TIMM21

Summary

TIMM21 (translocase of inner mitochondrial membrane 21, HGNC:25010) is a protein-coding gene on chromosome 18q22.3, encoding Mitochondrial import inner membrane translocase subunit Tim21 (Q9BVV7). Participates in the translocation of transit peptide-containing proteins across the mitochondrial inner membrane.

Involved in mitochondrial cytochrome c oxidase assembly; mitochondrial respiratory chain complex I assembly; and protein import into mitochondrial matrix. Located in mitochondrion. Part of TIM23 mitochondrial import inner membrane translocase complex.

Source: NCBI Gene 29090 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 43 total
• MANE Select transcript: NM_014177

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25010
Approved symbol	TIMM21
Name	translocase of inner mitochondrial membrane 21
Location	18q22.3
Locus type	gene with protein product
Status	Approved
Aliases	HSPC154, TIM21
Ensembl gene	ENSG00000075336
Ensembl biotype	protein_coding
OMIM	615180
Entrez	29090

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 3 retained_intron

ENST00000169551, ENST00000577952, ENST00000579071, ENST00000580087, ENST00000581467, ENST00000584925, ENST00000867086, ENST00000867087, ENST00000927805, ENST00000927806, ENST00000927807, ENST00000927808

RefSeq mRNA: 1 — MANE Select: NM_014177 NM_014177

CCDS: CCDS12003

Canonical transcript exons

ENST00000169551 — 6 exons

Exon	Start	End
ENSE00000908745	74155306	74155403
ENSE00001102320	74158376	74160531
ENSE00002703684	74148523	74149109
ENSE00003496598	74158171	74158276
ENSE00003543112	74155145	74155207
ENSE00003655723	74158014	74158087

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 98.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.4447 / max 354.5567, expressed in 1785 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
170740	18.2911	1779
170741	0.9986	606
170742	0.1550	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	98.76	gold quality
myocardium	UBERON:0002349	98.34	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.26	gold quality
vastus lateralis	UBERON:0001379	97.72	gold quality
quadriceps femoris	UBERON:0001377	97.57	gold quality
heart right ventricle	UBERON:0002080	97.51	gold quality
deltoid	UBERON:0001476	97.26	gold quality
epithelial cell of pancreas	CL:0000083	97.20	gold quality
cardiac ventricle	UBERON:0002082	96.99	gold quality
heart left ventricle	UBERON:0002084	96.99	gold quality
tibialis anterior	UBERON:0001385	96.93	gold quality
biceps brachii	UBERON:0001507	96.74	gold quality
cardiac atrium	UBERON:0002081	96.65	gold quality
right atrium auricular region	UBERON:0006631	96.54	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.51	gold quality
germinal epithelium of ovary	UBERON:0001304	96.33	gold quality
apex of heart	UBERON:0002098	96.31	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.30	gold quality
endothelial cell	CL:0000115	96.25	gold quality
skeletal muscle tissue	UBERON:0001134	96.18	gold quality
heart	UBERON:0000948	96.14	gold quality
parietal pleura	UBERON:0002400	95.97	gold quality
esophagus squamous epithelium	UBERON:0006920	95.97	gold quality
skeletal muscle organ	UBERON:0014892	95.88	gold quality
muscle tissue	UBERON:0002385	95.79	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.75	gold quality
body of tongue	UBERON:0011876	95.64	gold quality
muscle of leg	UBERON:0001383	95.61	gold quality
secondary oocyte	CL:0000655	95.57	gold quality
gastrocnemius	UBERON:0001388	95.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	6.89
E-ANND-3	yes	5.34

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting TIMM21, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-4999-5P	99.35	69.15	926
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-6871-5P	98.90	66.67	671
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-8060	98.61	66.93	1187
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-4277	98.34	67.17	1323
HSA-MIR-3166	98.24	66.63	1223
HSA-MIR-30C-1-3P	97.80	66.36	1499

Literature-anchored findings (GeneRIF, showing 1)

• TIM21 is dispensable for protein import but required for integration of early-assembling, presequence-containing subunits into respiratory-chain intermediates. (PMID:23260140)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	timm21	ENSDARG00000071594
mus_musculus	Timm21	ENSMUSG00000024645
rattus_norvegicus	Timm21	ENSRNOG00000015142
drosophila_melanogaster	CG7382	FBGN0031708
caenorhabditis_elegans		WBGENE00018934

Protein

Protein identifiers

Mitochondrial import inner membrane translocase subunit Tim21 — Q9BVV7 (reviewed: Q9BVV7)

Alternative names: TIM21-like protein, mitochondrial

All UniProt accessions (4): Q9BVV7, A8K1K8, J3KRJ3, J3QRI1

UniProt curated annotations — full annotation on UniProt →

Function. Participates in the translocation of transit peptide-containing proteins across the mitochondrial inner membrane. Also required for assembly of mitochondrial respiratory chain complex I and complex IV as component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex. Probably shuttles between the presequence translocase and respiratory-chain assembly intermediates in a process that promotes incorporation of early nuclear-encoded subunits into these complexes.

