2014 Group 2 Project

From CellBiology

UNSW ANAT3231 Course Coordinator Dr Mark Hill
2014 Projects: Group 1 | Group 2 | Group 3 | Group 4

Transport from the Cytoplasm to the Mitochondria

Introduction

Mitochondrial structure showing outer and inner membranes as well as cristae.

The movement of proteins and metabolites in and out of the mitochondria are important for normal cell functioning to occur. The transportation of such materials through the mitochondria involve various mitochondrial carriers. These carriers are roughly 30-35kDa in size[1] with six alpha helical transmembrane proteins, which are connected by a salt-bridge formed from the charge residues of the three homologous sequence repeats that consist of roughly one hundred amino acid residues each[2]. The rearrangement of the salt-bridges, due to interaction with various molecules, allows the carriers to open and allow proteins and metabolites to enter the matrix. These carriers are found in the inner and outer membrane of the mitochondria, however, majority of them are located on the inner membrane due to its permeability from the embedment of cadiolipins. In contrast, the outer membrane contains membranous protein channels that span the bi-lipid layer and allows ions and metabolites through to the intermembranous space. In this space, there are various enzymes and proteins that interact with the transmembrane protein carriers in the inner membrane to aid the movement of metabolites into the mitochondrial matrix[3].

Importation of RNA molecules into the mitochondria are essential as they are needed for the replication and translation mechanisms of mitochondrial genomes. It has puzzled researchers for years as to how RNA molecules from the nucleus makes its way through into the mitochondria mainly because the inner membrane is semipermeable and RNA molecules are not as flexible as proteins. Recently, there has been a discovery of a new function of the protein polynucleotide phosphorylase (PNPASE), which is the importation of RNA from the cytosol into the mitochondria. This protein, located in the intermembrane space[4], is important as it regulates the amount of RNA coming into the mitochondria which affects protein translation involved in maintenance of the electron transport chain and therefore mediates cell growth[5].

Another group of proteins that have been identified and hypothesized to be involved in cellular metabolism and cellular growth are the mitochondrial pyruvate carriers (MPCs). This family of proteins are involved in the transport of pyruvate into the mitochondria for further metabolism and are found in the inner mitochondrial membrane[6][7]. There are two particular proteins in the family of MPCs, MPC1 and MPC2, which have been identified as an essential part for the working mechanism of MPCs in the transportation of pyruvate into the mitochondria[8].

There are other various translocator proteins located on these membranes to aid with the translocation of proteins across the membranes. The main ones include the TOM and TIM complexes. These complexes are usually working together to transport cytosolic precursor proteins across the membranes, however, they can also work independently[9].

In the overall realm of cell biology, the mitochondrial import system shares several key features with the protein export systems of bacteria or the endoplasmic reticulum. All three systems involve one or more cytosolic recognition steps, a receptor system on the cytosolic face of the target membrane, a hetero-oligomeric protein transport channel, and a protein translocation motor, which is powered by the hydrolysis of nucleoside triphosphate[10].

Introduction Animation to the transport of Proteins into the Mitochondrial from the Cytosol. The media player is loading... Published by Garlandscience

Structure of the Mitochondria

A cartoon showing mitochondrial structure.

Mitochondria are important double membrane bound organelles in eukaryotic cells and are responsible for energy production, signal transduction and are involved in apoptosis. They are unique organelles as they contain their own DNA, RNA and some proteins. This leads to the idea that mitochondria are assembled by proteins that are encoded from their own DNA and are translated within the organelle, itself, and cytosolic proteins which are encoded from the eukaryotic cell’s DNA in the nucleus[9].

An appreciation for mitochondrial structure is crucial to understanding the different transport mechanisms. A mitochondrion contains outer and inner membranes composed of various arrangements of phospholipid bilayers and proteins which arises to different membranous properties. This double-membraned organization allows the mitochondrion to be defined into five distinct parts. They are:

  1. the inner mitochondrial membrane,
  2. the outer mitochondrial membrane,
  3. the cristae space (formed by infoldings of the inner membrane),
  4. the intermembrane space (the space between the outer and inner membranes), and
  5. the matrix (space within the inner membrane).

There are two subcompartments in mitochondria: the internal matrix space and the inter membrane space (4 and 5 from above). These compartments are formed by the two concentric mitochondrial membranes: the inner membrane, which forms extensive invaginations, the cristae, and encloses the matrix space, and the outer membrane, which is in contact with the cytosol. Each of the subcompartments in mitochondria contains a distinct set of proteins[11].

