/e 1.12.

Literature-anchored findings (GeneRIF, showing 10)

• apolipoprotein O is the first chondroitin sulfate chain containing apolipoprotein (PMID:16956892)
• relationships between plasma apoO levels and high-sensitive C-reactive protein (hs-CRP) levels, as well as other lipid parameters in healthy subjects and patients with established acute coronary syndrome (PMID:22693255)
• It is likely that apoO participates in fatty acid metabolism and the inflammatory response in HepG2 cells. (PMID:24341743)
• APOO represents a link between impaired mitochondrial function and cardiomyopathy onset, and targeting APOO-dependent metabolic remodeling has potential as a strategy to adjust heart metabolism and protect the myocardium from impaired contractility. (PMID:24743151)
• The human apolipoprotein MIC26 is a bona fide subunit of the MICOS complex. (PMID:25764979)
• Loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial location, is essential for the development of severe motor neuron disease. (PMID:30092269)
• Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features. (PMID:32439808)
• MIC26 and MIC27 cooperate to regulate cardiolipin levels and the landscape of OXPHOS complexes. (PMID:32788226)
• Role of apolipoprotein O in autophagy via the p38 mitogen-activated protein kinase signaling pathway in myocardial infarction. (PMID:35588578)
• A X-linked nonsense APOO/MIC26 variant causes a lethal mitochondrial disease with progeria-like phenotypes. (PMID:37649161)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	apoob	ENSDARG00000026444
danio_rerio	apooa	ENSDARG00000104696
mus_musculus	Apoo	ENSMUSG00000079508
rattus_norvegicus	Apoo	ENSRNOG00000046918
rattus_norvegicus	Apool2	ENSRNOG00000065327
drosophila_melanogaster	Mic26-27	FBGN0038400
caenorhabditis_elegans		WBGENE00019333

Paralogs (1): APOOL (ENSG00000155008)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1915566) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased circulating iron level	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5NVS6	98.7%	Diamond
Bos taurus	Q148H0	86.9%	Diamond
Gallus gallus	Q5ZK55	68.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PRDX4	protein-coding	10549
ACOT9	protein-coding	23597
SAT1	protein-coding	6303
EIF2S3	protein-coding	1968
CXorf58	protein-coding	254158
KLHL15	protein-coding	80311
SAT1-DT	ncRNA	105373148

Protein

Protein identifiers

MICOS complex subunit MIC26 — Q9BUR5 (reviewed: Q9BUR5)

Alternative names: Apolipoprotein O, MICOS complex subunit MIC23, Protein FAM121B

All UniProt accessions (6): A0A0J9YWW6, A0A0J9YXS4, A0A0J9YXT7, Q9BUR5, G3V1B6, H7C1U8

UniProt curated annotations — full annotation on UniProt →

Function. Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane. Plays a crucial role in crista junction formation and mitochondrial function. Can promote cardiac lipotoxicity by enhancing mitochondrial respiration and fatty acid metabolism in cardiac myoblasts. Promotes cholesterol efflux from macrophage cells. Detected in HDL, LDL and VLDL. Secreted by a microsomal triglyceride transfer protein (MTTP)-dependent mechanism, probably as a VLDL-associated protein that is subsequently transferred to HDL.

Subunit / interactions. Component of the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and MICOS13/MIC13. This complex was also known under the names MINOS or MitOS complex. he MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1 and MTX2 (together described as components of the mitochondrial outer membrane sorting assembly machinery (SAM) complex) and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9. The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex. Interacts with IMMT/MIC60. Interacts with MICOS10/MIC10 and APOOL/MIC27.

Subcellular location. Mitochondrion inner membrane. Secreted. Mitochondrion. Golgi apparatus membrane. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in all tissues examined. Up-regulated in diabetic heart.

Post-translational modifications. O-glycosylation; glycosaminoglycan of chondroitin-sulfate type.

Similarity. Belongs to the apolipoprotein O/MICOS complex subunit Mic27 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BUR5-1	1	yes
Q9BUR5-2	2

RefSeq proteins (1): NP_077027* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019166	MIC26/MIC27	Family
IPR033182	MIC26/MIC27_animal	Family

Pfam: PF09769

UniProt features (5 total): signal peptide 1, chain 1, transmembrane region 1, glycosylation site 1, splice variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BUR5-F1	74.34	0.05

Human Protein Atlas

Protein class: Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted secreted proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria; cytosol

Antibody reliability (HPA): IH supported · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (1)

Type	Positions
O-linked (xyl…) (chondroitin sulfate) serine	162

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-8949613	Cristae formation	electronic
R-HSA-1592230	Mitochondrial biogenesis	—
R-HSA-1852241	Organelle biogenesis and maintenance	—

