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Human Molecular Genetics Pages 1573-1579  

Nuclear genes of human complex I of the mitochondrial electron transport chain: state of the art
Introduction
Composition, Spatial And Functional Organization Of Complex I
Human Complex I Deficiency
Human Nuclear-Encoded Complex I Genes
Perspectives For Future Research
Acknowledgements
References

Nuclear genes of human complex I of the mitochondrial electron transport chain: state of the art

Nuclear genes of human complex I of the mitochondrial electron transport chain: state of the art

J. A. M. Smeitink, J. L. C. M. Loeffen, R. H. Triepels, R. J. P. Smeets, J. M. F. Trijbels and L. P. van den Heuvel*

Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, University Hospital Nijmegen, Geert Grooteplein 20, PO Box 9101, 6500 HB Nijmegen, The Netherlands

Received May 28, 1998

The mitochondrial electron transport chain (mtETC) consists of four multi-subunit enzyme complexes. Complex I or NADH:ubiquinone oxidoreductase, the largest mtETC multisubunit complex, consists of ~41 subunits. Seven of these subunits are encoded by the mitochondrial genome, the remainder by the nuclear genome. Among the mitochondriocytopathies, complex I deficiencies are encountered frequently. Although some complex I deficiencies have been associated with mitochondrial DNA mutations, the genetic defect has not been elucidated in the majority of complex I-deficient patients. It is expected that many of these patients have mutations in the nuclear-encoded subunits of this complex, so vital for cellular energy production. After a brief summary of the current knowledge of complex I from cow, bacteria and fungi, this review presents the state of the art of the knowledge of the human nuclear-encoded complex I genes which, in the last 18 months, has made enormous progress. At present, the complete gene structure of four subunits and the cDNA structure of 18 of the 34 complex I nuclear-encoded subunits are known. Mapping of these subunits shows a random distribution over the chromosomes. The chromosomal localization is known for 14 complex I genes. Recently, the first mutation, a 5 bp duplication in the 18 kDa (AQDQ) subunit, has been reported. We expect that within 1 year all human nuclear-encoded complex I subunits will be cloned. Mutational analysis of these subunits is warranted in complex I-deficient patients and will not only be important for genetic counselling but will also extend the knowledge regarding the functional properties of the individual human complex I subunits.

INTRODUCTION

Since the first description of a patient with a disturbance in the mitochondrial energy-generating system by Ernster et al. (1), numerous reviews about the mitochondrial electron transport chain (mtETC) and defects of its individual complexes have been published (2-9). The mtETC is located in the lipid bilayer of the inner mitochondrial membrane (IMM) and is composed of four multi-subunit enzyme complexes: complexes I-IV. Of these, complex II or succinate:ubiquinone reductase is the smallest one. The four subunits of complex II are all encoded by nuclear genes. This is in contrast with the subunits of complexes I, III and IV of which only a minority are encoded by the mitochondrial genome, the majority by the nuclear genome. About 30 years ago, the first structural characterization of human mitochondrial DNA (mtDNA) appeared in the literature (10,11). The mtDNA, a 16 569 bp genome present in several hundred copies per cell, encodes two rRNAs, 22 tRNAs and 13 mRNAs. The mRNAs encode the subunits for the mtETC and the F1-F0 ATP-synthetase (12). As an example, seven subunits of complex I are encoded by the mitochondrial genome (ND1-6, ND4L) (13,14). The remainder of the at least 34 subunits are encoded by the nuclear genome.

Since 1988, numerous mtDNA mutations in patients with mitochondriocytopathies have been reported (15-23). mtDNA mutations are either sporadic, maternally inherited or can be transmitted as Mendelian traits (24,25). Only a limited number of enzymatic deficiencies of one or more of the complexes of the mtETC are associated with mutations in the mtDNA (see below). Therefore, characterization of nuclear-encoded mtETC subunits and mutational analysis of these subunits have enormous implications for genetic counselling.

