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SYMPOSIUM: Mitochondrial Encephalomyopathies
Mitochondrial Respiratory Chain Diseases and
Mutations in Nuclear DNA: A Promising Start?

Carolyn M. Sue1 and Eric A. Schon1,2
units of the various respiratory chain complexes (Figure1). Each complex of the respiratory chain also contains Departments of 1Neurology and of 2Genetics and Develop- subunits encoded by nuclear genes, which are assem- ment, Columbia University, New York, NY, USA bled together with the mtDNA-encoded subunits into Introduction
the respective holoenzymes, located in the inner mito- For more than a decade, the search for pathogenic chondrial membrane. The coordination of the signals mutations in human diseases due to respiratory chain between the nucleus and the mitochondrion are poorly dysfunction has been focused on the mitochondrial understood, and only now are beginning to be elucidat- genome. Over 100 mutations affecting both tRNA genes and genes specifying subunits of respiratory chain com-plexes have now been found (11, 36). In the past few Mendelian-inherited respiratory chain diseases
years, the focus of attention has shifted to the search for Diseases associated with mtDNA defects typically mutations within the nuclear genome (nDNA), includ- follow a maternal pattern of inheritance, but some are ing genes that encode structural subunits of the respira- sporadic (see the review by DiMauro and Andreu). In tory chain, genes that are needed for the assembly of contrast, disorders associated with nDNA follow the tra- these subunits, and genes that are involved in interge- ditional mendelian patterns of inheritance. Even though nomic signalling. We will focus here on known nuclear all components of the respiratory chain contain nuclear- mutations affecting specific complexes of the respirato- encoded subunits, pathogenic mutations have been iden- ry chain, and their assembly. Disorders involving tified thus far only in Complexes I, II, and IV. Mutations intergenomic signalling are discussed in the review by in these complexes were identified by adopting the strat- egy of sequencing the most conserved subunits in well-selected patients with isolated Complex I deficiency.
The respiratory chain
Other techniques employed both a candidate gene The respiratory chain consists of four multisubunit approach and techniques that screen the entire nuclear complexes (Complexes I-IV) which, together with com- genome (e.g. linkage analysis; microcell-mediated chro- mosome transfer). Despite these search methods, muta- chain/oxidative phosphorylation system. The first four tions in Complex III and V have eluded detection thus complexes act together to generate a proton gradient far. Whether mutations in these respiratory chain com- that is coupled to the conversion of ADP and inorganic ponents are in fact rare (but await discovery), or are bio- phosphate to ATP in Complex V. The respiratory chain logically so severe that they are incompatible with life, is unique, in that it is under the control of two separate is a matter of speculation. What is clear however, is that genomes: mtDNA and nDNA. Unlike nDNA, the entire the search for the cause of mendelian-inherited respira- sequence of the human mitochondrial genome is known tory chain disorders has only just begun and will carry (2). It is a 16,569-bp circle of double-stranded DNA us well into the next developmental stage of mitochon- containing genes specifying 2 ribosomal RNAs, 22 transfer RNAs, and 13 structural proteins; all 13 are sub- Corresponding author:Eric A. Schon, Departments of Neurology and of Genetics and Development, Columbia University, 630 West 168th Street, New York,NY 10032, USA; Tel.: 212-305-1665; Fax: 212-305-3986; E-mail: Complex I disorders
present in all tissues examined (brain, heart and liver) Complex I, or nicotinamide adenine dinucleotide (18). Conversely, Complex I deficiency can also be tis- (NADH)-ubiquinone reductase, reduces NADH and sue-specific; in these cases, analysis of unaffected tis- sues will fail to detect a defect (32).
