Energy crisis – Mitochondrial carriers in health and disease

November 16, 2011

Together with Myriam Löffler and Katja Becker I wrote this piece on mitochondrial diseases based on carrier deficiencies during the bachelors course “Molecular Mechanisms of Disease” at Radboud University Nijmegen. This course, together with a bioinformatics and two biochemistry courses lead to my wish to study more about the world of protein functioning at the molecular level. Maybe this work is of interest to some people out there.

Adenosine triphosphate is the most essential and universal high-energy containing molecule of each cell and is synthesized within the mitochondrial cell compartment. In order to maintain the complex metabolic mitochondrial equilibrium, exchange of several compounds with the surrounding cytosol is necessary and facilitated by members of the mitochondrial carrier family. Since the carrier structure contains a number of highly conserved amino acid motifs that are important for carrier specificity, point mutations can already have strong negative effects on carrier function. The spectrum of metabolic diseases therefore contains a number of mitochondrial carrier associated syndromes, some of which are present here.

1. Introduction

The mammalian mitochondrion is a metabolically highly divers compartment of the eukaryotic cell. It is required for among others gluconeogenesis, amino and fatty acids metabolism (urea cycle and β-oxidation), synthesis of proteins encoded by mitochondrial DNA (mtDNA), synthesis of its own mtDNA by making use of nucleotides, and thermogenesis through for example uncoupling. In addition and most importantly the process of oxidative phosphorylation (OXPHOS) is accomplished by different structures within the mitochondria. In order to be able to synthesize the body’s most important energy rich molecule ATP, an intense substrate and product exchange of compounds that are directly and indirectly linked to OXPHOS is necessary. Thus, several members of the mitochondrial carrier family are present to link cytosolic and mitochondrial metabolism. The substrates of the transporters include nucleotides, amino acids, co-factors, carboxylic acids and inorganic anions 1.

2. Mitochondrial carriers in health

2.1 Importance of carriers and OXPHOS

In total the human genome (nDNA and mt DNA) encodes for 48 mitochondrial carriers. It is likely that there are about 39 different functions associated to these carriers since some carriers portray an almost identical amino acid sequence similarity which is attributed to a comparable function in vivo 1. Consequently the mitochondrial carrier family can be split up into two principal groups based upon their functional properties. The first one includes carriers that have a function in the metabolic generation of energy within the cell. Most importantly those carriers are directly associated to the transport of substrates and product which are essential for OHXPHOS reactions. Secondly, the carrier family includes a group of transporters that are needed for intermediary metabolism within the mitochondria. Among this group fall carriers that are related to for example amino acid metabolism and the replication of mtDNA.

2.2 Carriers can be directly or indirectly associated with OXPHOS

In order for the OXPHOS system to be functional several substrates are required which all have to enter the mitochondrial compartment with the help of carriers (for a review of the OXPHOS system see 2 and 3). In the following a number of important compounds will be described which are transported by specific membrane molecules. Pyruvate for example which is the aliphatic end product of glycolysation is transported by a, in humans presently not identified, monocarboxylase transporter 1, 4. Pyruvate is later converted into acetyl-CoA by a reaction requiring high levels of coenzyme A (CoA). This is achieved by a recently identified carrier in human mitochondria (SLC25A42) which exchanges the externally synthesized CoA with adenosine 3′,5′-diphosphate 5. Converting pyruvate in addition also requires a number of cofactors, which also enter the mitochondrion via carriers. Except for the thiamine pyrophosphate carrier (TPC) which was recently identified in Drosophila melanogaster 6 there is presently no proof that other cofactor transporters as for lipoamide, NAD+ and FAD structurally belong to the human mitochondrial carrier family since they have only been described for some prokaryotes, Saccharomyces cerevisiae and Arabidopsis thaliana 1. In addition intermediates of the citric acid cycle which convert acetyl-CoA into reducing equivalents and GTP must enter and leave the mitochondrion. A great number of identified carriers fulfil this task. Most importantly the exchange of ATP from the in- to the outside for ADP which is transported from the out- to the inside of the mitochondrion has to take place with the help of mitochondrial carriers. This process in combination with phosphate carriers ensures the functioning of ATPase within complex V of the respiratory chain and the supply of readily generated ATP for the cell 1. Further a variety of mitochondrial uncoupling proteins (UCPs) which uncouple elements of the electron transport chain can be used for thermogenic purposes through the release of the H+ proton gradient which generates heat in cells of especially the skeletal muscles 7.