Subunit / interactions. Component of the TIM23 complex. Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, the core components of this complex being COA3/MITRAC12 and COX14. Interacts with COA3 and MT-CO1/COX1.

Subcellular location. Mitochondrion membrane.

Similarity. Belongs to the TIM21 family.

RefSeq proteins (1): NP_054896* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013261	Tim21	Family
IPR038552	Tim21_IMS_sf	Homologous_superfamily

Pfam: PF08294

UniProt features (6 total): transit peptide 1, chain 1, transmembrane region 1, region of interest 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BVV7-F1	73.37	0.37

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 144 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, WEI_MYCN_TARGETS_WITH_E_BOX, WCTCNATGGY_UNKNOWN, GOCC_MITOCHONDRIAL_ENVELOPE, DODD_NASOPHARYNGEAL_CARCINOMA_UP, chr18q22, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_PROTEIN_TRANSMEMBRANE_TRANSPORT, MARTINEZ_RESPONSE_TO_TRABECTEDIN_DN, ZHANG_BREAST_CANCER_PROGENITORS_UP

GO Biological Process (5): intracellular protein transport (GO:0006886), protein import into mitochondrial matrix (GO:0030150), mitochondrial respiratory chain complex I assembly (GO:0032981), mitochondrial respiratory chain complex IV assembly (GO:0033617), protein transport (GO:0015031)

GO Molecular Function (2): molecular_function (GO:0003674), protein binding (GO:0005515)

GO Cellular Component (6): 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), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein localization	1
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular protein localization	2
mitochondrial respiratory chain complex assembly	2
mitochondrion	2
mitochondrial envelope	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
NADH dehydrogenase complex assembly	1
respiratory chain complex IV assembly	1
transport	1
establishment of protein localization	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
inner mitochondrial membrane protein complex	1
organelle envelope lumen	1
cellular anatomical structure	1
organelle membrane	1

Protein interactions and networks

STRING

1664 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIMM21	TIMM50	Q3ZCQ8	987
TIMM21	TIMM17A	Q99595	983
TIMM21	TOMM22	Q9NS69	922
TIMM21	TIMM44	O43615	910
TIMM21	DNAJC19	Q96DA6	890
TIMM21	PAM16	Q9Y3D7	879
TIMM21	TOMM70	O94826	822
TIMM21	TIMM23	O14925	813
TIMM21	ROMO1	P60602	798
TIMM21	TIMM9	Q9Y5J7	773
TIMM21	HSPA9	P30036	766
TIMM21	TOMM7	Q9P0U1	716
TIMM21	TOMM40	O96008	690
TIMM21	SAMM50	Q9Y512	671
TIMM21	TIMM10	P62072	667

IntAct

51 interactions, top by confidence:

A	B	Type	Score
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
COA3	MT-CO1	psi-mi:“MI:0914”(association)	0.610
TIMM21	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
GRK7	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
TIMM21	TIMM23	psi-mi:“MI:0915”(physical association)	0.500
TIMM21	TIMM23	psi-mi:“MI:0914”(association)	0.500
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
TIMM21	EMG1	psi-mi:“MI:0915”(physical association)	0.400
PB1	HAX1	psi-mi:“MI:0914”(association)	0.350
MAD2L2		psi-mi:“MI:0914”(association)	0.350
DND1	RPSA2	psi-mi:“MI:0914”(association)	0.350
NMES1	NDUFS8	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NUDT19	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NDUFS8	psi-mi:“MI:0914”(association)	0.350
MAIP1	COQ9	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	SURF4	psi-mi:“MI:0914”(association)	0.350
TAGLN	LOC392647	psi-mi:“MI:0914”(association)	0.350
EPHA2	MYO1C	psi-mi:“MI:0914”(association)	0.350
ERBB2	ILVBL	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
SLC19A2	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC39A11	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (59): TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS), TIMM21 (Affinity Capture-MS)

ESM2 similar proteins: A3KN05, A4IG66, B5DFG1, D3Z8X7, D4A4K3, O35144, O75182, P0DKR2, P82649, P82650, Q15554, Q28C41, Q3SZV6, Q3V0L5, Q5F479, Q5PPN7, Q5R8S0, Q5REP2, Q5RFI6, Q5TC12, Q5U2X7, Q6AY04, Q6IRU7, Q6P1H6, Q6PCG6, Q6ZNE5, Q7L8L6, Q7TP65, Q811I0, Q86XL3, Q8BHE8, Q8BM55, Q8C008, Q8CDJ3, Q8K1S6, Q8N163, Q8N9B5, Q8TF30, Q8VDP4, Q8WWC4