largest enzyme complex of the respiratory chain and is Even though isolated Complex I deficiency is comprised of at least 42 subunits (the exact number is encountered relatively frequently, pathogenic mutations unknown), of which 7 are encoded by the mitochondri- have been found in only four of the 35 nuclear-encoded al genome (40). It is therefore perhaps not surprising subunits of Complex I (see Table 1). All but one of these that isolated Complex I deficiency appears to be one of subunits are the human homologues of proteins found in the most common causes of mitochondrial encephalo- E. coli, implying that these are highly conserved and important subunits probably essential for Complex I Patients with Complex I deficiency usually present at function. Point mutations in the NDUFV1 flavoprotein birth or in early childhood with severe, often fatal, mul- gene caused a fatal leucodystrophy with, interestingly, tisystemic disorders frequently dominated by brain dys- myoclonic epilepsy (37). Mutations in three other sub- function. The most common clinical presentation is units of Complex I — a 5-bp tandem duplication in the Leigh syndrome (LS), with 40-50% of these cases hav- NDUFS4 iron-sulfur protein gene (50), and point muta- ing associated cardiomyopathy (23, 29, 31). Fatal tions in the hydrophobic protein genes NDUFS7 (48) neonatal lactic acidosis is also common. Less frequent and NDUFS8 (18) — all caused Leigh syndrome. The presentations include hepatopathy, renal tubulopathy, mechanisms by which the mutations cause these respi- exercise intolerance, and cardiomyopathy with cataracts Patients with LS and complex I deficiency typically Complex II disorders
have vomiting, failure to thrive, and respiratory difficul- Complex II, or succinate dehydrogenase-ubiquinone ties. Infants usually develop hypotonia and brainstem oxidoreductase, oxidizes succinate to fumarate (in the dysfunction, and, less frequently, seizures (18, 37). If citric acid cycle) and transfers electrons from FADH2 to children survive the neonatal period, they may develop CoQ (in the respiratory chain). It is comprised of four severe psychomotor retardation and depressed tendon subunits: the flavoprotein (Fp; subunit SDHA) and the reflexes. Progressive neurological dysfunction usually iron-sulfur protein (Ip; subunit SDHB) make up the cat- ensues until death in early to late infancy, although one alytic core, while the cytochrome b heme-protein that child with severe mental retardation survived into late anchors the core to the inner mitochondrial membrane is childhood (37). Heart involvement is rare in nDNA- composed of a large (cybL; subunit SDHC) and a small encoded Complex I disorders, as only one such case, (cybS; subunit SDHD) cytochrome b subunit. Complex with evidence of hypertrophic cardiomyopathy, has II is the only respiratory chain complex that is encoded been reported (18). All nDNA-encoded Complex I defi- ciencies described to date have been inherited as reces- There is a wide clinical spectrum of disease associat- ed with Complex II deficiency, including Kearns-Sayre Neuroimaging in patients usually shows bilateral syndrome (30), muscle weakness (13), hypertrophic car- basal ganglia and mesencephalic lesions, consistent diomyopathy (33), Leigh syndrome (6), optic atrophy with LS, but on occasions, white matter involvement and cerebellar ataxia (43), and hereditary paragan- (37) and non-specific atrophy are present (37, 50). Arte- glioma (4). However, to date, only three pathogenic rial and CSF lactate levels may be elevated, but are mutations in Complex II genes have been identified.
often normal. Muscle histology has shown non-specific The first mutation involved two sisters with LS. Both changes, such as reduced number of small type I fibers.
presented with motor regression in early infancy and Ragged-red fibers (RRF) have never been reported in developed rigidity, bilateral pyramidal signs, cortical muscle biopsies from patients with nuclear-encoded, blindness, and died within a few months of disease onset and only rarely in patients with mtDNA-encoded, Com- (7, 43). Succinate dehydrogenase (SDH) activity was decreased in muscle, fibroblasts, and lymphocytes. Both Biochemical evidence of isolated Complex I defi- sisters had a homozygous mutation in the Fp subunit of ciency is usually found in muscle or cultured skin Complex II (i.e. SDHA), converting Arg-544 to Trp.
fibroblasts of patients, although postmortem studies of Recently, another child with LS, who developed truncal one patient showed that the biochemical defect was ataxia in early infancy, was found to be a compound het- C. M. Sue and E. A. Schon: Mitochondrial Respiratory Chain Diseases and Mutations in Nuclear DNA Clinical features
Table 1. Nuclear-encoded gene mutations associated with mitochondrial disease.
* Denoted erroneously as G822T in (54); † Our unpublished data; ss = splice site mutation.
Genbank accession numbers: COX10 (U09466.1); NDUFS4 (AF020351.1); NDUFS7 (by PCR; nt+1 @ initiator Met); NDUFS8
(U65579.1; nt+1 @ initiator Met); NDUFV1 (AF053070.1; nt+1 @ initiator Met); SCO2 (AF177385.1); SDHA (L12936.1); SDHD
(AB006202.1); SURF1 (Z35093.1). SURF1 mRNA is numbered starting with the initiator Met codon either as nt+1 (references 9, 44,
45, 46, 54) or nt+15 (references 28, 42, 55).