MSigDB gene sets: 160 (showing top): CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, CAGCTG_AP4_Q5, GOBP_CRISTAE_FORMATION, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_INNER_MITOCHONDRIAL_MEMBRANE_ORGANIZATION, TGIF_01, GOCC_MITOCHONDRIAL_ENVELOPE, CYTAGCAAY_UNKNOWN, GOBP_MEMBRANE_ORGANIZATION, GATA1_02, GOBP_LIPID_LOCALIZATION, GOCC_LOW_DENSITY_LIPOPROTEIN_PARTICLE, GOCC_ORGANELLE_MEMBRANE_CONTACT_SITE, GOCC_OUTER_MITOCHONDRIAL_MEMBRANE_PROTEIN_COMPLEX

GO Biological Process (3): lipid transport (GO:0006869), inner mitochondrial membrane organization (GO:0007007), cristae formation (GO:0042407)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (13): Golgi membrane (GO:0000139), SAM complex (GO:0001401), extracellular region (GO:0005576), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), endoplasmic reticulum membrane (GO:0005789), very-low-density lipoprotein particle (GO:0034361), low-density lipoprotein particle (GO:0034362), high-density lipoprotein particle (GO:0034364), mitochondrial crista junction (GO:0044284), MICOS complex (GO:0061617), MIB complex (GO:0140275), mitochondrial membrane (GO:0031966)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Mitochondrial biogenesis	1
Organelle biogenesis and maintenance	1

GO top-level categories

23 GO namespaces:

Category	Terms
organelle membrane	2
plasma lipoprotein particle	2
inner mitochondrial membrane protein complex	2
transport	1
lipid localization	1
mitochondrial membrane organization	1
inner mitochondrial membrane organization	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
mitochondrial outer membrane translocase complex	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
triglyceride-rich plasma lipoprotein particle	1
mitochondrial inner membrane	1
organelle membrane contact site	1
mitochondrion	1
mitochondrial envelope	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 18 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
cristae formation	BP	mutant phenotype
Golgi membrane	CC	direct assay
MIB complex	CC	high-throughput assay
MICOS complex	CC	direct assay
SAM complex	CC	high-throughput assay
endoplasmic reticulum membrane	CC	direct assay
extracellular region	CC	direct assay
mitochondrial inner membrane	CC	direct assay
mitochondrion	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 961 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APOO	MTTP	P55157	855
APOO	CHCHD6	Q9BRQ6	817
APOO	CHCHD3	Q9NX63	800
APOO	MICOS13	Q5XKP0	778
APOO	MICOS10	Q5TGZ0	765
APOO	IMMT	Q16891	763
APOO	APOA1	P02647	712
APOO	APOOL	Q6UXV4	702
APOO	SAMM50	Q9Y512	658
APOO	DNAJC11	Q9NVH1	598
APOO	CHCHD5	Q9BSY4	549
APOO	MTX2	O75431	544
APOO	KLHL15	Q96M94	506
APOO	ACOT9	Q9Y305	479
APOO	APOL5	Q9BWW9	470

IntAct

BioGRID (150 interactions; top human partners by supporting records): APOOL (Affinity Capture-MS; 2 records), DNAJC11 (Proximity Label-MS; 2 records), IMMT (Proximity Label-MS; 2 records), OMA1 (Proximity Label-MS; 2 records), PARL (Proximity Label-MS; 2 records), TIMMDC1 (Affinity Capture-MS; 2 records), ABCB10 (Proximity Label-MS), ACAD9 (Proximity Label-MS), ACTR2 (Proximity Label-MS), ADCK2 (Proximity Label-MS), AFG3L2 (Proximity Label-MS), AIFM1 (Proximity Label-MS), ARHGEF2 (Proximity Label-MS), ASS1 (Proximity Label-MS), ATAD3A (Proximity Label-MS)

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
MIB complex, mitochondrial	12	MTX1, SAMM50, CHCHD3, DNAJC11, MICOS10, MTX2, MTX3, APOO, APOOL, CHCHD6, IMMT, MICOS13
MICOS complex, mitochondrial	7	CHCHD6, IMMT, MICOS10, MICOS13, APOO, APOOL, CHCHD3
MICOS subcomplex (APOO, IMMT), mitochondrial	2	APOO, IMMT

Disease & clinical

Genetic variants

Variant evidence for APOO: 115 ClinVar records (1 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

115 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	26
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
976657	NM_024122.5(APOO):c.350T>C (p.Ile117Thr)	Pathogenic	criteria provided, single submitter	2

Per-variant reference — Sugi Variant

Explore APOO’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 35 predictions of 934):

Position(s)	Effect	Δscore	Sites
X:23858640–23858641	donor_loss	1.0000	5
X:23878860	donor_gain	1.0000
X:23907692–23907693	donor_loss	1.0000	5
X:23840379–23840381	acceptor_gain	0.9900	2
X:23856383–23856384	acceptor_loss	0.9900	2
X:23856384	acceptor_gain	0.9900
X:23858734–23858735	acceptor_loss	0.9900	6
X:23858737	acceptor_gain	0.9900
X:23878913–23878914	donor_loss	0.9900	6
X:23879035–23879036	acceptor_loss	0.9900	6