Protein Transport Into Mitochondria

The mitochondrion only produces a small amount of its own proteins. Instead, it imports the majority of its proteins from the cytosol. Protein import into mitochondria is a complex process, since every protein must be routed to its specific destination within the organelle. Proteins are translocated in an unfolded state into the mitochondrial matrix space by passing through the TOM and TIM complexes at sites of adhesion between the outer and inner membranes known as contact sites. This translocation process is driven by both ATP hyrdrolysis and an electrochemical H+ gradient across the inner membrane[11]

The media player is loading...

Precursor Proteins

A self-drawn image illustrating the structure of a mitochondrial precursor protein.

Mitochondrial proteins are first fully synthesized as precursor proteins in the cytosol. The precursor proteins are synthesized with a transient N-terminal extension that functions as a targeting signal. This signal is a sequence of 20-30 amino acid residues capable of folding into a positively charged amphiphilic α helix. If this “matrix targeting signal" (frequently called MTS) is fused to a non-mitochondrial protein, this protein is transported to the mitochondrial matrix[12]. Proteins imported into other mitochondrial subcompartments usually have an additional signal downstream from the matrix targeting signal; in many cases, this “sorting signal” interrupts translocation across either the outer or the inner membrane, thereby rerouting the protein to the outer membrane, the intermembrane space, or the inner membrane. Targeting signals are usually quickly removed once the protein has reached its correct location. [10]

During or after the synthesis in the cytosol, mitochondrial precursor proteins are bound by chaperones that maintain them in an unfolded conformation. These chaperones include members of the Hsp70 heat-shock family as well as specific factors, such as the mitochondrial import stimulating factor (MSF), that recognise mitochondrial precursor protein sequences. Some small and hydrophilic precursors may travel through the cytosol without assistance by a chaperone, but this fact has not been clearly established[12].

TOM Complex

The translocase of the outer mitochondrial membrane (TOM complex) is the central front door for practically all nuclear-encoded mitochondrial proteins. As a first step in the import process, the mitochondrial precursor proteins bind to import receptor proteins of the TOM complex, which recognize the mitochondrial signal sequences. The interacting proteins are then stripped off, and the unfolded polypeptide chain is fed—signal sequence first—into the translocation channel. The TOM complex consists of several preprotein receptors and a general import pore. The TOM complex consists of seven different subunits that can be grouped into three categories.

  1. The receptors are TOM20, TOM22, and TOM70
  2. The channel-forming protein is TOM40.
  3. And lastly, three small TOM proteins, TOM5, TOM6, and TOM7.
Protein transport complexes in the Mitochondria.

TOM20 is the first receptor involved in recognizing the MTS (or presequence) of a preprotein. One half of the helix from the MTS possesses a hydrophobic surface that is recognized by a binding groove within TOM20, whereas the other half is positively charged and recognized by the receptor TOM22. With the help of the small protein TOM5, the preprotein is then transported to the general import pore formed by the essential Beta-barrel protein TOM40. After translocation through the TOM40 pore, the presequence binds to the intermembrane space domain of the receptor TOM22. TOM40 itself does not simply form a passive pore but rather interacts with the preproteins in transit. The other small TOM proteins, TOM6 and TOM7, do not directly interact with precursor proteins but are required for the assembly and stability of the TOM complex[13]. For import of preproteins into the matrix and into the inner membrane, the TOM complex cooperates with TIM complexes in the inner membrane, which differ in their substrate specificity’s for precursor proteins[14].

TIM Complex

After the translocation of the precursor proteins from the extracellular matrix through the outer membrane and into the inner membrane, the proteins undergo an interaction with the translocase inner membrane complex (TIM complex), more specifically, TIM23 complex. The complex consists of transmembrane integral protein subunits in order for it to function. Such subunits are TIM17, TIM23 and TIM44 which are found in a ratio of roughly 2:2:2. It has been discovered that in yeast, the TIM23 complex is structured as a dimer due to the presence of a membrane potential. However, when the precursor protein, floating around in the intermembranous space, binds to the TIM23 complex, it causes the complex to dissociate and therefore allow the movement of the protein across the membrane. After the precursor protein moves through the membrane, it comes in contact with the TIM44 subunit which has been suggested to guide the preprotein to the mitochondrial heat shock protein 40 (mt-Hsp40)[15]. This heat shock protein is part of a family of chaperones which means that they keep the incoming precursor protein in its unfolded structure so that it can be easily transported around the mitochondria[16].