C. M. Sue and E. A. Schon: Mitochondrial Respiratory Chain Diseases and Mutations in Nuclear DNA erozygote for mutations within the Fp gene, at amino 44-46, 54, 55), although the prevalence within different acid positions 1 (converting Met to Leu) and 524 (con- populations seems to vary. Patients usually present in early infancy with failure to thrive, and with brainstem Mutations in the SDHD gene that encodes the cybS and respiratory abnormalities, and die in early to late protein have been identified in patients with hereditary childhood. Patients have lactic acidosis and typically paraganglioma. This is a rare autosomal dominant dis- have lesions in the basal ganglia. Biochemical studies order associated with a genomically imprinted locus on show isolated COX deficiency in muscle and cultured chromosome 11 (with incomplete penetrance when fibroblasts. Histochemistry of muscle biopsies shows transmitted through fathers, but no expression of the dis- reduced COX activity but no ragged-red fibers.
ease when transmitted through mothers). It is character- Mutations in SURF1 are usually frameshifts; the ized by the development of benign vascularized tumors most common mutation is a deletion of 10 bp plus an in the head and neck, most commonly in the carotid insertion of an AT dinucleotide at encoded amino acid body. Both nonsense and missense mutations SDHD position 104 in Exon 4 (312del10/insAT) (42, 46).
were identified in eight unrelated families with this dis- Affected individuals may be homozygotes or compound order (4). In spite of the imprinting in the chromosomal heterozygotes. Western blot analysis has shown that region containing SDHD, the gene appears not to be pathogenic mutations are associated with a loss of pro- imprinted. In fact, the CybS defect in tumors is not due tein, due to mRNA instability or rapid protein degrada- to parental-allele-specific transcription, but rather to tion, or both (47, 53). To date, 25 mutations in SURF1 loss of heterozygosity of the normal maternal allele.
Reasons for the limited range of organ involvement that SCO2 is a mitochondrially-targeted protein thought occurs in this syndrome remain unclear, but may be due to be required for the insertion of copper into the to monoallelic expression of SDHD in the carotid body, mtDNA-encoded subunits I and II of COX (26). Muta- or to a specific vulnerability of the carotid body via tions in SCO2 are associated with hypertrophic car- hypoxic stimulation, providing a selective advantage for diomyopathy and encephalopathy that present soon after birth. Affected infants have respiratory difficulties andmetabolic acidosis, and die within the first year of life.
Complex IV disorders
Biochemical studies in affected tissues (brain, muscle, Complex IV, or cytochrome c oxidase (COX), trans- and heart) showed severe decreases in COX activity, but fers electrons from cytochrome c to molecular oxygen COX deficiency was less in cultured skin fibroblasts and pumps protons across the inner mitochondrial mem- (15, 26). Comparative biochemical and histochemical brane (22). It is comprised of thirteen subunits: the 3 studies showed that COX deficiency in muscle in largest are encoded by mtDNA and the other 10 by patients with mutations in SCO2 was more severe than nDNA. The mtDNA-encoded subunits have two heme- in those with mutations in SURF1 (42). In patients with containing cytochrome prosthetic groups (cytochromes SCO2 mutations, neuropathological findings were vari- a and a ) (3), as well as three copper atoms (located in able, including heterotopia, gliosis, early capillary pro- the Cu and Cu sites). Although isolated COX deficien- liferation, and atrophy. In contrast to patients with muta- cy due to mutations in mtDNA-encoded genes has been tions in SURF1, no child with SCO2 mutations had neu- associated with myopathies (16) and multisystemic dis- ropathological findings consistent with Leigh syndrome, ease (20), no pathogenic mutations in the nuclear- possibly because they died before they could manifest encoded subunits of COX have been found (1, 14).
However, three assembly proteins required for the prop- To date, five mutations in SCO2 have been reported er function and assembly of COX — SURF1 (45, 55), — one nonsense mutation (Q53X) and four missense SCO2 (26), and COX10 (49) — have now been associ- mutations (E140K, L151P, R171W, and S225F) — in ated with encephalomyopathies and COX deficiency.
seven unrelated families. Interestingly, all patients to SURF1, a homologue of yeast Shy1p, is a COX date have been compound heterozygotes, and even more assembly protein of unknown function that is imported remarkably, the E140K mutation was present in all into mitochondria (47, 53). It is required for the mainte- affected individuals (15, 26, and our unpublished data).
nance of COX activity and is possibly involved in the All heterozygous carriers were asymptomatic.
early stages of COX assembly (54). Numerous groups COX10 encodes a heme A:farnesyltransferase, which have now confirmed that mutations in SURF1 are asso- catalyzes the conversion of protoheme to heme O, the ciated with COX-deficient Leigh syndrome (9, 28, 42, immediate precursor of heme A, which is the prosthetic C. M. Sue and E. A. Schon: Mitochondrial Respiratory Chain Diseases and Mutations in Nuclear DNA Figure 1. The mitochondrial respiratory chain, showing nDNA-encoded (light-shaded) and mtDNA-encoded (dark-shaded) subunits.