2.3 Carriers associated with the metabolism of non-OXPHOS related compounds are important for housekeeping

Several carriers are needed to maintain the more general functional properties of mitochondria in order to produce ATP molecules. Apart from the carriers that have a direct influence on the metabolic cycles and the respiratory chain there are carriers needed for the metabolism of amino acids and replication of mtDNA.

Nitrogen rich compounds which originate from the degeneration of aminoacids in the form of citrulline after a number of conversions leave the mitochondrion through carriers. The urea cycle for example depends on carriers such as the citrulline/ornithine exchanger. In addition also structurally complete amino acids are transported into or out of the mitochondrion. This is achieved by a number of single amino acid carriers or transport molecules that exchange one amino acid for another one 1.

For the intra mitochondrial metabolism of mtDNA deoxynucleotides are needed within this cell compartment. The deoxynucleotide carrier (DNC) encoded by the gene SLC25A19 seems to fulfil this function 8. However and despite the structural properties of DNC there is increasing evidence that DNC might not be the appropriate deoxynucleotide carrier of the mitochondrion based on metabolomic and enzyme kinetical studies 9. Other specific carriers are utilized to transport methyl containing compounds for the methylation of DNA, RNA and proteins 1.

2.4 General structure of the mitochondrial carrier family

Multiple sequence alignment of several carriers was applied to identify residues that play a role in substrate transport and binding points since it was expected that residues that play a role in transport are more symmetrically conserved than the asymmetric residues that provide substrate binding capabilities 10.

The atomic model of the Bos taurus ADP/ATP carrier provided first insights into the exact structural and functional properties of members of the mitochondrial carrier family. Presently this whole group of carrier proteins is classified based upon its structure. When comparing their amino acid sequences several aspects are noticeable. First of all the sequence consists out of three homologous tandem repeats of about 100 amino acids that form a pseudosymmetric structure (Fig. 1A) and a 3D barrel structure within the mitochondrial membrane. Each repeat consists out two α-helices, termed H1-H6, which are linked by a short α-helix on the mitochondrial matrix site of the carrier. Within this region also the conserved signature motif PX[DE]XX[RK] can be found. The odd numbered helices (H1, H3, and H5) are linked by the proline residues kinking them in a certain angle based on the fused backbone properties of the prolines. Charged residues within the signature motif form salt bridges and lock the odd numbered transmembrane helices together closing the carrier structure on the matrix site 10.

For the transport of substrates across the membrane the carriers exist in two distinct conformational states. During the cytoplasmic state (c-state) the carrier accepts its substrate from the cytoplasmic site and during the matrix state the carrier binds to a substrate from the mitochondrial matrix side. Binding of substrates occurs within a mid-membrane internal aqueous cavity (Fig. 1B) consistent with the two opening states at a specific and functionally conserved binding site in all mitochondrial carriers. This conservation can especially be observed at three carrier-substrate contact points named contact point I-III on the even numbered helices (H2, H4, and H6). Especially contact point II offers some interesting insights in carrier function because the conservation of amino acids at this point correlates precisely with the subfamily of the carrier. Different signature motifs of for example amino acid, keto acid or adenine nucleotide carriers at contact point II are thus able to bind and distinguish the specific substrate that belongs to the subfamily (Fig. 1B) 11.

The precise structural changes a carrier undergoes during substrate binding and release are presently unknown but modelling with the yeast ADP/ATP carrier proposed a probable mechanism. According to this mechanism carriers act as monomers and binding of the substrate disrupts the fragile but normally stable salt bridge network at the edges of the carrier enabling it to change its conformational state into one of the two possibilities 10. Other mitochondrial carriers are expected to work in a similar way.