Pyruvate transport into the Mitochondria

Location of MPC1 and MPC2 in mitochondrial membrane.

Pyruvate is an important molecule which is required for the production of oxidative fuel for cell energy requirements[17]. It is transported from the cell cytoplasm into the mitochondrial matrix for processing via mitochondrial pyruvate carriers (MPCs). MPCs are believed to be a heterocomplex [17] and are formed by 2 subunits, mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2). Scientists have located these MPCs in the inner membrane of the mitochondria by use of protease treatment. They have shown that these two specific carriers were resistant to such treatment unless the outer membrane of the mitochondria was ruptured[18]. Hence, they were able to conclude that MPC1 and MPC2 are embedded in the inner mitochondrial membrane. These 2 subunits are relatively small in comparison to other carrier subunits as they are only roughly 12 kDa – 14 kDa in size. However, when combined together they form a larger complex at approximately 150 kDa in size[18].

It has been recognised that if either MPC1 or MPC2 genes were silenced, it would gravely affect pyruvate metabolism of the cells and lead to various diseases. Such diseases include lactic acidosis and hyperpyruvatemia which are cause by changes in the amino acid sequence of the carriers[18].


Diseases

Various diseases can develop when there are mutations or lesions in the mitochondrial genome or the membrane itself. Such mutations can cause protein dysfunction due to the fact that the protein code has been changed which leads to the possibility of the protein becoming misfolded. These abnormal proteins will no longer be able to carry out their normal function. With regards to transport into the mitochondria, translocators are composed mainly of proteins and therefore a mutation will gravely affect its function to transport proteins and metabolites across the phospholipid bilayer which ultimately affects regular mitochondrial and cellular function.

Parkinson's Disease

Fragmentation of Mitochondria in PINK1 neurons when under stress conditions.

Proper function of mitochondria is crucial for the survival of the the cell as it provides energy and is involved in numerous metabolic activities[19]. Viruses can interfere with mitochondrial function and therefore infect the cell host[20]. The complex biogenesis and dynamics of the mitochondria are necessary for quality control measurement to make sure that damaged or mutated organelles are eliminated from the cell. When this mitochondrial feature is affected, it may result in Parkinson's disease[21]. PTEN-induced putative kinase 1 (PINK1) is a protein that is situated in the outer mitochondrial membrane. Its function is to be the gatekeeper of the mitochondria, that is, its job is to eliminate all the mutated and diseased organelles within the mitochondria[22]. It also coorperates with other proteins such as Parkin and E3 ubiquitin ligases to carry out its function. Under normal circumstances, PINK1 is made in the cytosol and imported into the outer mitochondrial membrane via the TOM complex, where it is then transferred into the inner mitochondrial membrane. When the outer membrane is disrupted, the mitochondria becomes damaged by loss of its membrane potential which results in PINK1 not being imported to the inner mitochondrial membrane and hence avoids processing by PARL. PINK1 stays in the outer mitochondrial membrane and recruits Parkin which induces mitophagy[21].

Mutations in PINK1 causes an autosomal recessive familial disease known as Parkinson's disease[21]. PINK1 influences the shape and the function of the mitochondria and which means that if PINK1 becomes mutated, it will result in a change in shape and hence mitochondrial dysfunction[21]. Many PINK1 gene mutations change and/or eliminate the kinase domain which leads to a loss of protein function. One mutation in the PINK1 gene affects the mitochondrial-targeting motif and may disrupt delivery of the protein to mitochondria[23]. When there is a reduction or lack of PINK1 activity, the mitochondria may malfunction, particularly when cells are stressed[24]. Cells can degenerate if there is insufficient energy for essential activities[25]. As these cells mutate and degrade, the communication between the brain and the muscles becomes slow and weak and eventually the brain becomes unable to control muscle movement, which gives us the irregular movement patterns that are involved in Parkinson’s disease[26].

Mitochondria have many metabolic pathways that supply cells with energy in the form of ATP which means that it needs to be controlled so that it can eliminate damaged proteins and organelles. If the mitochondria is not working the way that it needs to, it can cause gaps within the mitochondrial network which will result in death. Therefore the end result of mitochondrial dysfunction and lack of quality control can lead to Parkinson's disease.