In the past 18 months, increasing information has become available concerning the nuclear-encoded complex I subunits in man. After a brief description concerning the composition, spatial distribution and function of complex I and the consequences of a deficient activity of this complex, so vital for cellular energy production, we will summarize the present knowledge about the nuclear genes encoding subunits of the human complex I.

COMPOSITION, SPATIAL AND FUNCTIONAL ORGANIZATION OF COMPLEX I

Most knowledge regarding the composition, spatial and functional organization of the first mtETC enzyme complex has been obtained from Bos taurus, bacteria and fungi (26-32). Unless otherwise mentioned, we now first briefly summarize the bovine data. In one of the subsequent paragraphs, the human data will be presented extensively. Bovine heart complex I has ~41 subunits with a total molecular mass of ~103 kDa. It consists of seven mitochondrial- and at least 34 nuclear-encoded subunits and has, like in Neurospora crassa, an L-shaped configuration of which the peripheral arm partly protrudes in the mitochondrial matrix (31,32). The bovine complex differs from that of N.crassa by having a thin stalk region linking the membrane-bound globular arm with the intrinsic membrane domain. Most of the electron carriers, such as flavine mononucleotides (FMNs) and iron-sulfur clusters, are located in the peripheral arm. With the use of chaotropic agents, the complex can be separated into three different fractions (33). The flavoprotein (FP) fraction and the iron-sulfur protein (IP) fraction are both water-soluble, whereas the hydrophobic protein (HP) fraction forms a water-insoluble aggregate. The FP fraction (51, 24 and 10 kDa) and the IP fraction (75, 49, 30, 18, 15 and 13 kDa and B13) form the principal catalytic sector and are located in the peripheral arm of the complex (34). The HP fraction (containing the seven mtDNA-encoded subunits and ~24 nuclear-encoded subunits) is involved in proton translocation (34,35). This fraction contains, besides hydrophobic subunits, also globular water-soluble ones, and the presence of a particular subunit in this fraction should not be taken to imply that the protein is either hydrophobic or a component of the membrane part of the enzyme complex (28). The 51 kDa FP subunit carries the NADH-binding site (36,37), and contains an FMN and a tetranuclear iron-sulfur cluster (38). The 24 kDa FP subunit contains a binuclear iron-sulfur cluster (39). The 75 kDa IP subunit contains a tetranuclear and probably also a binuclear iron-sulfur cluster (40). Sequencing of the bovine 23 kDa HP subunit revealed that this subunit contains two cysteine motifs which probably provide the ligands to accommodate two 4Fe-4S clusters (41). The FP and IP water-soluble fractions make contact through the 51 kDa FP and 75 kDa IP subunits. The FP and IP subunit stoichiometry, which is a sine qua non for the study of the structure of an enzyme complex, and the substrate-induced conformational changes have been partly elucidated by Belogrudov and Hafeti (34). They showed that the proximity of the three FP subunits to one another, the proximity of the 51 kDa FP subunit to the 75 kDa IP subunit, and the proximity of all studied IP subunits to one another and to some of the HP subunits are altered when the catalytic sector of complex I is reduced by NADH or NADPH prior to the addition of a cross-linking reagent. The authors speculated that these conformational changes may well be the device by which the energy derived from electron transfer through the catalytic components of complex I is transduced and conveyed to the subunits of the membrane sector. Here, pKa changes of appropriate residues induced by these conformational changes would result in proton uptake and release on opposite sides of the membrane.

The overall function of complex I of the mtETC is the dehydrogenation of NADH and the transportation of electrons to coenzyme Q. This electron transport creates, like for complexes III and IV, a proton gradient which is the proton-motive force for the production of ATP by F1-F0 ATP-synthetase (complex V). Besides some general functional properties of the various complex I fractions, only limited information is available about the functional properties of the individual subunits (see below).

The crystal structure of the N.crassa complex has been determined and, by immunolabelling, the 49 kDa subunit has been pinpointed to the matrix-localized protruding arm of the complex (31). Immunolabelling of other subunits will give further insight into the interrelationships of the various subunits.