When looking at these fragile binding and transport mechanisms it is not astonishing that already single amino acid mutations can distort carrier function heavily leading to malfunctions and disease.

 Fig. 1: (A) displays the tripartite structure of the mitochondrial carrier family consisting out of three tandem repeats (dotted red lines) each containing two conserved helices (black). Red bars mark the conserved signature motif at the matrix site which probably fulfils functions in transport and structure 1. (B) is a lateral view model of the mid membrane aqueous cavity substrate binding site, displaying the contact points I-III, of the carrier BtAAC1. H6 is removed. The purple arrow denotes the position of the substrate, the yellow arrow the position of the salt bridges 11.

3. Mitochondrial carriers in disease

In case of defects in mitochondrial carriers, involved metabolic routes get disturbed. Possible impacts of this are the accumulation of products and substrates and failure of the system due to malfunctioning of metabolic routes. Fig. 2 shows fifteen mitochondrial carriers and their roles in transport of important metabolic substrates and products. This chapter describes a few of them and which, if damaged, cause diseases. A number of mitochondrial carrier associated diseases are presently known (Tab. 1) and some of them will be discussed here.

Fig. 2: Overview of the most important carriers in the mitochondrial membrane and their interactions. The ATP/ADP carrier (red circle) function is essential for the OXPHOS system, especially for the complex V ATPsynthase (light blue structure), since it delivers substrate (ADP) and catalyzes the transport of product out of the mitochondrion (ATP). The PiC carrier (blue circle) is directly linked to the synthethis of ATP through Pi supply for the ATPsynthase. The carnitine/ arylcarnitine carrier (green circle) imports acylCoA derived from the breakdown of fatty acids into the mitochondrial lumen. This acylCoA is further used as a substrate in the β-oxidation. The glutamate carrier (black circle) transports glutamate into the mitochondrial lumen. This transport depends on an H+ gradient, provided by the OXPHOS system 12.

Tab. 1: Diseases associated with mitochondrial carriers 12.

3.1 Diseases due to defects of mitochondrial carriers directly linked to oxidative phosphorylation

Oxidative phosphorylation of ADP to ATP acquires uptake of inorganic phosphate (Pi) and ADP into the mitochondria. Therefore, two carriers in the mitochondrial membrane are needed to catalyze the uptake: the ADP/ATP translocase and the PiC carrier.


The ATP/ADP carrier (Fig. 2) catalyzes as an antiporter the transport of adenosine triphosphate (ATP) out of the mitochondria, and conversely transports adenosine diphosphate (ADP) out of cytsol into the mitochondria. ADP is needed for the synthesis of new ATP molecules inside the mitochondria.

One ATP is exchanged for one ADP molecule simultaneously:

ATP4-(matrix) + ADP3-(cytosol) → ATP4-(cytosol)+ ADP3-(matrix)

Therefore ATP preferentially moves along the membrane potential (concentration gradient) across the inner membrane, towards the cytosol.

  • AAC1 deficiency

AAC1 is the heart-/muscle-specific ADP/ATP carrier. It is encoded by the SLC25A4 gene.

In case of an AAC1 deficiency, a homozygous mutation is located in this gene. Alanine at position 123 is replaced by an aspartic acid (A123D), resulting in a complete loss of the protein’s ability to transport ADP and ATP. A123D is the first recessive mutation found in the AAC1 gene 13. When looking at crystal structure of the bovine AAC1 the structural and functional importance of A123 becomes apparent. A123 is localized between H5 and H6 in the consencus sequence GXXXG and reaches into the central substrate binding cavity which lies two helix turns above the fragile salt bridge network that controls the carriers transport conformation (cytoplasmic or matrix state, see above). It is thus imaginable that A123 substitutions can cause carrier deficiencies 14.

The symptoms which are observed in patients with AAC1 deficiency constitute exercise intolerance, lactic acidosis, hypertrophic cardiomyopathy and a mild myopathy. Significantly lower activities of the respiratory chain complexes I, III and IV were measured when compared to physiologically normal values. These complexes are encoded by mtDNA. Due to the changes of adenine nucleotides in addition mtDNA is negatively affected and therefore also the mtDNA dependent respiratory chain complexes.

