TIMM23

Summary

TIMM23 (translocase of inner mitochondrial membrane 23, HGNC:17312) is a protein-coding gene on chromosome 10q11.22, encoding Mitochondrial import inner membrane translocase subunit Tim23 (O14925). Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane. It is a selective cancer dependency (DepMap: 87.6% of cell lines).

The protein encoded by this gene is part of a complex located in the inner mitochondrial membrane that mediates the transport of transit peptide-containing proteins across the membrane. Multiple transcript variants, one protein-coding and others not protein-coding, have been found for this gene.

Source: NCBI Gene 100287932 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 16 total
• Cancer dependency (DepMap): dependent in 87.6% of screened cell lines
• MANE Select transcript: NM_006327

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17312
Approved symbol	TIMM23
Name	translocase of inner mitochondrial membrane 23
Location	10q11.22
Locus type	gene with protein product
Status	Approved
Aliases	TIM23
Ensembl gene	ENSG00000265354
Ensembl biotype	protein_coding
OMIM	605034
Entrez	100287932

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 15 protein_coding

ENST00000580018, ENST00000904349, ENST00000904350, ENST00000904351, ENST00000904352, ENST00000904353, ENST00000904354, ENST00000904355, ENST00000904356, ENST00000904357, ENST00000933866, ENST00000933867, ENST00000933868, ENST00000933869, ENST00000933870

RefSeq mRNA: 1 — MANE Select: NM_006327 NM_006327

CCDS: CCDS73091

Canonical transcript exons

ENST00000580018 — 7 exons

Exon	Start	End
ENSE00003442845	45972489	45972730
ENSE00003480647	45975454	45975512
ENSE00003539590	45985383	45985441
ENSE00003586231	45982523	45982616
ENSE00003641247	45988737	45988847
ENSE00003679535	45982846	45982930
ENSE00003739963	46003203	46003742

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.7995 / max 55.0864, expressed in 1670 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104792	3.0421	1593
104794	0.3121	146
205841	0.2991	125
205839	0.1462	60

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	98.84	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.63	gold quality
sperm	CL:0000019	98.31	gold quality
biceps brachii	UBERON:0001507	98.10	gold quality
heart right ventricle	UBERON:0002080	98.09	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.97	gold quality
gingiva	UBERON:0001828	97.90	gold quality
male germ cell	CL:0000015	97.86	gold quality
endothelial cell	CL:0000115	97.67	gold quality
secondary oocyte	CL:0000655	97.52	gold quality
adult organism	UBERON:0007023	97.52	gold quality
vastus lateralis	UBERON:0001379	97.44	gold quality
middle temporal gyrus	UBERON:0002771	97.27	gold quality
left ventricle myocardium	UBERON:0006566	97.26	gold quality
quadriceps femoris	UBERON:0001377	97.12	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.93	gold quality
palpebral conjunctiva	UBERON:0001812	96.80	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.79	gold quality
myocardium	UBERON:0002349	96.78	gold quality
jejunal mucosa	UBERON:0000399	96.75	gold quality
substantia nigra pars compacta	UBERON:0001965	96.74	gold quality
left testis	UBERON:0004533	96.65	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.59	gold quality
body of tongue	UBERON:0011876	96.58	gold quality
esophagus squamous epithelium	UBERON:0006920	96.57	gold quality
jejunum	UBERON:0002115	96.55	gold quality
right testis	UBERON:0004534	96.53	gold quality
oocyte	CL:0000023	96.52	gold quality
parotid gland	UBERON:0001831	96.52	gold quality
gastrocnemius	UBERON:0001388	96.49	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.61
E-MTAB-7606	no	1056.04

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 87.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 12)