HUMAN COMPLEX I DEFICIENCY

Among the group of mitochondriocytopathies (estimated incidence 1:10 000 live births), isolated complex I deficiency is frequently encountered (42). The primary underlying genetic cause of the observed deficiencies may either be at the mtDNA or at the nuclear DNA (nDNA) level. Elucidation of the underlying defect of these disorders is important for genetic counselling and indirectly will extend our knowledge of the functional properties of the individual subunits. A great variety in clinical presentation, age of onset, course of the disease and clinical chemical results exist in complex I-deficient patients. It may therefore not come as a surprise that the diagnostic process is rather complicated and that the judgement of instituted treatments is almost impossible in individual patients. In general, most affected tissues are those with a high energy demand, such as brain (mental retardation, convulsions, movement disorders), heart (cardiomyopathy, conduction disorders such as Wolf-Parkinson-White syndrome), kidney (Fanconi syndrome) and/or skeletal muscle (exercise intolerance, muscle weakness, hypotonia). Frequently ophthalmological signs such as external ophthalmoplegia, ptosis, cataract and retinopathy may also be present (43). The diagnosis `enzymatic complex I deficiency' is often made in early childhood and, although exceptions to this exist, the course is often that of a progressive multisystem disorder with a fatal outcome. In most patients, lactic acidaemia with increased lactate:pyruvate ratios, due to the altered redox state of the cytosol, is present, although we are aware of several familial cases of complex I deficiency in which lactic acid, even after provocation (exercise, glucose tolerance test), is completely normal (44). In order to correlate genotype to phenotype, which may become possible in the next few years, a detailed clinical description of patients is of utmost importance. In suspected patients, diagnosis can be made by enzymatic and immunochemical measurements, for which a skeletal muscle biopsy sample is the tissue of choice although cultured skin fibroblasts may also be used. Noteworthy in this context is that not all deficiencies observed in skeletal muscle specimens are present in fibroblasts (45). This phenomenon, together with the diverse involvement of tissues and organs in affected patients, may be caused by differences in tissue expression of the individual subunits of the complex. In most patients, there exists some or even a considerable residual enzymatic activity. To the best of our knowledge, no patients have been described in which the complex I activity was immeasurably low. Such a condition may not be compatible with life.

Under certain conditions, prenatal diagnosis at the enzymatic level is possible and has been performed with success in specialized laboratories (45,46). Because of the fact that these measurements are technically difficult, as is the interpretation of the results, it would be very helpful if prenatal diagnosis in complex I deficiency would be possible at the DNA level.

Table 1. Present molecular genetic knowledge of human nuclear-encoded subunits of complex I of the mtETC
Homo sapiens B.taurus E.coli cDNA sequence nDNA sequence Chromosomal localization References
NDUFV1 51 (FP) kDa NuoF + + 11q13 72,75
NDUFV2 24 (FP) kDa NuoE + + 18p11.2-11.3a 39,76
NDUFV3 10 (FP) kDa n.p. + + 21q22.3 77
NDUFA1 MWFE n.p. + + Xq24-25 62
NDUFA2 B8 n.p. + - 5q31 78
NDUFA3 B9 n.p. - - -  
NDUFA4 MLRQ n.p. + - - 79
NDUFA5 B13 (IP) n.p. + - 7q32a 80,81
NDUFA6 B14 n.p. + - 21q22 78,82
NDUFA7 B14.5A n.p. - - -  
NDUFA8 PGIV n.p. - - -  
NDUFA9 39 kDa n.p. - - -  
NDUFA10 42 kDa n.p. + - 12p 83
NDUFAB1 SDAP n.p. - - -  
NDUFB1 MNLL n.p. - - -  
NDUFB2 AGGG n.p. - - -  
NDUFB3 B12 n.p. + - - 78
NDUFB4 B15 n.p. - - -  
NDUFB5 SGDH n.p. + - - 78
NDUFB6 B17 n.p. + - - 73
NDUFB7 B18 n.p. - - -  
NDUFB8 ASHI n.p. - - 12q21 82
NDUFB9 B22 n.p. + - 8q13.3 84
NDUFB10 PDSW n.p. - - -  
NDUFS1 75 (IP) kDa NuoG + - 2q33-34 85
NDUFS2 49 (IP) kDa NuoD - - -  
NDUFS3 30 (IP) kDa NuoC - - -  
NDUFS4 18 (IP) kDa n.p. + - 5 56
NDUFS5 15 (IP) kDa n.p. - - -  
NDUFS6 13 (IP) kDa n.p. - - -  
NDUFS7 PSST NuoB + - 19p13 86
NDUFS8 TYKY NuoI + - 11q13 82,87
NDUFC1 KFYI n.p. + - - 78
NDUFC2 B14.5B n.p. - - -  
n.p., not present; -, not known; +, known.
aPseudogene present.