AAC1 deficiency may be compensated by glycolysis and transport by other AAC isoforms or other adenine nucleotide mitochondrial carriers, for instance the ATP-Mg/Pi carrier.

  • Sengers’ syndrome

The genetic defect that causes this form of AAC1 deficiency is still unknown. Presently no mutation has been found in SLC25A4 and linkage analysis excluded that the AAC1 locus is involved. Sengers’ syndrome has been described in two unrelated patients with symptoms like congenital cataracts, hypertrophic cardiomyopathy, mitochondrial myopathy and lactic acidosis. There was reduced amount of AAC1 protein and also impaired adenine nucleotide transport found in the muscle tissues of these patients. A molecular relation to AAC1 deficiency thus is possible. It is feasible that steps within DNA metabolism processes such as defective transcription, translation or targeting of AAC1 could basis of this disease 15.

  • Autosomal dominant progressive external ophthalmoplegia (adPEO)

adPEO is a heterogeneous disorder with a dominant inheritance pattern. The disease is caused by defects in certain nuclear genes affecting the mtDNA. Thus, it is resulting in multiple deletions of mtDNA in post-mitotic tissues, in particular in brain, muscle and heart. In turn, these deletions induce the deficiency of respiratory chain proteins and therefore defective energy production 12.

adPEO usually appears at the age of 20–40 years. The symptoms found in patients with this disease are for example weakness of the external eye muscles, ptosis, mild descending myopathy, also possible symptoms imply bilateral cataract, sensorineural hypocusia,  tremor, ataxia, sensorimotor peripheral neuropathy, generalized muscle weakness, exercise intolerance, depression, parkinsonism and endocrine dysfunction.

Research showed that not only primary mtDNA deletions are responsible for PEO.  By linkage analysis it has been shown, that also mutations of three nuclear genes, leading to secondary multiple deletions of mtDNA, can cause this disorder:

a) SLC25A4, encoding the heart-/muscle-specific mitochondrial AAC1

b) Twinkle, encoding a mtDNA helicase

c) POLG1,encoding the catalytic subunit of mtDNA-specific polymerase γ.

AAC1 deficiency is described in the above section. The genes Twinkle and POLG1 are directly involved in the repair and replication of mtDNA. This type of nuclear-dependent PEO can be inherited through heterozygous mutations in the POLG1 gene, but more common as an autosomal dominant disorder 16, 17. All three mutations thus lie within nuclear DNA, but then in genes which affect the metabolism of mtDNA. These intragenome interactions lay the basis for adPEO. Treatment of PEO medicates the symptoms, such as eye props and ptosis surgery.

PiC carrier

The PiC carrier (Fig. 2) catalyzes as a symporter the transport of phosphate ions out of the cytosol into the mitochondria by H+ co-transport. Phosphate (Pi) is essential for the oxidative phosphorylation of ADP into ATP.

  • PiC deficiency

The PiC carrier is encoded by the SLC25A3 gene. Two isoforms of this carrier, which are alternative transcripts, have been identified. PiC-A is expressed only in heart and muscle, and PiC-B is expressed in all tissues 12.

A homozygous mutation in PiC-A is the cause of PiC deficiency. Glycine is substituted by a

glutamic acid residue, resulting in a damage of the protein function. It is remarkable that this mutation is localized within exon 3A, which is one of the alternatively spliced variants (PiC-A). Gly72Glu is located within the first transmembrane helix (H1, see above ). Substituting a small non-charged amino acid (Gly) with a charged and thus polar and relatively large amino acid (Glu) is expected to have severe effects on folding and thus functional and structural properties of the protein. Multiple sequence alignment of SLC25A3 from several eukaryotic organisms showed a high degree of glycine conservation at position 72 indicating an important and specific role of this residue 18. In addition this glycine lies within the conserved H1 region of the carrier family (see above) which is important for the opening and closing state of the carrier. These results indicate that Gly72Glu might be the reason for PiC deficiency.