Charcot-Marie-Tooth Disease

Mitofusion2 mutations alter Mitochondrial Dynamics.png

Charcot-Marie-Tooth disease (CMT) is an inherited disorder of the nervous system[27]. CMT symptoms usually involve a slow onset of distal weakness, muscle atrophy and sensory loss[28]. It is caused by mutations in mitofusion 2(MFN 2), an outer mitochondrial membrane protein. MFN 2 is a dynamin family GTPase involved in mitochondrial fusion. MFN 2 and MFN 1 participate in docking and tethering of neighbouring mitochondria and outer membrane fusion[29].

Kearnes-Sayre Syndrome

Kearnes-Sayre syndrome (KSS) is a mitochondrial myopathy[30]. KSS usually occurs before the age of 20 (ref). KSS is characterised by isolated movement of the muscles controlling eye and eyelid movement[30]. KSS is a result of deletions of the mitochondrial DNA. It occurs due to mutations in the transport proteins involved in the electron transport chain (ETC), which gives us an impaired production of energy[31]. This will affect all the tissues which require enery.

Leber Hereditary Optic Neuropathy

Leber Hereditary Optic Neuropathy(LHON) is one of the most common mitochondrial syndromes[32]. This is caused by a mitochondrial DNA mutation hence affecting the production of various proteins and RNA molecules[33]. LHON’s disease occurs usually from age 15 until 30[32] with men being affected much more than women. LHON’s disease affects the vision whereby it damages one eye at a time and produce symptoms such as blurry vision which eventually affects the other eye after a few months[34]. The range of vision is very varied, with most ranging about 10% of normal sight.

Mitochondrial encephalomyapathy

Mitochondrial targeting sequence (MTS) has properties which are needed in order to affectively transport mitochondrial proteins[35]. It has been suggested that a mutation in 9 ALA allele targeting sequence can cause an interruption in mitochondrial transport of human MnSOD which can also result Parkinson’s disease. Myoclonic epilepsy associated with ragged red fibers (MERRF syndrome) is a disease caused by disruption in the mitochondrial DNA. Patients with MERRF have various neurological symptoms which vary from seizures, ataxia and muscle weakness[36]. Another key marker for this disease is the lactic acid build up due to excess pyruvate being converted to lactic acid which enters the blood stream[36]. Mitochondrial encephalomyapathy, lactic acidosis, and stroke like episodes (MELAS syndrome) are indicated by stroke episodes and causes severe debilitating and are associated with infarctions in the brain. These diseases are caused by a mutation in the DNA of the mitochondria[36].

Current or Future Research

MTS polymorphism in humans

Mitochondrial targeting sequence (MTS) is essential for its effective transport of mitochondrial protein. Natural polymorphism in human MTS which affects its mitochondrial transport ability has not been reported. Furthermore, no structural polymorphism for manganese superoxide dismutase (MnSOD) gene has been studied in human population. Researchers in Tokyo, Japan at the Juntendo University School of Medicine took a stab at these unknown areas. They identified diallelic polymorphism (Ala-9Val) in the MTS of human MnSOD in a Japanese population. Calculation of a helix forming potential predicted the typical amphiphilic helical structure in -9Ala allele and its disruption in -9Val allele. The researchers suggest that this mutation may reflect functional polymorphism of mitochondrial transport of human MnSOD. An association study using this polymorphism showed significant allelic deviation for -9Ala allele in Parkinson’s disease[37].

Introducing TOM into Entamoeba histolytica

Under stressed anaerobic environments, the mitochondria have undergone remarkable reduction and transformation into highly reduced structures to adapt. In agreement with the concept of reductive evolution, mitosomes of Entamoeba histolytica lack most of the components of the TOM complex. Researchers from the Department of Parasitology, National Institute of Infectious Diseases in Tokyo, Japan discovered that Entamoeba has invented a novel lineage-specific shuttle receptor of the TOM complex as a consequence of adaptation to an anaerobic environment. In their study the researchers showed, in E. histolytica mitosomes, the presence of a 600-kDa TOM complex composed of Tom40and Tom60[38].

RNA transport into Mitochondria

PNPase complexes located in the intermembranous space of the mitochondria assisting with RNA importation.