Diamond homologs: Q1G3L1, Q3SZV6, Q5XKA2, Q7S8S5, Q8CCM6, Q9BVV7, Q5REP2, Q5U2X7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TIMM21	“form complex”	“MITRAC complex”	binding
TIMM21	“form complex”	“TIM23 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 57 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Complex IV assembly	5	31.7×	1e-04
Respiratory electron transport	5	13.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

838 predictions. Top by Δscore:

Variant	Effect	Δscore
18:74158243:G:T	donor_gain	1.0000
18:74158252:A:T	donor_gain	1.0000
18:74158008:CTGCA:C	acceptor_loss	0.9900
18:74158009:TGCA:T	acceptor_loss	0.9900
18:74158010:GCAGG:G	acceptor_loss	0.9900
18:74158011:CAG:C	acceptor_loss	0.9900
18:74158165:CGACA:C	acceptor_loss	0.9900
18:74158166:GACA:G	acceptor_loss	0.9900
18:74158167:ACAG:A	acceptor_loss	0.9900
18:74158168:CAG:C	acceptor_loss	0.9900
18:74158265:C:T	donor_gain	0.9900
18:74158229:GGCTC:G	donor_gain	0.9800
18:74158243:G:GT	donor_gain	0.9800
18:74155221:GCAA:G	donor_gain	0.9700
18:74155225:G:GG	donor_gain	0.9700
18:74158169:A:AG	acceptor_gain	0.9700
18:74158170:G:GG	acceptor_gain	0.9700
18:74158251:G:GT	donor_gain	0.9700
18:74158274:G:GT	donor_gain	0.9700
18:74158013:GGT:G	acceptor_gain	0.9600
18:74158256:GT:G	donor_gain	0.9600
18:74158374:A:AG	acceptor_gain	0.9600
18:74158375:G:GG	acceptor_gain	0.9600
18:74158083:GTCAG:G	donor_loss	0.9500
18:74158084:TCAG:T	donor_loss	0.9500
18:74158085:CAGGT:C	donor_loss	0.9500
18:74158086:AG:A	donor_loss	0.9500
18:74158087:G:GT	donor_loss	0.9500
18:74158088:G:T	donor_loss	0.9500
18:74158089:T:C	donor_loss	0.9500

AlphaMissense

1593 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:74158217:T:C	F195L	0.994
18:74158219:C:A	F195L	0.994
18:74158219:C:G	F195L	0.994
18:74158218:T:C	F195S	0.985
18:74158224:T:A	I197N	0.982
18:74155386:T:C	C149R	0.979
18:74155306:G:A	G122D	0.978
18:74155388:C:G	C149W	0.975
18:74155193:G:A	G117E	0.974
18:74158416:T:A	V228E	0.969
18:74155374:G:C	A145P	0.966
18:74158257:T:A	V208E	0.965
18:74155198:A:C	S119R	0.964
18:74155200:C:A	S119R	0.964
18:74155200:C:G	S119R	0.964
18:74155181:T:A	V113E	0.963
18:74158410:T:A	I226K	0.961
18:74158218:T:G	F195C	0.960
18:74155375:C:A	A145D	0.958
18:74155207:G:C	G122R	0.954
18:74155184:T:A	V114E	0.953
18:74158251:G:A	G206E	0.952
18:74158015:T:A	V155E	0.951
18:74158250:G:A	G206R	0.948
18:74158250:G:C	G206R	0.948
18:74155192:G:A	G117R	0.946
18:74155192:G:C	G117R	0.946
18:74158452:T:A	I240N	0.945
18:74155205:C:A	T121K	0.944
18:74158212:T:A	V193E	0.942

dbSNP variants (sampled 300 via entrez): RS1000194548 (18:74147177 C>G), RS1000227084 (18:74147932 C>G,T), RS1000265302 (18:74149885 C>A,T), RS1000474573 (18:74147923 A>C,G,T), RS1000599469 (18:74151125 C>T), RS1000829340 (18:74147189 C>A), RS1001155304 (18:74146844 T>C), RS1001409119 (18:74159164 G>A,T), RS1001729239 (18:74149615 C>G,T), RS1001956261 (18:74156277 G>A,T), RS1002009342 (18:74150473 A>C,G), RS1002022795 (18:74154874 T>A,C), RS1002120591 (18:74159475 C>G), RS1002399764 (18:74153056 T>C), RS1002401942 (18:74159749 T>A)

Disease associations

OMIM: gene MIM:615180 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Leflunomide	decreases expression	2
aristolochic acid I	decreases expression	1
afuresertib	decreases expression	1
dicrotophos	decreases expression	1
bisphenol A	decreases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Coumestrol	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Folic Acid	decreases expression	1
Phthalic Acids	decreases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Testosterone	affects cotreatment, decreases expression	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

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