• The non-bound hydrophilic domain of the human Tim23 is in a molten globule configuration with marginal stability, existing as a dimer. (PMID:22306744)
• Study establishes an unexpected molecular link between the TIM23 transport machinery and assembly of respiratory-chain complexes that regulate mitochondrial protein synthesis in response to their assembly state. (PMID:23260140)
• MCJ functions as J co-chaperone of the human TIM23 pre-protein translocase. (PMID:23263864)
• GST pull-down experiments and tryptophan fluorescence indicated that there is no interaction between Tim23IMS and Tim50IMS (PMID:23811401)
• Three distinct Tim23 complexes, namely, B1, B2, and A, are involved in the maintenance of normal mitochondrial function. (PMID:24636990)
• Modulating the sorting of nuclear-encoded proteins into mitochondria, mediated by the TIM23 complex, proves therapeutic in both yeast and patient-derived cells exhibiting ATP synthase deficiency. (PMID:25519239)
• The interaction of presequence peptides with Tim23 intermembrane space domain is weakened in presence of Ca2+ ion, which implicates that Ca2+ ion may play an important role in the protein import by TIM23 complex. (PMID:27178215)
• Data indicate the essential role of the GABP transcription factor in activating translocase of inner mitochondrial membrane 23 TIMM23 and TIMM23B expression. (PMID:29413900)
• mutant HTT specifically binds to the TIM23 subunit and that full-length wild-type huntingtin (wtHTT) and mHTT reside in the mitochondrial intermembrane space. (PMID:31346086)
• From TOM to the TIM23 complex - handing over of a precursor. (PMID:32074073)
• Mitochondrial Oxidative Stress Induces Rapid Intermembrane Space/Matrix Translocation of Apurinic/Apyrimidinic Endonuclease 1 Protein through TIM23 Complex. (PMID:33197464)
• NOX4-TIM23 interaction regulates NOX4 mitochondrial import and metabolic reprogramming. (PMID:37044213)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	timm23a	ENSDARG00000071396
danio_rerio	timm23b	ENSDARG00000100375
mus_musculus	Timm23	ENSMUSG00000013701
rattus_norvegicus	Timm23-ps8	ENSRNOG00000019811
rattus_norvegicus	Timm23b	ENSRNOG00000031285
rattus_norvegicus	Timm23	ENSRNOG00000032900
drosophila_melanogaster	Tim23	FBGN0267976
caenorhabditis_elegans	timm-23	WBGENE00008857

Paralogs (1): TIMM23B (ENSG00000204152)

Protein

Protein identifiers

Mitochondrial import inner membrane translocase subunit Tim23 — O14925 (reviewed: O14925)

All UniProt accessions (1): O14925

UniProt curated annotations — full annotation on UniProt →

Function. Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane. Has a role in the activation of stress-induced mitophagy by protecting PINK1 from OMA1-mediated degradation and facilitating its accumulation at the outer mitochondrial membrane in response to depolarization.

Subunit / interactions. Component of the TIM23 complex at least composed of TIMM23, TIMM17 (TIMM17A or TIMM17B) and TIMM50; within this complex, directly interacts with TIMM50. The complex interacts with the TIMM44 component of the PAM complex and with DNAJC15. Upon mitochondrial depolarization, interacts with PINK1; the interaction is required for PINK1 accumulation at the outer mitochondrial membrane, kinase activation by autophosphorylation and PRKN recruitment to mitochondria.

Subcellular location. Mitochondrion inner membrane.

Similarity. Belongs to the Tim17/Tim22/Tim23 family.

RefSeq proteins (1): NP_006318* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005681	Tim23	Family
IPR045238	Tim23-like	Family

Pfam: PF02466

UniProt features (6 total): transmembrane region 3, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14925-F1	59.54	0.00

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import

MSigDB gene sets: 161 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, ELVIDGE_HYPOXIA_DN, MULLIGHAN_NPM1_SIGNATURE_3_UP, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_PROTEIN_TARGETING, TGACCTY_ERR1_Q2, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_MACROAUTOPHAGY, GOCC_MITOCHONDRIAL_ENVELOPE, TIEN_INTESTINE_PROBIOTICS_24HR_UP, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_PROTEIN_TRANSMEMBRANE_TRANSPORT

GO Biological Process (5): obsolete protein targeting to mitochondrion (GO:0006626), intracellular protein transport (GO:0006886), protein import into mitochondrial matrix (GO:0030150), type 2 mitophagy (GO:0061734), protein transport (GO:0015031)