In recent years, several complex I-deficient patients have been found in which the study of mtDNA revealed abnormalities, the most frequent being the so-called MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), MERRF (myoclonic epilepsy with ragged-red fibres) and LHON (Leber's hereditary optic neuropathy) mutations (15,18, 20,47,48). Of the ~50 mtDNA point mutations reported so far that cause human disease, ~35 occur in tRNA genes (49). Perhaps the best studied is the A->G transition at position 8344 in the tRNALys gene, the mutation that causes MERRF syndrome (50). Based on the knowledge of the entire mtDNA genome, the lysine content of each polypeptide is known, and three of the seven mtDNA-encoded complex I subunits have >10 lysine residues (51). Due to the MERRF mutation, these subunits have only a small probability of being completed, which explains the biochemical defects, such as complex I deficiency, observed in cybrids and in muscle biopsies of MERRF patients (52). The unique nature of the mitochondrial genome calls for a different approach to genetic counselling and risk analysis (53). Currently, parents of patients with a mtDNA point mutation, which is normally the case in isolated complex I-deficient patients in which a mtDNA mutation is found, cannot be offered accurate genetic counselling because of the uncertainty of predicting the clinical effect of the mutation (54,55).

Recently, the first mutation in one of the nuclear-encoded genes has been found (56). Adequate genetic counselling and reliable prenatal diagnosis is now possible in this family and in future families with this mutation. As discussed, for reliable genetic counselling and prenatal diagnosis, the elucidation of all nuclear-encoded complex I genes is urged and mutational detection in all complex I-deficient patients is of utmost importance.

HUMAN NUCLEAR-ENCODED COMPLEX I GENES

As stated above, mutations in either mtDNA or nuclear genes can lead to clinical syndromes resulting from defects in complex I of the mtETC. Since the initial description 10 years ago (57), syndromes caused by mtDNA mutations have been studied and reviewed extensively (58-60). Nuclear DNA mutations for complex I are significantly less characterized. The domination of the mitochondrial disease field by mtDNA mutations originates in part from their ease of detection. The somewhat slower mutation rate of nuclear than mitochondrial genes, but the larger number of nuclear genes involved in complex I allows the prediction of about equal number of mutations occurring in each genome (61). Despite the theoretical expectation of numerous nuclear mutation-based complex I deficiencies, only one has been clearly identified (56). Nevertheless, numerous families with Mendelian patterns of transmission for complex I deficiency have been described. Several studies mention a possible male preponderance in complex I deficiency, suggesting an X-linked inheritance pattern (62-64). Cloning of the key mediators of complex I activity in other species set the stage for molecular genetic studies of the nuclear contribution to this disorder in man.