The defect in the PiC-A-mediated uptake of Pi into the mitochondria inhibits the ATP synthesis by oxidative phosphorylation and thereby leads to a severe shortage of energy supply within the affected cells. However the ATP synthesis in patients was only defective in muscle tissue since PiC-B is not affected as it lies on another transcript version. Analysis of the heart mitochondria showed reduced levels of ADP-stimulated respiration of pyruvate, but normal activity of the respiratory chain enzymes, pyruvate dehydrogenase and oligomycinsensitive ATP-ase. This suggests that there is no defect in the SLC25A4 gene as in AAC1 deficiency. Patients with this disorder suffer from muscular hypotonia, progressive hypertrophic cardiomyopathy, elevated plasma lactate levels, and lactic acidosis. Newborns die within 4 to 9 months because of heart failure due to the missing PiC-A carrier. The function of the PiC-A carrier cannot be compensated by another protein 12.

3.2 Diseases due to defects of mitochondrial carriers involved in intermediary and housekeeping metabolism

Next to the carriers directly related to the oxidative phosphorylation, there are a lot of carriers playing an important role in processes that are not directly linked to ATP synthesis. These range from carriers that provide intermediary compounds for the oxidative phosphorylation to carriers that transport amino acids and nucleotides for the replication and translation of mitochondrial DNA (mtDNA) 1 (Fig. 2).

For example the carnitine/arylcarnitine carrier (CAC) for example is related to generating energy, but not ATP directly as opposed to PiC, because it imports acylCoA from lipid degeneration in the cytoplasm to the mitochondrial lumen so that it can be used in β-oxidation. This process also generates energy as NADH en FADH2 which are used in the oxidative phosphorylation by the complexes I-V to transport electrons (Fig 2). This carrier is thus indirectly linked to the ATP generation 19.

On the other hand, the glutamate carrier (GC) manages the symport of protons and glutamate that can be used in the synthesis of proteins from mtDNA (Fig. 2). The Py carrier (PyC) among others imports pyrimidines for the replication of mtDNA. Defects in these processes will first impair the mitochondrion itself and as a result they will disturb the ATP generation 12.

Pathological mutations in one of these carriers involved in intermediary mitochondrial metabolism are expected to cause severe diseases. There are five defects in the carriers known that play an important role in the development of severe symptoms, mainly related to the function of the heart, liver, brain and muscles. The CAC deficiency influences the β-oxidation and so the energy supply of the oxidative phosphorylation while the HHH syndrome is associated with a defect in the ornithine/citrulline carrier (ORC) impairing the urea cycle. The AGC2 deficiency, Amish microcephaly and neonatal myclonic epilepsy are related to the transport of nucleotids and amino acids (table 3.1) 12.

Carnitine/ Arylcarnitine Carrier

The carnitine/arylcarnitine carrier exchanges arylcarnitine from the cytoplasm with carnitine from the mitochondrial matrix. In the cytoplasm carnitine reacts with acylCoA derived from lipid degeneration. The product, acycarnitine, enters the mitochondrion supported by the CAC. In the mitochondrial matrix a reaction of acylcarnitine with CoA results in carnitine and acylCoA. Carnitine is exported by CAC while acylCoA takes part in the ß-oxidation (Fig. 2) 19.

  • CAC deficiency

CAC is encoded by the gene SLC25A20 which is located on chromosome 3p21.31 and contains 9 exons. It is expressed in high levels in skeletal muscles, liver and heart. This might explain the symptoms that are caused by mutations. So far, mainly missense mutations such as D32N, R133W or P230R have been identified to cause CAC deficiency 20. All three are mutations within different signature motifs that appear in all mitochondrial carriers. Other mutations related to the disease are R178Q and G81R which concern residues that are expected to be part of the substrate binding site (Fig. 3) 21. Furthermore, frameshift mutations in exon 1 and 3 in combination with missense mutations are found to cause the appearance of an early stopcodon affecting the amino acid at position 127 22.

 Fig. 3: Protein structure of CAC. The different colours represent different domains and the binding site is predicted to be around the violet area. The mutations found in CAC deficiency are also shown 12.