RNA translocation into the mitochondria is currently under research as not much is known about its mechanisms. However, the polynucleotide phosphoylase (PNPASE) has been recently discovered to be involved in RNA transport, despite its other functions such as its involvement in RNA degradation. PNPase is a 3’ to 5’exoribonuclease and a poly-A polymerase and is found to exist as a homotrimer [39]. Structurally, it has two external domains that bind the RNA near the opening of the processing pore in the complex[40]. It has been identified that the lack of PNPase in the intermembranous space influences the importation of various RNA components such as ribonuclease P, 5S rRNA and mitochondrial RNA processing RNAs. Some studies showed that mitochondrial RNA targeting signals allow such RNA importation to be dependent on PNPases[40]. That is, if there is no PNPase present, the signal cannot interact with the complex and therefore, no RNA components are able to be translocated into the mitochondria.

The location of the PNPases in mammalian cells is an interest to scientists as they predicted that they would be located in the matrix area that is RNA abundant due to its original function of RNA degradation and the regulation of adenine nucleotide levels. However, now, scientists have discovered that PNPase is actually located in the intermembranous space, as shown in the diagram, and have speculated that it is involved in enhancing the import of small RNA components needed for genetic processing of DNA and RNA in the mitochondria[40].

The exact mechanisms of how the importation of RNA into the mitochondria is still unknown, however, the discovery of this translocation function in PNPases has led scientists to believe that it may be the first receptor-like binding complex that binds RNA into the mitochondrial matrix. It has been proposed that further studies should be done to determine how the structure of the PNPase helps in the importation and deciphering of the RNA molecule[40].

Lipid transport into Mitochondria

Location and structure of Endoplasmic Reticulum and Mitochondrial tethering complex.

Lipid transport into the mitochondria differs from the transport of other materials such as proteins and pyruvate. The specific mechanisms of this process are still unknown and are being researched but some basic concepts have been identified. Lipid is synthesised in the smooth endoplasmic reticulum and combined with calcium ions in order to travel to the mitochondria. There is a small area between the endoplasmic reticulum and the mitochondria which is referred to as the mitochondria-associated membranes. This is where the combination of newly produced lipids and calcium ions occur. It has been hypothesised that the calcium aids in the guiding of the lipid to a section of the mitochondrial membrane known as a membrane contact site. This is a basic site where exchange of metabolites and materials could traverse between two membrane bound organelles[41].

The membrane contact site hypothesis leads to the idea of endoplasmic reticulum to mitochondria tethers. This is where physical coupling occurs between these two organelles by various proteins and protein complexes. These protein complexes, composed of Mmm1, Mdm10, Mdm12 and Mdm34 subunits, are composed of proteins found in both the endoplasmic reticulum and mitochondria. Each of these subunits is different structural proteins, for example Mm1 is an integral endoplasmic reticulum protein whereas Mdm10 is an outer mitochondrial membrane β-barrel protein. Genetic analysis has allowed scientists to speculate that this tethering complex is connected to the synthesis of phospholipids and calcium signalling genes[42].

Glossary

Terms Description
Apoptosis The process of cell death that may occur in multicellular organisms
Cellular transport A vital function of cells that allows the cell to bring molecules and individual atoms into the cell and send unwanted molecules and atoms out of the cell
Cytosol The intracellular fluid that surrounds the organelles and other insoluble cytoplasmic structures
DNA Deoxyribonucleic acid, present in nearly all living organisms and located in the nucleus or mitochondria that is the carrier of genetic information
Entamoeba histolytica A protozoan parasite responsible for a disease called amoebiasis that occurs usually in the large intestine and causes internal inflammation
Hsp70 proteins 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins and are an important part of the cell's machinery for protein folding, and help to protect cells from stress
Mitochondria Organelle found in most eukaryotic cells, in which the biochemical processes of respiration and energy production occur that has a double membrane
Mdm10, Mdm12, Mdm34 Mitochondrial distribution and morphology proteins 10, 12 and 34 respectively - involved in the tethering complex between endoplasmic reticulum and mitochondria for lipid transport
Mm1 Mitochondrial morphology protein 1 - involved in the tethering complex between endoplasmic reticulum and mitochondria for lipid transport
MnSOD Manganese superoxide dimutase gene - influences the activity of transcription factors and stabilises DNA
MSF Mitochondrial import stimulating factor - chaperone that allows the binding of precursor proteins and causes the hydrolysis of ATP
MTS Mitochondrial targeting sequence - peptide sequence ranging from 3-70 amino acids used to guide the transport of proteins towards specific areas in the cell
Pyruvate The carboxylate anion of pyruvic acid and the end product of gylcolysis that is required for the production of oxidative fuel for cell energy requirements
TIM Translocase of the inner mitochondrial membrane - protein complex found in the inner membrane of the mitochondria that translocates protein from the intermembranous space to the mitochondrial matrix
TOM Translocase of the outer mitochondrial membrane - protein complex found in the outer membrane of mitochondria that aids in the translocation of proteins into the mitochondrial inter membranous space
TOM 5, TOM 6, and TOM 7 small Tom proteins that regulate the conformation of the Tom channel named after their approximate molecular masses in kDa
TOM 40 Hydrophobic protein that is the core subunit of the TOM channel named after its molecular mass in kDa
TOM20, TOM22, and TOM70 The TOM subunits that function as receptors in protein transport that are named after their approximate molecular masses in kDA

