Mitochondrial trifunctional protein

Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, LCHAD deficiency

Mitochondrial trifunctional protein (MTP) is a protein attached to the inner mitochondrial membrane which catalyzes three out of the four steps in beta oxidation. MTP is a hetero-octamer composed of four alpha and four beta subunits:

* HADHA
* HADHB

The three functions are 2-enoyl coenzyme A (CoA) hydratase, long-chain 3-hydroxy acyl-coenzyme A dehydrogenase and long-chain 3-ketoacyl CoA thiolase.[1]

## Association with the electron transport chain[edit]

Fatty acid beta-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two major metabolism pathways in the mitochondria. Reducing equivalents from FAO enter OXPHOS at the level of Complexes I and III. In 2010, Wang et al. discovered a functional and physical association between MTP and ETC respirasomes. Not only does MTP appear to be bound to Complex I, but it also appears to channel substrates between the two enzymes.[2] This is especially interesting, because up until then it was unknown exactly how MTP was associated with the inner mitochondrial membrane, and this discovery may provide the explanation.

## Hormonal influences[edit]

Recent research has revealed that MTP can be affected by various hormones, via hormone receptors located in the mitochondria. Chochron et al. (2012) demonstrated that thyroid hormone stimulates mitochondrial metabolism in a pathway mediated by MTP.[3] Zhou et al. (2012) used 2D gel electrophoresis and mass spectrometry to identify MTP as one of the proteins that interacts with ER alpha, a receptor triggered by estrogen.[4]

## Cardiolipin remodeling[edit]

In 2009, Taylor et al. identified a human mitochondrial protein,  monolysocardiolipin acyltransferase (MLCL AT-1), that is identical in amino acid sequence to the 59-kDa C-terminal end of MTP, linking MTP to the remodeling of cardiolipin from monolysocardiolipin.[5] Although MLCL AT-1 and MTP are different proteins, in 2012 the same lab discovered that MTP did indeed have cardiolipin remodeling capabilities.[6] This suggests a possible link between mitochondrial membrane cardiolipin content and beta oxidation.

## Clinical significance[edit]

Disorders associated MTP are:

* Mitochondrial trifunctional protein deficiency
* LCHAD deficiency
* Acute fatty liver of pregnancy

## References[edit]

1. ^ "Long-Chain Acyl CoA Dehydrogenase Deficiency: eMedicine Pediatrics: Genetics and Metabolic Disease". Retrieved 2009-07-11.
2. ^ Wang, Y.; Mohsen, A.-W.; Mihalik, S. J.; Goetzman, E. S.; Vockley, J. (2010). "Evidence for Physical Association of Mitochondrial Fatty Acid Oxidation and Oxidative Phosphorylation Complexes". Journal of Biological Chemistry. 285 (39): 29834–29841. doi:10.1074/jbc.M110.139493. ISSN 0021-9258. PMC 2943265. PMID 20663895.
3. ^ Chocron, E. S.; Sayre, N. L.; Holstein, D.; Saelim, N.; Ibdah, J. A.; Dong, L. Q.; Zhu, X.; Cheng, S.-Y.; Lechleiter, J. D. (2012). "The Trifunctional Protein Mediates Thyroid Hormone Receptor-Dependent Stimulation of Mitochondria Metabolism". Molecular Endocrinology. 26 (7): 1117–1128. doi:10.1210/me.2011-1348. ISSN 0888-8809. PMC 3385793. PMID 22570332.
4. ^ Zhou, Z.; Zhou, J.; Du, Y. (2012). "Estrogen Receptor Alpha Interacts with Mitochondrial Protein HADHB and Affects Beta-Oxidation Activity". Molecular & Cellular Proteomics. 11 (7): M111.011056. doi:10.1074/mcp.M111.011056. ISSN 1535-9476. PMC 3394935. PMID 22375075.
5. ^ Taylor, W. A.; Hatch, G. M. (2009). "Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)". Journal of Biological Chemistry. 284 (44): 30360–30371. doi:10.1074/jbc.M109.048322. ISSN 0021-9258. PMC 2781591. PMID 19737925.
6. ^ Beh, Christopher; Taylor, William A.; Mejia, Edgard M.; Mitchell, Ryan W.; Choy, Patrick C.; Sparagna, Genevieve C.; Hatch, Grant M. (2012). "Human Trifunctional Protein Alpha Links Cardiolipin Remodeling to Beta-Oxidation". PLOS ONE. 7 (11): e48628. Bibcode:2012PLoSO...748628T. doi:10.1371/journal.pone.0048628. ISSN 1932-6203. PMC 3494688. PMID 23152787.