A small form of complex I, consisting of 14 subunits, is found in Escherichia coli (30,65). In this bacterium, all complex I genes are organized in the so-called nuo-operon (NADH:ubiquinone oxidase). Seven genes code for peripheral proteins, including all proteins with binding motifs for NADH, FMN and all FeS clusters (Table 1). The seven remaining genes code for the hydrophobic membrane intrinsic proteins. All 14 proteins originating from these genes were found in purified complex I preparations (66). Most eukaryotes (with the exception of some fermentative yeasts such as Saccharomyces cerevisae, Schizosaccharomyces pompe and Kluyveromyces lactis) contain complex I in their mitochondrial respiratory chain (67). Purified complex I preparations exist for several animals (28). Many cDNA sequences coding for the mitochondrial complex I subunits are known in different species. They include the homologues of the 14 subunits that made up the E.coli complex I. Seven membrane intrinsic subunits, the homologues of E.coli Nuo A, H and J-N, are mitochondrial encoded in animals as well. All other subunits are nuclear encoded in most eukaryotes. The large group of additional subunits of which no counterparts exist in E.coli is a specific feature of the mitochondrial complex I. The number of nuclear-encoded complex I subunits increases as the evolutionary complexity of the organism increases.

In humans, all of the seven mitochondrial-encoded complex I subunits, together with those encoded by the nucleus, assemble to form complex I. We collected families with an autosomal or X-linked mode of inheritance of complex I deficiency. We took a candidate gene approach to study complex I deficiency in man. The cDNA sequences encoding complex I subunits in E.coli. and B.taurus had been established. The bovine cDNAs and human expressed sequence tags were used to isolate homologous nuclear-encoded human complex I cDNAs. We started to clone the cDNA sequence of human nuclear-encoded complex I subunits for which functional significance could be expected and performed mutational analysis in a group of 20 enzymatic complex I-deficient patients. Using this approach, we observed the first pathogenic mutation in a nuclear gene (NDUFS4) encoding the 18 kDa (AQDQ) subunit of the mitochondrial respiratory chain complex I (56). It concerns a homozygous 5 bp duplication, destroying a consensus phosphorylation site, and elongates the protein by 14 amino acids. The mutation was associated with a fatal progressive course in a complex I-deficient patient without lactic acidaemia.

Thanks to the outstanding work of Walker (28), who cloned most of the nuclear complex I cDNAs in B.taurus, the Human Genome Project (68), and the ever increasing possibilities for computer-based cloning of the human complex I cDNA/genes, considerable progress has been made during the last few years. This concerns especially the elucidation of the human cDNA sequence, gene structure and chromosomal localization of nuclear-encoded complex I subunits. The time has come to use a universal nomenclature for the human complex I subunits (Table 1). The human cDNA sequence of 18 nuclear-encoded subunits of complex I are known and are listed in GenBank. The remaining 16 nuclear-encoded subunits of human complex I have not yet been cloned. The human cDNA sequences provided insights into the structure and putative function(s) of complex I subunits. For example, the 18 kDa (NDUFS4) subunit has a phosphorylation consensus site and is the substrate of the mitochondrial cAMP-dependent protein kinase (mtPKA). It has been suggested that the cAMP-dependent phosphorylation by mtPKA of the 18 kDa (AQDQ) subunit of bovine heart complex I might have a role in the regulation of the function and/or biogenesis of the complex (56,69). The SDAP (NDUFAB1) subunit is an acyl carrier protein and contains a consensus phosphopantetheine-binding site. Phosphopantetheine serves as the binding site of activated fatty acids or amino acids and, therefore, the putative function of acyl carrier proteins is related to fatty acid and polypeptide biosynthesis (70). The cDNA sequence of the human 24 kDa (NDUFV2) subunit and comparative binding studies of [[gamma]-35S]GTP to complex I and its 24 kDa protein provided evidence that the 24 kDa subunit (NDUFV2) is a G protein (71). We recently showed that the human 51 kDa subunit (NDUFV1) reveals 100% antisense homology of its 3[prime]-untranslated region (3[prime]-UTR) with the 5[prime]-UTR of the [gamma]-interferon-inducible protein (IP-30) precursor, which may be the link between complex I deficiency and inflammatory myopathy which repeatedly have been described to occur together (72).

