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Mitochondrial membrane transport proteins, also known as mitochondrial carrier proteins, are proteins which exist in the membranes of mitochondria. They serve to transport molecules and other factors, such as ions, into or out of the organelles. Mitochondria contain both an inner and outer membrane, separated by the inter-membrane space, or inner boundary membrane. The outer membrane is porous, whereas the inner membrane restricts the movement of all molecules. The two membranes also vary in membrane potential and pH. These factors play a role in the function of mitochondrial membrane transport proteins. There are 53 discovered human mitochondrial membrane transporters, with many others that are known to still need discovered.


Mitochondrial outer membrane


The outer mitochondrial membrane forms the border of mitochondria towards the cellular environment. The outer membrane mitochondrial proteins carry out functions for mitochondrial biogenesis and integration between mitochondria and the cellular system. The outer membrane consists of two types of integral proteins, including proteins with transmembrane β-barrel and proteins with one or more α-helical membrane anchors.


β-Barrel Outer Membrane Proteins





TOM complex


The TOM complex is essential for the translocase of almost all mitochondrial proteins which consists of at least 7 different subunits. Tom20 and Tom70 are the primary receptors while Tom40, Tom22, Tom7, Tom6, and Tom5 subunits form the stable TOM Complex. The receptor proteins Tom70 and Tom20 recognize incoming precursor proteins, in which Tom70 is responsible for docking of precursors of hydrophobic proteins accompanied by cytosolic chaperones and Tom 20 recognizes precursor proteins of the presequence pathways. Tom40 is the protein-conducting channel of the complex with beta-barrel structure, which forms a cation-selective channel. Tom40 has a large pore diameter of 22Å that can allow the accommodation of partially folded protein structure The inner wall of Tom40 has a charged region that allows interaction with hydrophilic precursor proteins while the hydrophobic precursor of ADP/ATP carrier can be crosslinked with the hydrophobic region of Tom40. Three small proteins Tom5, Tom6, Tom7 interact closely with Tom40 to assemble and stabilize the complex. The TOM complex also consists of a dimer of Tom40 or small Tom proteins that are held together by two Tom22 subunits. Protein sorting into the mitochondrial compartments always starts at the TOM complex. The TOM complex forms two exit sites for precursor proteins-- Tom40, Tom7, and the intermembrane space domain of Tom22-- promote the transfer of presequence-containing precursors to the TIM23 complex.


SAM complex


The SAM Complex is essential for sorting and assembling beta-barrel proteins from the intermembrane space side into the outer membrane. The SAM complex consists of three subunits: The β-barrel protein Sam50 and two peripheral subunits Sam35 and Sam37. Sam50 belongs to the conserved Omp85 protein family which can be characterized by a 16-stranded β-barrel and by a different number of polypeptide transport-associated (POTRA) domains. Sam50 exposes a single POTRA domain towards the intermembrane space. Sam35 caps the Sam50 β-barrel, stabilizing the core of the protein translocase. Sam50 and Sam35 are responsible for the binding of precursors of β-barrel proteins, which contain conserved β-signal that is formed by the last β-strand. The β-barrel of Sam50 is the functional domain that inserts and folds substrate proteins into the outer membrane. Sam35 binds to Sam50 and closely interacts with Sam37, in which Sam37 does not bind to Sam50. Sam37 and Sam35 have a conformation similar to glutathione-S-transferase, except they do not possess residues required for enzymatic activity. Sam37 accommodates the release of the folded β-barrel proteins from the SAM complex.


Voltage-dependent anion ion channel or VDAC


VDAC (voltage-dependent anion ion channel) is important for the exchange of small hydrophilic ions and metabolites with the cytosol, which is driven by the gradient concentration across the outer membrane. VDAC is the most abundant protein in the outer membrane. Like Tom40, VDAC has a β-barrel structure with antiparallel β-strands that can facilitate the passage of β-barrel membrane proteins. VDAC has a pore size of 2-4 nm for small hydrophilic molecules. VDAC plays a crucial role in facilitating energy metabolism by transporting ADP and ATP in and out of the outer membrane. VDAC also accommodates the passage of NADH and many anionic metabolites. VDAC operation is voltage-dependent in which it closes at high voltage and can partially open towards slightly reduced anion selectivity.