Protons (H+) are first pumped from the matrix to the intermembrane space through Complexes I, III, and IV. They are then pumped
back into the matrix through Complex V to produce ATP. Coenzyme Q (CoQ) and cytochrome c (Cyt c) are electron transfer carri-
group of the COX I subunit. Homozygous mutations in nDNA-encoded subunits have yet been found.
exon 4 of COX10, converting an asparagine to lysine at One candidate disorder, however, is Luft disease, amino acid position 204 (N204K), were found in three which might be due to defects in Complex V. First of nine siblings born to consanguinous parents (49).
described in 1962 (19), Luft disease is a rare condition Both parents and some unaffected siblings were het- that presents in adolescence with fever, heat intolerance, erozygotes for this mutation. Neurological features profuse sweating, polyphagia, polydipsia, tachycardia, included hypotonia, myopathy, ataxia, and seizures.
and mild to moderate weakness (10). Basal metabolic Lactic acidosis and renal proximal tubulopathy were rate is elevated but patients are euthyroid. Muscle biop- also present in one child. Biochemical studies showed sies from the two known patients had RRFs and capil- reduced COX activity in muscle, lymphocytes, and lary proliferation, while polographic studies on isolated fibroblast cell lines. Western blot analysis showed that muscle mitochondria showed loose coupling of proton this mutation was associated with almost complete lack flow to ATP synthesis. Defective calcium handling by of COX II, moderately reduced levels of COX III and mitochondria, with abnormal spontaneous release, has VIc, and mild reductions in the other COX subunits.
also been documented (10). Notably, fibroblast mito- Complementation studies using yeast COX10 null chondria from a patient with Luft disease seem to lack mutants showed that, compared to the wild-type human the Pullman-Monroy inhibitor, a mitochondrial ATPase protein, the mutant human protein had markedly inhibitor protein, in the face of normal ATPase, ATP- synthetase, and SDH activities (52). However, themolecular basis for this rare disorder remains elusive.
Complex V
Complex V (ATP synthase or F F ATPase) synthe- Coenzyme Q10
sizes ATP from ADP using the proton gradient generat- ed by the respiratory chain (see Figure 1). It is com- accepts electrons from Complex I and Complex II and prised of 2 mtDNA-encoded subunits and 12 subunits transfers them to Complex III (Figure 1). Partial defects encoded by nDNA. While mutations in the mitochondr- ial-encoded components have been associated with with KSS and a number of undefined myopathies (12, human disease (see article by DiMauro and Andreu in 21, 24, 25, 56), but CoQ concentration in muscle was this issue), no pathogenic mutations involving the extremely low in four patients (5, 38, 41). These seem to C. M. Sue and E. A. Schon: Mitochondrial Respiratory Chain Diseases and Mutations in Nuclear DNA form a homogeneous subgroup, typically presenting in plasmic (albeit at high mutational loads), implying that early to late childhood with exercise intolerance, weak- homoplasmic levels of those mutations would be as ness, myoglobinuria, and cerebral dysfunction. Muscle severe, if not more so, than “homoplasmic” (i.e.
weakness is generally mild, and myoglobinuria may be homozygous, compound heterozygous, or hemizygous) induced by exercise (38), fever, or seizures (41). Ptosis and external ophthalmoplegia have also been reported Perplexingly, pathogenic mutations have been identi- (38). Cerebral dysfunction includes seizures (general- fied only in nuclear-encoded polypeptides of Complex- ized or complex partial), cognitive impairment, and es I and II, but not (at least, not yet) in those of Com- cerebellar ataxia. Cardiac involvement, if present, is plexes III, IV, or V. This may be due to the fact both mild (38). Serum creatine kinase levels may be mildly to Complexes I and II feed into ubiquinone “in parallel,” moderately elevated between attacks of myoglobinuria, and the organism may be able to cope with the loss of and serum lactate levels are increased. Biochemical either complex separately — something that cannot be assays of Complex I+II and Complex I+III activities (all said for complexes III or IV, which are downstream of of which require CoQ ) show low activities. Muscle ubiquinone and are in “series” in the respiratory chain.
biopsies from patients show RRFs and excess lipid In fact, in some organisms (most notably, the yeast Sac- droplets, and CoQ levels ranged from 3-25% of normal charomyces cerevisiae) Complex I is not even present! Similarly, Complex V is absolutely required for oxida- fibroblasts, and lymphoblast cell lines of affected tive ATP synthesis and thus, cannot be bypassed.
patients, implying that this is a tissue specific disorder.