References

<references>
  1. Andrew P Halestrap The mitochondrial pyruvate carrier: has it been unearthed at last? Cell Metab.: 2012, 16(2);141-3 PubMed 22883228
  2. Edmund R S Kunji, Alan J Robinson The conserved substrate binding site of mitochondrial carriers. Biochim. Biophys. Acta: 2006, 1757(9-10);1237-48 PubMed 16759636
  3. Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. Mitochondria. Available from: http://www.ncbi.nlm.nih.gov/books/NBK9896/
  4. Victoria Portnoy, Gili Palnizky, Shlomit Yehudai-Resheff, Fabian Glaser, Gadi Schuster Analysis of the human polynucleotide phosphorylase (PNPase) reveals differences in RNA binding and response to phosphate compared to its bacterial and chloroplast counterparts. RNA: 2008, 14(2);297-309 PubMed 18083836
  5. Geng Wang, Hsiao-Wen Chen, Yavuz Oktay, Jin Zhang, Eric L Allen, Geoffrey M Smith, Kelly C Fan, Jason S Hong, Samuel W French, J Michael McCaffery, Robert N Lightowlers, Herbert C Morse, Carla M Koehler, Michael A Teitell PNPASE regulates RNA import into mitochondria. Cell: 2010, 142(3);456-67 PubMed 20691904
  6. Andrew P Halestrap The mitochondrial pyruvate carrier: has it been unearthed at last? Cell Metab.: 2012, 16(2);141-3 PubMed 22883228
  7. Sébastien Herzig, Etienne Raemy, Sylvie Montessuit, Jean-Luc Veuthey, Nicola Zamboni, Benedikt Westermann, Edmund R S Kunji, Jean-Claude Martinou Identification and functional expression of the mitochondrial pyruvate carrier. Science: 2012, 337(6090);93-6 PubMed 22628554
  8. Daniel K Bricker, Eric B Taylor, John C Schell, Thomas Orsak, Audrey Boutron, Yu-Chan Chen, James E Cox, Caleb M Cardon, Jonathan G Van Vranken, Noah Dephoure, Claire Redin, Sihem Boudina, Steven P Gygi, Michèle Brivet, Carl S Thummel, Jared Rutter A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science: 2012, 337(6090);96-100 PubMed 22628558
  9. 9.0 9.1 Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. Mitochondria. Available from: http://www.ncbi.nlm.nih.gov/books/NBK9896/
  10. 10.0 10.1 G Schatz The protein import system of mitochondria. J. Biol. Chem.: 1996, 271(50);31763-6 PubMed 8943210
  11. 11.0 11.1 Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. The Transport of Proteins into Mitochondria and Chloroplasts. Available from: http://www.ncbi.nlm.nih.gov/books/NBK26828/
  12. 12.0 12.1 Johannes M Herrmann, Walter Neupert Protein insertion into the inner membrane of mitochondria. IUBMB Life: 2003, 55(4-5);219-25 PubMed 12880202
  13. Doron Rapaport How does the TOM complex mediate insertion of precursor proteins into the mitochondrial outer membrane? J. Cell Biol.: 2005, 171(3);419-23 PubMed 16260501
  14. Nils Wiedemann, Ann E Frazier, Nikolaus Pfanner The protein import machinery of mitochondria. J. Biol. Chem.: 2004, 279(15);14473-6 PubMed 14973134
  15. J M Herrmann, W Neupert Protein transport into mitochondria. Curr. Opin. Microbiol.: 2000, 3(2);210-4 PubMed 10744987
  16. Melanie K Bhangoo, Stefan Tzankov, Anna C Y Fan, Kurt Dejgaard, David Y Thomas, Jason C Young Multiple 40-kDa heat-shock protein chaperones function in Tom70-dependent mitochondrial import. Mol. Biol. Cell: 2007, 18(9);3414-28 PubMed 17596514