GO Molecular Function (3): transmembrane protein transporter activity (GO:0008320), protein binding (GO:0005515), transmembrane transporter activity (GO:0022857)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), TIM23 mitochondrial import inner membrane translocase complex (GO:0005744), mitochondrial intermembrane space (GO:0005758), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular protein localization	2
protein transport	1
intracellular transport	1
protein transmembrane import into intracellular organelle	1
protein localization to mitochondrion	1
import into the mitochondrion	1
mitochondrial protein import pathway	1
mitophagy	1
transport	1
establishment of protein localization	1
macromolecule transmembrane transporter activity	1
protein transmembrane transport	1
protein transporter activity	1
binding	1
transporter activity	1
transmembrane transport	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
inner mitochondrial membrane protein complex	1
mitochondrial envelope	1
organelle envelope lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1688 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIMM23	TIMM17A	Q99595	988
TIMM23	TIMM17B	O60830	984
TIMM23	TIMM50	Q3ZCQ8	979
TIMM23	TIMM13	P62206	945
TIMM23	TOMM20	Q15388	932
TIMM23	TIMM9	Q9Y5J7	904
TIMM23	TIMM8A	O60220	903
TIMM23	TOMM40	O96008	884
TIMM23	TIMM10	P62072	882
TIMM23	TOMM22	Q9NS69	876
TIMM23	SLC25A13	Q9UJS0	856
TIMM23	TIMM44	O43615	849
TIMM23	TIMM22	Q9Y584	838
TIMM23	SLC25A12	O75746	829
TIMM23	TIMM21	Q9BVV7	813

IntAct

119 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TIMM17B	TIMM23	psi-mi:“MI:0914”(association)	0.670
TIMM23	TIMM17B	psi-mi:“MI:0915”(physical association)	0.670
TIMM23	TSPAN8	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	SLC16A7	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	TMEM88	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	TMEM86B	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	FAM210B	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	EBP	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	TLCD4	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	GOLT1A	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	AQP6	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	SCN3B	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	JAGN1	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	FXYD3	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	LAMP2	psi-mi:“MI:0915”(physical association)	0.560
TIMM23	SH3GLB1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (102): TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-Western), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS), TIMM23 (Affinity Capture-MS)

ESM2 similar proteins: A2RVP7, A2VDV9, A4IFL0, O14925, O35093, O35094, O35857, O43615, O60830, P0CR88, P0CR89, P59670, Q02921, Q2HJE9, Q2KHV4, Q2UAP8, Q38820, Q3B8P0, Q3ZBE6, Q4V8S3, Q5BIN4, Q5M7K0, Q5R5H4, Q5RDD0, Q5REX0, Q5SRD1, Q5U4F4, Q5U4U5, Q5XH94, Q5XJY4, Q5ZLL0, Q6BZY4, Q6GQ39, Q6INU6, Q6NWD4, Q7T2P6, Q86UB9, Q9C1E8, Q9CQ85, Q9CYV5

Diamond homologs: A4IFL0, O14925, O35093, Q5RDD0, Q5SRD1, Q5XH94, Q6INU6, Q7T2P6, Q9S837, Q9USM7, Q9WTQ8, Q38820, Q9LNQ1, P32897

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TIMM23	“form complex”	“TIM23 complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	11
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1209 predictions. Top by Δscore:

Variant	Effect	Δscore
10:45972727:CCGC:C	donor_gain	1.0000
10:45972729:C:CA	donor_gain	1.0000
10:45972729:CG:C	donor_gain	1.0000
10:45972729:CGCG:C	donor_gain	1.0000
10:45972729:GC:G	donor_gain	1.0000
10:45972730:A:AC	donor_gain	1.0000
10:45972731:G:GG	donor_gain	1.0000
10:45975451:C:CC	acceptor_gain	1.0000
10:45975454:TTA:T	acceptor_gain	1.0000
10:45975455:GTTA:G	acceptor_gain	1.0000
10:45982520:C:CC	acceptor_gain	1.0000
10:45982520:CTA:C	acceptor_loss	1.0000
10:45982521:CC:C	acceptor_gain	1.0000
10:45982522:TC:T	acceptor_gain	1.0000
10:45982615:C:CC	donor_gain	1.0000
10:45982615:CCT:C	donor_gain	1.0000
10:45982615:CCTGT:C	donor_gain	1.0000
10:45982616:A:AC	donor_gain	1.0000
10:45982617:CA:C	donor_loss	1.0000
10:45982618:TCAC:T	donor_loss	1.0000
10:45982929:C:CA	donor_gain	1.0000
10:45982929:CTGTA:C	donor_gain	1.0000
10:45982930:A:AC	donor_gain	1.0000
10:45988734:C:CC	acceptor_gain	1.0000
10:45988738:AAAG:A	acceptor_gain	1.0000
10:45988739:CAAAG:C	acceptor_gain	1.0000
10:45972726:CCCGC:C	donor_gain	0.9900
10:45972728:CGC:C	donor_gain	0.9900
10:45972729:CGC:C	donor_gain	0.9900
10:45972729:CGCGG:C	donor_gain	0.9900