It is worth noting that the mtDNA-encoded subunits To date, no known mutations responsible for defective of complexes I and IV specify the essential catalytic CoQ activity have been identified. However, identifi- activities of the holoprotein (witness the absence of cation of patients is extremely important, as symptoms “nDNA-encoded” subunits in these complexes in prokaryotes). While the biological importance of the mtDNA-encoded “core” subunits is obvious, the rela-tive contribution of the nDNA-encoded subunits to Discussion
overall function (e.g. modulation of activity commensu- Although the first nuclear-encoded gene defect of the rate with varying metabolic needs of the cell; tissue-spe- respiratory chain was reported six years ago, the past cific activity) is far less clear. As is the case with com- two years have seen the identification of many more plex V, however, it is possible that the functions of the such errors. These mutations are not only in proteins nDNA-encoded subunits of Complexes III and IV are as that comprise the enzyme complexes themselves, but essential as those of the mtDNA-encoded subunits, in are also in “ancillary” proteins required for their assem- which case mutations in nuclear genes would lead to bly and proper functioning. With the sequencing of the embryonic lethals. It is noteworthy in this regard that entire human genome, the development of DNA chip even the known assembly mutations in Complex IV in arrays, and a greater understanding of the role that the infants who at least survive birth do not obliterate COX respiratory chain plays in the pathophysiology of human enzyme activity completely, but rather allow affected disease, it is predictable that many more nuclear muta- tissues to maintain a residual (albeit low, and ultimately tions will be identified in the near future.
insufficient) level of normal respiratory function. Of In contrast to the diversity of phenotypic expression course, mutations in “less critical” proteins within the associated with mitochondrial DNA mutations, each respiratory chain complexes may result in less deleteri- mendelian-inherited mitochondrial disorder usually ous effects or in subclinical disease, and may thus go causes a distinct clinical phenotype, such as Leigh syn- drome or, less commonly, fatal infantile cardioen- Finally, mutations in Complex II in hereditary para- cephalomyopathy. Also, while disorders due to mtDNA ganglioma represent the first errors in a respiratory mutations often have late onset, pathogenic mutations in chain gene associated causally with neoplastic transfor- nuclear genes controlling respiratory chain complexes mation (4). While mutations in mitochondrial DNA seem to cause diseases of infancy or early childhood.
have been postulated to play a role in tumorigenesis This may be because recessive mendelian disorders tend (39), no solid evidence supporting this concept had been to be “all-or-none” phenotypically, in the sense that both obtained prior to this finding. It is possible that abnor- alleles must be mutated for the disease to be expressed.
mal respiratory chain function may play an important In contrast, most mtDNA-based disorders are hetero- role in the activation or inhibition of tumor suppressor C. M. Sue and E. A. Schon: Mitochondrial Respiratory Chain Diseases and Mutations in Nuclear DNA genes, but identification of other mutations and their 12. Fischer JC, Ruitenbeel W, Gabreels FJ, Janseen AJ, pathophysiologic mechanisms will be necessary to con- Renier WO, Sengers RCA, Stadhouders AM, ter Laak HJ,J.M.
encephalomyopathy: the first case with an establisheddefect at the level of coenzyme Q. Eur J Pediatr 144: 441- Acknowledgements
This work was supported by grants from the Nation- 13. Haller RG, Henriksson KG, Jorfeld L, Hultman E, Wilbom al Institutes of Health (NS11766, NS28828, NS39854, R, Sahlin K, Areskog NH, Gunder M, Ayyad K, Blomqvist and HD32062), the Muscular Dystrophy Association, CG, Hall RE, Thuillier P, Kennaway NG, Lewis S (1991)Deficiency of skeletal muscle succinate dehydrogenase and a Neil Hamilton Fairley NHMRC Postdoctoral Fel- and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect. J Clin Invest 88: 1197-1206 References
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Europäisches Patentamt European Patent Office Office européen des brevets EP 0 989 848 B1 EUROPEAN PATENT SPECIFICATION (51) Int Cl.7: A61K 9/28 of the grant of the patent: 29.09.2004 Bulletin 2004/40 PCT/IB1998/000883 (21) Application number: 98921690.8 (22) Date of filing: 08.06.1998 WO 1998/056360 (17.12.1998 Gazette 1998/50) (54) FILM-COATED TABLET FOR IMP


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