  17. 17.0 17.1 Sébastien Herzig, Etienne Raemy, Sylvie Montessuit, Jean-Luc Veuthey, Nicola Zamboni, Benedikt Westermann, Edmund R S Kunji, Jean-Claude Martinou Identification and functional expression of the mitochondrial pyruvate carrier. Science: 2012, 337(6090);93-6 PubMed 22628554
  18. 18.0 18.1 18.2 Daniel K Bricker, Eric B Taylor, John C Schell, Thomas Orsak, Audrey Boutron, Yu-Chan Chen, James E Cox, Caleb M Cardon, Jonathan G Van Vranken, Noah Dephoure, Claire Redin, Sihem Boudina, Steven P Gygi, Michèle Brivet, Carl S Thummel, Jared Rutter A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science: 2012, 337(6090);96-100 PubMed 22628558
  19. Anna Sandebring, Kelly Jean Thomas, Alexandra Beilina, Marcel van der Brug, Megan M Cleland, Rili Ahmad, David W Miller, Ibardo Zambrano, Richard F Cowburn, Homira Behbahani, Angel Cedazo-Mínguez, Mark R Cookson Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. PLoS ONE: 2009, 4(5);e5701 PubMed 19492085
  20. Hiroki Kato, Qiping Lu, Doron Rapaport, Vera Kozjak-Pavlovic Tom70 is essential for PINK1 import into mitochondria. PLoS ONE: 2013, 8(3);e58435 PubMed 23472196
  21. 21.0 21.1 21.2 21.3 Chun Zhou, Yong Huang, Yufang Shao, Jessica May, Delphine Prou, Celine Perier, William Dauer, Eric A Schon, Serge Przedborski The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc. Natl. Acad. Sci. U.S.A.: 2008, 105(33);12022-7 PubMed 18687899
  22. Hitoshi Murata, Masakiyo Sakaguchi, Yu Jin, Yoshihiko Sakaguchi, Jun-ichiro Futami, Hidenori Yamada, Ken Kataoka, Nam-ho Huh A new cytosolic pathway from a Parkinson disease-associated kinase, BRPK/PINK1: activation of AKT via mTORC2. J. Biol. Chem.: 2011, 286(9);7182-9 PubMed 21177249
  23. Z Szweykowska-Kulinska, H Beier Sequence and structure requirements for the biosynthesis of pseudouridine (psi 35) in plant pre-tRNA(Tyr). EMBO J.: 1992, 11(5);1907-12 PubMed 1582418
  24. Patrick M Abou-Sleiman, Miratul M K Muqit, Nicholas W Wood Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat. Rev. Neurosci.: 2006, 7(3);207-19 PubMed 16495942
  25. Ira E Clark, Mark W Dodson, Changan Jiang, Joseph H Cao, Jun R Huh, Jae Hong Seol, Soon Ji Yoo, Bruce A Hay, Ming Guo Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature: 2006, 441(7097);1162-6 PubMed 16672981
  26. Joe H Pogson, Rachael M Ivatt, Alexander J Whitworth Molecular mechanisms of PINK1-related neurodegeneration. Curr Neurol Neurosci Rep: 2011, 11(3);283-90 PubMed 21331528
  27. FoSheng Hsu, Yuxin Mao The Sac domain-containing phosphoinositide phosphatases: structure, function, and disease. Front Biol (Beijing): 2013, 8(4);395-407 PubMed 24860601
  28. Elisa Tinelli, Jorge A Pereira, Ueli Suter Muscle-specific function of the centronuclear myopathy and Charcot-Marie-Tooth neuropathy-associated dynamin 2 is required for proper lipid metabolism, mitochondria, muscle fibers, neuromuscular junctions and peripheral nerves. Hum. Mol. Genet.: 2013, 22(21);4417-29 PubMed 23813975
  29. Páris N M Sidiropoulos, Michaela Miehe, Thomas Bock, Elisa Tinelli, Carole I Oertli, Rohini Kuner, Dies Meijer, Bernd Wollscheid, Axel Niemann, Ueli Suter Dynamin 2 mutations in Charcot-Marie-Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination. Brain: 2012, 135(Pt 5);1395-411 PubMed 22451505