## External links[edit]

* mitochondrial+trifunctional+protein+TP at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

* v
* t
* e

Enzymes: multienzyme complexes

Photosynthesis|

* Photosynthetic reaction center complex proteins
* Photosystem
* I
* II

Dehydrogenase|

* Pyruvate dehydrogenase complex
* E1
* E2
* E3
* Oxoglutarate dehydrogenase
* OGDH
* DLST
* DLD
* Branched-chain alpha-keto acid dehydrogenase complex
* BCKDHA
* BCKDHB
* DBT
* DLD

Other|

* CAD
* Carbamoyl phosphate synthase II
* Aspartate carbamoyltransferase
* Dihydroorotase
* P450-containing systems
* Cytochrome b6f complex
* Electron transport chain
* Fatty acid synthetase complex
* Glycine decarboxylase complex
* Mitochondrial trifunctional protein
* HADHA
* HADHB
* Phosphoenolpyruvate sugar phosphotransferase system
* Polyketide synthase
* Sucrase-isomaltase complex
* Tryptophan synthase

* v
* t
* e

Metabolism: lipid metabolism / fatty acid metabolism, triglyceride and fatty acid enzymes

Synthesis|

| Malonyl-CoA synthesis|

* ATP citrate lyase
* Acetyl-CoA carboxylase

|

Fatty acid synthesis/
Fatty acid synthase|

* Beta-ketoacyl-ACP synthase
* Β-Ketoacyl ACP reductase
* 3-Hydroxyacyl ACP dehydrase
* Enoyl ACP reductase

Fatty acid desaturases|

* Stearoyl-CoA desaturase-1

Triacyl glycerol|

* Glycerol-3-phosphate dehydrogenase
* Thiokinase

Degradation|

| Acyl transport|

* Carnitine palmitoyltransferase I
* Carnitine-acylcarnitine translocase
* Carnitine palmitoyltransferase II

|

Beta oxidation|

| General|

* Acyl CoA dehydrogenase (ACADL
* ACADM
* ACADS
* ACADVL
* ACADSB)
* Enoyl-CoA hydratase

* MTP: HADH
* HADHA
* HADHB

* Acetyl-CoA C-acyltransferase

|

Unsaturated|

* Enoyl CoA isomerase
* 2,4 Dienoyl-CoA reductase

Odd chain|

* Propionyl-CoA carboxylase

Other|

* Hydroxyacyl-Coenzyme A dehydrogenase

To acetyl-CoA|

* Malonyl-CoA decarboxylase

Aldehydes|

* Long-chain-aldehyde dehydrogenase

* v
* t
* e

Mitochondrial proteins

Outer membrane|

| fatty acid degradation|

* Carnitine palmitoyltransferase I
* Long-chain-fatty-acid—CoA ligase

|

tryptophan metabolism|

* Kynureninase

monoamine neurotransmitter
metabolism|

* Monoamine oxidase

Intermembrane space|

* Adenylate kinase
* Creatine kinase

Inner membrane|

| oxidative phosphorylation|

* Coenzyme Q – cytochrome c reductase
* Cytochrome c
* NADH dehydrogenase
* Succinate dehydrogenase

|

pyrimidine metabolism|

* Dihydroorotate dehydrogenase

mitochondrial shuttle|

* Malate-aspartate shuttle
* Glycerol phosphate shuttle

steroidogenesis|

* Cholesterol side-chain cleavage enzyme
* Steroid 11-beta-hydroxylase
* Aldosterone synthase

other|

* Glutamate aspartate transporter
* Glycerol-3-phosphate dehydrogenase
* ATP synthase
* Carnitine palmitoyltransferase II
* Uncoupling protein

Matrix|

| citric acid cycle|

* Citrate synthase
* Aconitase
* Isocitrate dehydrogenase
* Oxoglutarate dehydrogenase complex
* Succinyl coenzyme A synthetase
* Fumarase
* Malate dehydrogenase

|

anaplerotic reactions|

* Aspartate transaminase
* Glutamate dehydrogenase
* Pyruvate dehydrogenase complex

urea cycle|

* Carbamoyl phosphate synthetase I
* Ornithine transcarbamylase
* N-Acetylglutamate synthase

alcohol metabolism|

* ALDH2

* PMPCB

Other/to be sorted|

* Frataxin
* Mitochondrial membrane transport protein
* Mitochondrial permeability transition pore
* Mitochondrial carrier
* Translocator protein

Mitochondrial DNA|

| Complex I|

* MT-ND1
* MT-ND2
* MT-ND3
* MT-ND4
* MT-ND4L
* MT-ND5
* MT-ND6

|

Complex III|

* MT-CYB

Complex IV|

* MT-CO1
* MT-CO2
* MT-CO3

ATP synthase|

* MT-ATP6
* MT-ATP8

tRNA|

* MT-TA
* MT-TC
* MT-TD
* MT-TE
* MT-TF
* MT-TG
* MT-TH
* MT-TI
* MT-TK
* MT-TL1
* MT-TL2
* MT-TM
* MT-TN
* MT-TP
* MT-TQ
* MT-TR
* MT-TS1
* MT-TS2
* MT-TT
* MT-TV
* MT-TW
* MT-TY

see also mitochondrial diseases
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