AlphaMissense

332 missense substitutions predicted likely pathogenic (of 1,269 scored), across 110 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F110	7	0.846	0.959
F142	7	0.764	0.944
P152	6	0.970	0.978
W181	6	0.839	0.925
E61	6	0.793	0.910
G124	5	0.939	0.990
R113	5	0.907	0.934
K134	5	0.905	0.970
Y151	5	0.898	0.942
Y43	5	0.892	0.933
Y138	5	0.864	0.988
L40	5	0.854	0.963
R129	5	0.841	0.938
M143	5	0.797	0.968
F111	5	0.787	0.908
P112	5	0.785	0.850
G130	5	0.781	0.862
E178	5	0.775	0.918
F119	5	0.773	0.807
K135	5	0.765	0.867

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Breast Invasive Carcinoma (TCGA)	unfavorable	0.00057
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	favorable	0.000854

Disease associations

OMIM: gene MIM:300753 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
mitochondrial disease	Moderate	X-linked	2

Mondo (2): lactic acidosis (MONDO:0006040), mitochondrial disease (MONDO:0044970)

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D000140	Acidosis, Lactic	C18.452.076.176.180

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	3
bisphenol A	decreases methylation, affects cotreatment, decreases expression	2
sodium arsenite	decreases expression, increases expression	2
bisphenol S	affects expression, increases methylation	2
Benzo(a)pyrene	increases expression, increases methylation	2
bisphenol F	affects cotreatment, decreases expression	1
benzo(e)pyrene	increases methylation	1
beta-methylcholine	affects expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic	affects methylation	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Tretinoin	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Cyclosporine	increases expression	1
Acrylamide	increases expression	1
Particulate Matter	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SC98	HAP1 APOO (-) 1	Cancer cell line	Male
CVCL_SC99	HAP1 APOO (-) 2	Cancer cell line	Male
CVCL_SD00	HAP1 APOO (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 126 trials:

NCT	Phase	Status	Title
NCT03351998	Phase 4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00202228	Phase 4	COMPLETED	Lactate Metabolism Study in HIV Infected Persons
NCT01354652	Phase 4	TERMINATED	Lactic Acidosis During Entecavir(ETV)Treatment
NCT00432744	Phase 3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	Phase 3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	Phase 3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT00004490	Phase 3	COMPLETED	Phase III Randomized Study of Sodium Dichloroacetate in Children With Congenital Lactic Acidosis
NCT02398201	Phase 2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	Phase 2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	Phase 2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	Phase 2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	Phase 2	COMPLETED	The KHENERGY Study
NCT02976038	Phase 2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	Phase 2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	Phase 2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	Phase 2	COMPLETED	The KHENERGYZE Study
NCT04604548	Phase 2	COMPLETED	The KHENEREXT Study
NCT04802707	Phase 2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	Phase 2	SUSPENDED	The KHENERGYC Study
NCT05650229	Phase 2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	Phase 2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	Phase 2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	Phase 2	RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00004493	Phase 2	COMPLETED	Phase II Pilot Randomized Study of Sodium Dichloroacetate in Patients With Congenital Lactic Acidemia
NCT01973504	Phase 2	WITHDRAWN	Phase 2c Dose Comparison Study of MP4OX in Trauma
NCT02974257	Phase 2	TERMINATED	Thiamine vs. Placebo to Increase Oxygen Consumption After Cardiac Arrest
NCT00060515	Phase 1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	Phase 1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	Phase 1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	Phase 1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	Phase 1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	Phase 1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	Phase 1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	Phase 1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	Phase 1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	Phase 1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT03122678	Phase 1	WITHDRAWN	Thiamine Supplementation in Patients With Septic Shock
NCT04378075	Phase 2/3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	Phase 1/2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	Phase 1/2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	Phase 1/2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	Early Phase 1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies
NCT01264471	Not specified	COMPLETED	Mechanisms of Mitochondrial Defects in Gulf War Syndrome
NCT01301235	Not specified	COMPLETED	Defining 31Phosphorous Magnetic Resonance Spectroscopy Characteristics in Patients With Mitochondrial Myopathy
NCT01370447	Not specified	NO_LONGER_AVAILABLE	EPI-743 for Mitochondrial Respiratory Chain Diseases
NCT01694940	Not specified	RECRUITING	North American Mitochondrial Disease Consortium Patient Registry and Biorepository (NAMDC)
NCT01776918	Not specified	COMPLETED	Energy Requirements in Mitochondrial Disease
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT02000284	Not specified	ACTIVE_NOT_RECRUITING	Mitochondrial Dysfunction in Autism Spectrum Disorder
NCT02053766	Not specified	TERMINATED	Anesthesia in Patients With Mitochondrial Disease
NCT02154711	Not specified	COMPLETED	Magnetic Resonance Imaging (MRI) Muscle Phenotyping in Mitochondrial Disease
NCT02284334	Not specified	COMPLETED	Glycemic Index in Mitochondrial Disease
NCT02311257	Not specified	COMPLETED	Survey on Supplement Use in Mitochondrial Disease
NCT02375438	Not specified	COMPLETED	Nutritional Assessment in Mitochondrial Cytopathy