AlphaMissense

1332 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:45982858:G:A	G91D	1.000
10:45982535:T:C	F60L	0.999
10:45982537:T:A	F60L	0.999
10:45982537:T:G	F60L	0.999
10:45982599:G:A	G81E	0.999
10:45982604:T:C	C83R	0.999
10:45982616:G:A	G87R	0.999
10:45982616:G:C	G87R	0.999
10:45982616:G:T	G87W	0.999
10:45982846:G:A	G87E	0.999
10:45982857:G:C	G91R	0.999
10:45982870:G:A	G95D	0.999
10:45985432:G:C	G132R	0.999
10:45985433:G:A	G132D	0.999
10:45988748:A:C	S139R	0.999
10:45988750:T:A	S139R	0.999
10:45988750:T:G	S139R	0.999
10:45988812:C:A	A160D	0.999
10:45988814:G:A	G161R	0.999
10:45988814:G:C	G161R	0.999
10:45988815:G:A	G161E	0.999
10:45988827:G:A	G165D	0.999
10:45975484:T:C	L46S	0.998
10:45982539:T:C	I61T	0.998
10:45982578:A:T	E74V	0.998
10:45982581:T:C	L75P	0.998
10:45982584:C:A	A76D	0.998
10:45982596:T:A	I80N	0.998
10:45982598:G:A	G81R	0.998
10:45982598:G:C	G81R	0.998

dbSNP variants (sampled 300 via entrez): RS1001390892 (10:46000250 C>A,T), RS1002799759 (10:45999112 C>A), RS1003062577 (10:45999267 A>G), RS1003335082 (10:46003880 C>T), RS1003393807 (10:45998169 C>T), RS1003449167 (10:45998373 T>C), RS1005008573 (10:45999316 A>G,T), RS1005183697 (10:45998391 G>A), RS1005259959 (10:45999452 C>T), RS1005277512 (10:46004192 G>C), RS1005705870 (10:46003901 C>G), RS1005752259 (10:45998200 C>A,T), RS1006042724 (10:46002611 C>A,T), RS1006952849 (10:46002860 G>A,T), RS1007703681 (10:46000996 T>C)

Disease associations

OMIM: gene MIM:605034 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000585_12	Mean corpuscular volume	7.000000e-09
GCST000587_13	Mean corpuscular hemoglobin	6.000000e-10
GCST002890_7	Prostate cancer	1.000000e-15
GCST003586_4	Prostate cancer	6.000000e-10
GCST007830_2	Anti-thyroid peroxidase (TPOAb) levels in Hashimoto’s thyroiditis	1.000000e-06
GCST007851_9	Anti-thyroid peroxidase (TPOAb) and anti-thyroglobulin (TgAb) levels in Hashimoto’s thyroiditis	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases expression, increases abundance, affects cotreatment	3
sodium arsenite	increases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Carbonyl Cyanide m-Chlorophenyl Hydrazone	decreases expression, increases reaction, affects cotreatment, decreases reaction, increases degradation	2
bisphenol A	decreases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	affects cotreatment, decreases reaction, increases degradation, increases reaction	1
afimoxifene	decreases expression, decreases reaction	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
Decitabine	affects expression	1
Acetylcysteine	affects cotreatment, decreases reaction, increases degradation	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Cadmium	increases expression	1
Cisplatin	affects expression	1
Diethylhexyl Phthalate	affects cotreatment, increases degradation	1
Chlorpyrifos	decreases expression	1
Estrogens	decreases expression, decreases reaction	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Hydrogen Peroxide	affects expression	1
Ivermectin	increases expression	1
Oxygen	decreases expression	1
Piroxicam	increases expression	1
Plant Extracts	increases expression, affects cotreatment	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1661	ZR-75-30	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.