The symptoms of a CAC deficiency especially affect the organs showing a high expression of CAC. So, cardiac arrhythmia, muscle weakness and abnormal liver function appear due to an accumulation of acylcarnitines and fatty acids that cannot be oxidized. Normally, fatty acid oxidation provides energy in form of NADH and FADH2 in periods of fasting and physical exercise leading to severe complications in fasting patients. Furthermore, hypoketosis occurs because of the reduced fatty acid oxidation and acidosis and hyperammonemia might develop from an increase in amino acid oxidation to compensate the diminished β-oxidation 21. CAC deficiency is inherited autosomal recessivly and denotes two phenotypes. It can emerge in the neonatal period which is most common and the more severe form. Patients suffer a high mortality rate within the first hours or days after birth and present no CAC activity. However, patients displaying a later onset during childhood posses the milder variation and a rest activity of CAC remains. They can be treated by administrating medium-chain triglycerides. These can enter the mitochondrial matrix without the aid of CAC and carnitine. In the mitochondrion the triglycerides can take part in the β-oxidation and energy can be generated despite of the CAC deficiency 12. To make treatment efficient an early recognition of the disease is required. CAC deficiency can be identified by mass spectrometry which is used in neonatal screening programs. As a reaction on the diagnosis of CAC deficiency patients get a special diet consisting of frequent meals with low lipid content and rich in carbohydrates. So they will not become hypoglycemic as a result of the frequent meals. Low lipid levels in the food are required to prevent the accumulation of fatty acids and acycarnitine that lead to cardiac arrhythmia, muscle weakness and abnormal liver function 12.

Glutamate Carrier (GC)

The glutamate carrier symports glutamate with protons into the mitochondrial matrix. Within the mitochondrion a proton motive force (PMF) is used to generate ATP, and GC can profit from this H+ gradient, too (Fig. 2). Two known isoforms of GC exist. GC2 is expressed in the mitochondria of almost all tissues and is responsible for the fulfillment of basic glutamate requirements. Only in tissues with an extended demand GC1 is expressed. In the neonatal myoclonic epilepsy a deficiency in GC1 leads to severe symptoms 12.

  • Neonatal myoclonic epilepsy

The mutations found to cause neonatal myoclonic epilepsy are P206L and G236W in the SLC25A22 gene mapped on chromosome 11p15.5. Multiple sequence aligments showed that these mutational sites are located within highly conserved regions in helices (H1, H3, and H5) near the cytosolic membrane side 23. The effect might be that the carrier protein cannot fold any more or that there is no substrate binding possible due to a disturbed salt-bridge network (see above).

The symptoms are hypotony, progressive microcephaly, abnormal visual nerve conduction, encephalopathy and spasticity. These mainly neurological effects can arise due to the fact that glutamate is an important neurotransmitter and that effective transmission requires a particular intracellular glutamate concentration 23. However, the detailed mechanisms of the development of these symptoms remain elusive. Treatment could target the concentration of glutamate within cells. An increase of the concentration gradient would facilitate the transport of more glutamate.

4. Conclusion

Due to the complexity of the metabolic pathways that are present within the mitochondrial cell compartment deficiencies of mitochondrial carriers with different functions cause severe metabolic diseases. These defects are mostly based on mutations within the nDNA, but can also originate from mtDNA. The mitochondrial carrier family is organized and built up in a highly specific and conserved manner and even a small number of point mutations and therefore amino acid substitutions within these regional motifs can have great negative implications on carrier structure and thus function.

The phenotypic effects of the described malfunctions can especially be observed in organs with high energy demand such as liver, heart, skeletal muscle and brain. Due to the systemic importance of these organs severe diseases are the consequence, frequently with high mortality in early childhood.

One carrier can affect several metabolic routes directly or indirectly and therefore compensation of the described deficiencies is seldom possible due to the high specificity of the carriers. In some cases treatment might be promising and can involve bypassing the critical transport route through the supply of alternative compounds.

Since metabolic diseases are accompanied by severe health effects and cure is currently not possible, more insights in the molecular functioning of mitochondrial metabolism in general and especially carrier properties are essential.


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