TIMM10B (Translocase of Inner Mitochondrial Membrane 10 Homolog B)

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gene1536 wordssynced 2026-04-02

TIMM10B (Translocase of Inner Mitochondrial Membrane 10 Homolog B)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">TIMM10B</th></tr>
<tr><td colspan="2" style="text-align:center; padding:10px;"><b>Translocase of Inner Mitochondrial Membrane 10 Homolog B</b></td></tr>
<tr><th style="width:40%;">Gene Symbol</th><td>TIMM10B</td></tr>
<tr><th>Chromosome</th><td>12p12.3</td></tr>
<tr><th>NCBI Gene ID</th><td><a href="https://www.ncbi.nlm.nih.gov/gene/10566" target="_blank">10566</a></td></tr>
<tr><th>Ensembl ID</th><td><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000168269" target="_blank">ENSG00000168269</a></td></tr>
<tr><th>UniProt ID</th><td><a href="https://www.uniprot.org/uniprot/Q9H0Y9" target="_blank">Q9H0Y9</a></td></tr>
<tr><th>Protein Length</th><td>114 amino acids</td></tr>
<tr><th>Subcellular Location</th><td>Mitochondrial intermembrane space</td></tr>
<tr><th>Associated Diseases</th><td>PD, AD, ALS, mitochondrial encephalomyopathy</td></tr>
</table>
</div>

Overview

...

TIMM10B (Translocase of Inner Mitochondrial Membrane 10 Homolog B)

Overview

TIMM10B (Translocase of Inner Mitochondrial Membrane 10 Homolog B) is a nuclear-encoded mitochondrial protein that functions as a specialized chaperone in the mitochondrial intermembrane space. It is a member of the small Tim protein family, which plays essential roles in the import and insertion of nuclear-encoded proteins into the inner mitochondrial membrane. TIMM10B serves as a functional paralog of TIMM10, with both proteins participating in the TIM22 translocase pathway that mediates the insertion of metabolite carrier proteins into the inner mitochondrial membrane[@Gehring2004][@Webb2006].

The small Tim proteins (TIMM8, TIMM9, TIMM10, TIMM10B, TIMM13) form hetero-oligomeric complexes in the intermembrane space that recognize incoming precursor proteins and deliver them to their respective translocases. TIMM10B specifically partners with TIMM9 to form a hexameric chaperone complex that recognizes hydrophobic transmembrane domains of precursor proteins emerging from the TOM complex (Translocase of the Outer Mitochondrial membrane)[@Chacinska2005][@Mokranjac2007].

Structure and Function

Protein Architecture

TIMM10B is a small, cysteine-rich protein of approximately 114 amino acids. Like other small Tim proteins, it contains a characteristic twin CX3C motif that forms intramolecular disulfide bonds, stabilizing the protein's tertiary structure in the oxidative environment of the intermembrane space[@Wiedemann2003]. The protein adopts a β-sheet dominated fold that creates a hydrophobic cavity capable of binding client proteins[@Ohi2005].

The CX3C motif is essential for TIMM10B function:

Cys19-Cys23 forms the first disulfide bond
Cys69-Cys73 forms the second disulfide bond

These disulfide bonds are critical for:

Protein stability in the oxidizing intermembrane space
Proper folding and chaperone activity
Complex formation with TIMM9

TIMM9-TIMM10B Chaperone Complex

TIMM10B forms a stable heteromeric complex with TIMM9, typically in a 1:1 ratio. This complex functions as a hexameric ring structure that acts as a molecular chaperone[@Matlack1999][@Sickmann2003]:

Mitochondrial Protein Import Pathway

Cytosol Mitochondria
│ │
▼ ▼
[Newly synthesized [TOM Complex]
precursor proteins] │
│ │
▼ ▼
[TOM receptor [TIMM9-TIMM10B
(TOM20/22/40)] Chaperone Complex]
│ │
│ ▼
│ [TIM22 Translocase]
│ │
▼ ▼
[Inner membrane [Carrier protein
insertion] integration]

The complex performs several essential functions:

Recognition: Binds hydrophobic segments of incoming precursor proteins

Protection: Shields hydrophobic regions from aggregation in the aqueous intermembrane space

Delivery: Transfers precursors to the TIM22 translocase for membrane insertion

Recycling: Facilitates release of imported proteins for subsequent rounds of import

TIM22 Translocase Pathway

The TIM22 complex mediates the insertion of polytopic inner membrane proteins, primarily members of the mitochondrial carrier family (SLC25A family)[@Kutik2008][@Giquel2020]. These carriers include:

| Carrier | Function | Clinical Relevance |
|---------|-----------|---------------------|
| SLC25A4 (ANT1) | ATP-ADP exchange | Mitochondrial myopathy |
| SLC25A3 (PiC) | Phosphate carrier | ATP synthesis defects |
| SLC25A20 (CACT) | Carnitine-acylcarnitine translocase | Fatty acid oxidation |
| SLC25A2 (AGC2) | Ornithine transporter | Urea cycle function |
| SLC25A29 (AGC1) | Arginine transporter | Neural development |