Up to now, the chromosomal localization of 14 out of the 34 nuclear-encoded subunits of complex I has been established (Table 1). So far, only one gene (NDUFA1) is localized on the X-chromosome. We obtained no evidence that this subunit was responsible for enzymatic complex I deficiency in a group of 20 patients who had no mutations in mitochondrial-encoded subunits of complex I (64). For four human nuclear-encoded subunits (NDUFV1-3, NDUFA1), the gene structure has been elucidated. Analysis of the transcriptional regulation of the complex I genes will become a future research topic. At present, data available for human NDUFA1 and NDUFB6 suggest that the expression pattern of the nuclear-encoded complex I subunits is comparable with that of housekeeping genes. The level of expression seems to be related to the energy demand of the tissue. The highest expression levels were observed in adult heart, skeletal muscle and fetal heart. Also, expression in kidney, liver, pituitary gland and adrenal gland seems to be slightly higher than in other tissues investigated (64,73). For some nuclear-encoded complex I subunits, the possible involvement in human pathology (e.g. Parkinson's disease) has been reported by molecular genetic studies (74). Only one mutation has been described in a nuclear-encoded subunit of complex I in isolated human complex I deficiency (56). Mutation detection studies have been performed in complex I-deficient patients for only five nuclear-encoded genes of complex I (NDUFV1-3, NDUFA1 and NDUFS4). Mutation detection studies in the remaining genes will increase insight into complex I deficiencies. These studies will be performed in the near future, since pathogenic mutations in mtDNA have been excluded in many complex I-deficient patients and the cDNA sequences of 18 out of 34 nuclear-encoded subunits of human complex I are known.

PERSPECTIVES FOR FUTURE RESEARCH

Cell biological and molecular cloning studies are increasingly providing crucial information for suggesting, and testing, candidate genes in inherited disorders. The elucidation of the pathogenesis of complex I deficiency requires the synergy of molecular genetics, clinical medicine and basic physiology. The contribution of numerous nuclear-encoded subunits to isolated complex I deficiency still has to be established. First of all, the remaining human genes for complex I have to be cloned. We expect this will be done by various research groups around the world. If not, we will be able to obtain this information from the Human Genome Project which is running ahead of schedule. Mapping of these genes on the human genome may be used for selecting candidate genes for human pathology. To prove the definite involvement of the genes, mutation detection studies will have to be performed. Patients can be selected based on enzymatic analyses of complex I activity performed in specialized laboratories. We propose to start with the nuclear genes already present in the minimal form of complex I in E.coli. We would then analyse the remaining subunits belonging to the FP and IP fraction for the presence of mutations. Finally, we suggest concentrating on the HP subunits. Although the frequency of mutations in nuclear genes for subunits of complex I still has to be established, initial experimental data suggest that the future findings will be important for improving the potential for genetic counselling and prenatal diagnosis. An additional major area of investigation will be the generation of animal models to study the regulation and function of complex I genes. These animal models may also be used for therapeutic intervention studies which are almost impossible in patients due to the great clinical variability. Clearly, much work still has to be done with regard to the pathogenesis and improvement of the treatment of complex I deficiency. It goes without saying that different scientific disciplines are crucial to these investigations and will continue to play vital roles in these processes.

ACKNOWLEDGEMENTS

The authors would like to thank all the former and present members of the NCMD for ongoing enthusiastic participation and for their permission to use some of their unpublished data. Special thanks to Professors Frans Trijbels and Rob Sengers who, already >20 years ago, started the studies on mitochondriocytopathies in our centre. These studies were possible due to grants from the Prinses Beatrix Fonds and the Stichting voor kinderen die wel willen maar niet kunnen granted to J.S. and L.v.d.H.

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*To whom correspondence should be addressed. Tel: +31 24 3614430; Fax: +31 24 3616428; Email: b.vandeheuvel@ckslkn.azn.nl

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