  30. 30.0 30.1 P Lestienne, G Ponsot Kearns-Sayre syndrome with muscle mitochondrial DNA deletion. Lancet: 1988, 1(8590);885 PubMed 2895391
  31. P Lertrit, A Imsumran, P Karnkirawattana, V Devahasdin, T Sangruchi, L Atchaneeyasakul, C Mungkornkarn, N Neungton A unique 3.5-kb deletion of the mitochondrial genome in Thai patients with Kearns-Sayre syndrome. Hum. Genet.: 1999, 105(1-2);127-31 PubMed 10480366
  32. 32.0 32.1 Íñigo Martínez-Romero, M Dolores Herrero-Martín, Laura Llobet, Sonia Emperador, Antonio Martín-Navarro, Bernat Narberhaus, Francisco J Ascaso, Ester López-Gallardo, Julio Montoya, Eduardo Ruiz-Pesini New MT-ND1 pathologic mutation for Leber hereditary optic neuropathy. Clin. Experiment. Ophthalmol.: 2014, 42(9);856-64 PubMed 24800637
  33. Agata Kodroń, Maciej R Krawczyński, Katarzyna Tońska, Ewa Bartnik m.3635G>A mutation as a cause of Leber hereditary optic neuropathy. J. Clin. Pathol.: 2014, 67(7);639-41 PubMed 24747208
  34. S Leruez, P Amati-Bonneau, C Verny, P Reynier, V Procaccio, D Bonneau, D Milea Mitochondrial dysfunction affecting visual pathways. Rev. Neurol. (Paris): 2014, 170(5);344-54 PubMed 24798923
  35. S Shimoda-Matsubayashi, H Matsumine, T Kobayashi, Y Nakagawa-Hattori, Y Shimizu, Y Mizuno Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease. Biochem. Biophys. Res. Commun.: 1996, 226(2);561-5 PubMed 8806673
  36. 36.0 36.1 36.2 David C Chan Mitochondria: dynamic organelles in disease, aging, and development. Cell: 2006, 125(7);1241-52 PubMed 16814712
  37. Satoe Shimoda-Matsubayashi, Hiroto Matsumine, Tomonori Kobayashi, Yuko Nakagawa-Hattori, Yumiko Shimizu, Yoshikuni Mizuno, Structural Dimorphism in the Mitochondrial Targeting Sequence in the Human Manganese Superoxide Dismutase Gene: A Predictive Evidence for Conformational Change to Influence Mitochondrial Transport and a Study of Allelic Association in Parkinson's Disease, Biochemical and Biophysical Research Communications, Volume 226, Issue 2, 13 September 1996, Pages 561-565, ISSN 0006-291X, http://dx.doi.org/10.1006/bbrc.1996.1394. (http://www.sciencedirect.com/science/article/pii/S0006291X96913947)
  38. Takashi Makiuchi, Fumika Mi-ichi, Kumiko Nakada-Tsukui, Tomoyoshi Nozaki Novel TPR-containing subunit of TOM complex functions as cytosolic receptor for Entamoeba mitosomal transport. Sci Rep: 2013, 3;1129 PubMed 23350036
  39. Lukasz S Borowski, Andrzej Dziembowski, Monika S Hejnowicz, Piotr P Stepien, Roman J Szczesny Human mitochondrial RNA decay mediated by PNPase-hSuv3 complex takes place in distinct foci. Nucleic Acids Res.: 2013, 41(2);1223-40 PubMed 23221631
  40. 40.0 40.1 40.2 40.3 Geng Wang, Hsiao-Wen Chen, Yavuz Oktay, Jin Zhang, Eric L Allen, Geoffrey M Smith, Kelly C Fan, Jason S Hong, Samuel W French, J Michael McCaffery, Robert N Lightowlers, Herbert C Morse, Carla M Koehler, Michael A Teitell PNPASE regulates RNA import into mitochondria. Cell: 2010, 142(3);456-67 PubMed 20691904
  41. Benoît Kornmann The molecular hug between the ER and the mitochondria. Curr. Opin. Cell Biol.: 2013, 25(4);443-8 PubMed 23478213
  42. Benoît Kornmann, Erin Currie, Sean R Collins, Maya Schuldiner, Jodi Nunnari, Jonathan S Weissman, Peter Walter An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science: 2009, 325(5939);477-81 PubMed 19556461