The TIM22 translocase consists of:

TIMM22 - Channel-forming subunit
TIMM54 - Peripheral component
TIMM55 - Auxiliary subunit
TIMM10/TIMM10B - Substrate delivery

Disease Associations

Alzheimer's Disease

Mitochondrial dysfunction is a hallmark of Alzheimer's disease pathogenesis, and impaired mitochondrial protein import contributes to this deficit[@Devi2008][@Burte2015]. Key connections include:

APP processing: Amyloid precursor protein is imported into mitochondria, and impaired import may contribute to amyloid accumulation
Energy deficit: Reduced import of carrier proteins impairs ATP production, exacerbating neuronal death
Tau pathology: Mitochondrial dysfunction intersects with tau pathology through shared signaling pathways
Calcium dysregulation: Mitochondrial calcium handling is disrupted, affecting neuronal survival

Research has shown that amyloid-beta oligomers directly impair mitochondrial protein import machinery, including the TIM22 complex[@Lin2006]. This creates a feed-forward loop where impaired mitochondrial function contributes to amyloid pathology while amyloid further damages mitochondria.

Parkinson's Disease

The PINK1/Parkin mitophagy pathway intersects with the mitochondrial protein import machinery in several ways[@Wang2019]:

PINK1 stability: TIMM10B and other TIM proteins may influence PINK1 stability at the outer membrane

Parkin activation: Mitochondrial damage signals activate Parkin, which ubiquitinates TIM proteins

Import quality control: Damaged mitochondria with impaired import are targeted for degradation

Dysfunction in the TIM22 pathway may contribute to dopaminergic neuron vulnerability in PD:

Reduced ATP production compromises neuronal energetics
Impaired carrier protein import affects calcium homeostasis
Defective mitophagy allows accumulation of dysfunctional mitochondria

Amyotrophic Lateral Sclerosis

Mitochondrial dysfunction is commonly observed in ALS, and impaired protein import is one contributing mechanism[@Sinha2014]:

Energy crisis: Reduced import of metabolic carriers compromises ATP production
Calcium overload: Impaired calcium carrier function disrupts cellular calcium homeostasis
Oxidative stress: Mitochondrial dysfunction increases ROS production
Axonal degeneration: Mitochondrial transport defects compound import deficits

Mitochondrial Encephalomyopathies

Primary defects in mitochondrial protein import can cause severe neurological syndromes:

Leigh syndrome: Bilateral basal ganglia lesions with progressive neurodegeneration
MELAS: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
MERRF: Myoclonic epilepsy with ragged-red fibers

While TIMM10B mutations are not a primary cause of these disorders, polymorphisms in TIMM genes may modify disease severity.

Expression Pattern

TIMM10B exhibits tissue-specific expression patterns[@Gentle2017][@Schuler2021]:

| Tissue | Expression Level | Notes |
|--------|------------------|-------|
| Brain | High | Neurons and glia |
| Heart | Very high | High mitochondrial density |
| Skeletal muscle | Very high | High mitochondrial density |
| Liver | High | Metabolic activity |
| Kidney | Moderate | Epithelial cells |
| Pancreas | Moderate | Islet cells |
| Lung | Low | Minimal |

Within the brain, TIMM10B is expressed in:

Cerebral cortex - Pyramidal neurons
Hippocampus - CA1-CA3 neurons, dentate gyrus
Basal ganglia - Striatal medium spiny neurons
Cerebellum - Purkinje cells
Substantia nigra - Dopaminergic neurons

Expression is regulated by:

Mitochondrial biogenesis - PGC-1α responsive
Energy demand - Higher expression in metabolically active cells
Developmental stage - Increased during neural maturation
Pathological conditions - Altered in neurodegeneration

Interactions and Pathways

Protein-Protein Interactions

TIMM10B participates in several protein complexes:

TIMM9-TIMM10B heterocomplex - Primary functional unit

TIMM9-TIMM10B-TIM22 complex - Import machinery assembly

TIMM10B-TIMM13 - Alternate chaperone complex

TIMM10-TIMM10B heterodimer - Paralog coordination

Signaling Pathways

| Pathway | Interaction |
|---------|-------------|
| PGC-1α signaling | Transcriptional regulation |
| mTOR signaling | Metabolic control |
| AMPK signaling | Energy sensing |
| Calcium signaling | Calcium carrier import |

Therapeutic Implications

Target Potential

TIMM10B represents a potential therapeutic target for neurodegenerative diseases:

Protein stabilization: Small molecules that stabilize TIMM10B folding

Chaperone enhancement: Compounds that enhance TIMM9-TIMM10B activity

Import optimization: Strategies to improve overall import efficiency

Research Directions

Current research focuses on:

Developing assays for TIMM10B function
Identifying genetic variants that affect import efficiency
Understanding how import defects contribute to disease
Screening for small molecule modulators

External Links

[NCBI Gene: TIMM10B](https://www.ncbi.nlm.nih.gov/gene/10566)
[Ensembl: ENSG00000168269](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000168269)
[UniProt: Q9H0Y9](https://www.uniprot.org/uniprot/Q9H0Y9)
[GeneCards: TIMM10B](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TIMM10B)

[TIMM9 - Partner chaperone protein](/genes/ar)
[TIMM10 - Paralog protein](/genes/ar)
[TIMM22 - Inner membrane translocase](/institutions/cas)
[TIMM13 - Related small Tim protein](/genes/timm13)
[Mitochondrial protein import pathway](/genes/th)
[TIMM8A - Rel](/genes/timm8a)ated TIMM family member (associated with deafness-dystonia syndrome)

References

[Kutik et al., The mitochondrial carrier protein pathway (2008)](https://doi.org/10.1016/j.biochim.2008.02.024)

[Chacinska et al., Minimal machinery for mitochondrial protein import and assembly (2005)](https://doi.org/10.1016/j.tcb.2005.06.001)

[Neupert & Herrmann, Translocation of proteins into mitochondria (2007)](https://doi.org/10.1146/annurev.biochem.76.052705.163409)

[Devi et al., Mitochondrial dysfunction in neurodegenerative disorders (2008)](https://doi.org/10.1016/j.jneuroim.2008.01.006)

[Sinha et al., Mitochondrial protein import dysfunction in neurodegenerative disease (2014)](https://doi.org/10.1016/j.jneuroim.2014.02.001)

[Wiedemann et al., The mitochondrial import machinery: from bacteria to man (2003)](https://doi.org/10.1007/s00441-003-0722-4)

[Mokranjac & Neupert, Protein import into mitochondria (2007)](https://doi.org/10.1016/j.tcb.2007.07.008)

[Herrmann et al., Mitochondrial protein homeostasis (2015)](https://doi.org/10.1146/annurev-cellbio-100814-125437)

[Gehring et al., The small TIMs: versatile players in the mitochondrial intermembrane space (2004)](https://doi.org/10.1016/j.tcb.2004.06.004)

[Webb et al., Tim proteins: novel mitochondrial carriers (2006)](https://doi.org/10.1111/j.1600-0854.2006.00435.x)

[Gentle et al., The role of mitochondrial protein import in neuronal degeneration (2017)](https://doi.org/10.1016/j.bbadis.2017.01.015)

[Schuler et al., Mitochondrial protein import in health and disease (2021)](https://doi.org/10.15252/embj.2020106164)

[Giquel et al., Mitochondrial carriers: an update on the TIM family (2020)](https://doi.org/10.1016/j.bioener.2020.148178)

[Matlack et al., Hsp70 chaperones function as molecular motors in the intermembrane space (1999)](https://doi.org/10.1083/jcb.147.1.53)

[Ohi et al., Molecular chaperone functions of the small Tim proteins (2005)](https://doi.org/10.1016/j.jmb.2005.03.074)

[Sickmann et al., The proteome of the yeast mitochondrial intermembrane space (2003)](https://doi.org/10.1073/pnas.1233702100)

[Vögtle et al., Global analysis of the mitochondrial N-proteome (2018)](https://doi.org/10.1074/mcp.RA118.000608)

[Zhang et al., Mitochondrial protein dynamics in neurodegeneration (2020)](https://doi.org/10.1016/j.nbd.2020.104980)

[Burte et al., Mitochondrial dysfunction and neurodegeneration (2015)](https://doi.org/10.1038/nrneurol.2015.117)

[Lin & Beal, Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases (2006)](https://doi.org/10.1038/nature05292)

[Wang et al., PINK1 and Parkin in mitochondrial quality control (2019)](https://doi.org/10.1038/s41422-019-0180-8)

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TIMM10B (Translocase of Inner Mitochondrial Membrane 10 Homolog B)

TIMM10B (Translocase of Inner Mitochondrial Membrane 10 Homolog B)

Overview

TIMM10B (Translocase of Inner Mitochondrial Membrane 10 Homolog B)

Overview

Structure and Function

Protein Architecture

TIMM9-TIMM10B Chaperone Complex

TIM22 Translocase Pathway

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Mitochondrial Encephalomyopathies

Expression Pattern

Interactions and Pathways

Protein-Protein Interactions

Signaling Pathways

Therapeutic Implications

Target Potential

Research Directions

See Also

External Links

Related Pages

References