α-Helical outer membrane proteins





The Mitochondrial import complex (MIM)


The import pathways of α-helical membrane anchors or signal-anchored proteins are carried out mainly by outer membrane proteins. Precursors of the polytopic or multi-spanning proteins can be recognized by Tom70, but cannot be passed through the Tom40 channel. Tom70 transfers the precursor proteins to the MIM Complex. The MIM complex constitutes the major inserts for alpha-helical proteins into the target membrane. The MIM Complex consists of several copies of Mim1 and one or two copies of Mim2. Both subunits are necessary for stabilizing partner proteins and for outer membrane protein biogenesis


Mitochondrial inner membrane


The inner mitochondrial membrane is a structure that surrounds the mitochondrial matrix, characterized by many folds and compartments that form crista and is the site of oxidative phosphorylation and ATP synthesis. The high concentration of cardiolipin makes it impermeable to most molecules. Specialized transporters arranged in specific configurations are required to regulate the diffusion of molecules across the membrane. The inner membrane's structure causes a membrane potential of approximately 180 mV.


Respiratory chain supercomplex


The respiratory chain supercomplex is located in the cristae of the inner membrane. It is composed of multiple complexes that work together to drive oxidative phosphorylation and ATP synthesis. The complexes cannot function without the other parts of the respiratory supercomplex being present. The supercomplex is the site of the mitochondrial electron transport chain.


NADH/ubiquinone oxidoreductase


NADH/ubiquinone oxidoreductase, also known as complex I, is the first and largest protein in the mitochondrial respiratory chain. It consists of a membrane arm, embedded inside the inner mitochondrial membrane, and a matrix arm, extending out of the membrane. There are 78 transmembrane helices and three proton pumps. The junction of the two arms is the site of conduction of NADH to ubiquinol. Complex I is a scaffold needed for complex III and IV, and it will not function without these other complexes being present.


Cytochrome ''c'' reductase, succinate dehydrogenase, and cytochrome ''c'' oxidase


Cytochrome ''c'' reductase, also known as complex III, is the second protein in the respiratory chain. It pumps electrons from complex I, through succinate dehydrogenase (complex II) to cytochrome ''c'' (complex IV). Complex III and IV are proton pumps, pumping H+ protons out of the mitochondrial matrix, and work in conjunction with complex I to create the proton gradient found at the inner membrane. Cytochrome ''c'' is and electron carrier protein that travels between complex III and IV, and triggers apoptosis if it leaves the cristae. Complex IV passes electrons to oxygen, the final acceptor in the mitochondrial electron transport chain.


ATP synthase


ATP synthase (complex V) is responsible for ATP production by adding a phosphate ion to an ADP molecule in the cristae. F1-Fo ATP synthase produces ATP via rotary catalysis. It is made up of a rotor ring composed of ''c-''subunits, a peripheral stalk, a central stalk, F1 head, and Fo complex. The rotor ring is turned by protons passing through the Fo complex. This generates torque to the F1 head, causing production of ATP from ADP and phosphate. In addition to ATP production, ATP synthase is partially responsible for the overall structure of the inner mitochondrial membrane in eukaryotic organisms. The complexes form dimers, which bend the lipid bilayer of the membrane through the energy of elastic membrane deformation and the dimers self-associate into rows. These rows form the deep curves of the inner membrane cristae.


Mutations of mitochondrial membrane transporters


Mutations of DNA coding for mitochondrial membrane transport proteins are linked to a wide range of diseases and disorders, such as cardiomyopathy, encephalopathy, muscular dystrophy, epilepsy, neuropathy, and fingernail dysplasia. Most mutations of mitochondrial membrane transporters are autosomal recessive. Mutations to transporters within the inner mitochondrial membrane mostly affect high-energy tissues due to the disruption of oxidative phosphorylation.

Examples

Examples of mitochondrial transport proteins include the following: *The mitochondrial permeability transition pore, which opens in response to increased mitochondrial calcium (Ca2+) load and oxidative stressCrompton M. 1999.
The mitochondrial permeability transition pore and its role in cell death
''Biochemical Journal''. Volume 341, Pages 233-249. . Retrieved on January 23, 2007.
*The mitochondrial calcium uniporter which transports calcium from the cytosol of the cell into the mitochondrial matrixNicholls DG. (2005) Mitochondria and calcium signaling. ''Cell Calcium'', Volume 38, Issues 3-4, Pages 311-317. . Retrieved on January 23, 2007. *The mitochondrial sodium/calcium exchanger, which carries Ca2+ ions out of the matrix in exchange for Na+ ions. These transport proteins serve to maintain the proper electrical and chemical gradients in mitochondria by keeping ions and other factors in the right balance between the inside and outside of mitochondria.


See also


* Mitochondrial carrier * Membrane transport protein


References


Category:Transport proteins Category:Mitochondria Category:Transmembrane proteins {{membrane-protein-stub