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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Diseases of Mitochondrial Metabolism

and .

Correspondence to Salvatore diMauro, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.

Mitochondrial dysfunction produces syndromes involving muscle and the central nervous system

Although some energy can be obtained quickly from glucose or glycogen through anaerobic glycolysis, most of the energy derives from oxidation of carbohydrates and fatty acids in the mitochondria. The common metabolic product of sugars and fats is acetyl-CoA, which enters the Krebs cycle. Oxidation of one molecule of acetyl-CoA results in the reduction of three molecules of NAD and one of FAD. These reducing equivalents flow down a chain of carriers (Fig. 42-3) through a series of oxidation-reduction events. The final hydrogen acceptor is molecular oxygen, and the product is water. The released energy “charges” the inner mitochondrial membrane, converting the mitochondrion into a veritable biological battery. This oxidation process is coupled to ATP synthesis from ADP and inorganic phosphate (Pi), catalyzed by mitochondrial ATPase [9,12,13]. Considering the enormous amount of information collected since 1960 on mitochondrial structure and function, it is surprising that diseases of terminal mitochondrial metabolism, that is, the Krebs cycle and respiratory chain, have attracted the attention of clinical investigators only recently [9,1214].

Initial clues that some diseases might be due to mitochondrial dysfunction come from electron-microscopic studies of muscle biopsies showing fibers with increased numbers of structurally normal or abnormal mitochondria. These fibers have a “ragged red” appearance in the modified Gomori trichrome stain. Because the diagnosis was based on mitochondrial changes in muscle biopsies, these disorders were initially labeled mitochondrial myopathies. It soon became apparent, however, that many mitochondrial diseases with ragged red fibers were not confined to skeletal muscle but were multisystem disorders. In these patients, the clinical picture is often dominated by signs and symptoms of muscle and brain dysfunction, probably due to the great dependence of these tissues on oxidative metabolism. This group of disorders, often called mitochondrial encephalomyopathies, includes three more common syndromes (Table 42-1) [9,12,13].

Table 42-1. Distinguishing Features of Mitochondrial Encephalomyopathies.

Table 42-1

Distinguishing Features of Mitochondrial Encephalomyopathies.

The first, Kearns-Sayre syndrome (KSS), is characterized by childhood onset of progressive external ophthalmoplegia and pigmentary degeneration of the retina. Heart block, cerebellar syndrome or high CSF protein may also appear. Almost all cases are sporadic. The second syndrome, myoclonus epilepsy with ragged red fibers (MERRF), is characterized by myoclonus, ataxia, weakness and generalized seizures. The third syndrome, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), affects young children, who show stunted growth, episodic vomiting and headaches, seizures and recurrent cerebral insults resembling strokes and causing hemiparesis, hemianopsia or cortical blindness. Unlike KSS, MERRF and MELAS are usually familial, and analysis of several pedigrees has documented non-Mendelian maternal inheritance [9,12,13].

Mitochondrial DNA is inherited maternally

What makes mitochondrial diseases particularly interesting from a genetic point of view is that the mitochondrion has its own DNA (mtDNA) and its own transcription and translation processes. The mtDNA encodes only 13 polypeptides; nuclear DNA (nDNA) controls the synthesis of 90 to 95% of all mitochondrial proteins. All known mitochondrially encoded polypeptides are located in the inner mitochondrial membrane as subunits of the respiratory chain complexes (Fig. 42-3), including seven subunits of complex I; the apoprotein of cytochrome b; the three larger subunits of cytochrome c oxidase, also termed complex IV; and two subunits of ATPase, also termed complex V.

In the formation of the zygote, almost all mitochondria are contributed by the ovum. Therefore, mtDNA is transmitted by maternal inheritance in a vertical, non-Mendelian fashion. Strictly maternal transmission of mtDNA has been documented in humans by studies of restriction fragment length polymorphisms (RFLPs) in DNA from platelets. In theory, diseases caused by mutations of mtDNA should also be transmitted by maternal inheritance: an affected mother ought to pass the disease to all of her children, were it not for the “threshold effect,” which is described later, but only her daughters would transmit the trait to subsequent generations [9,12,13]. Characteristics that distinguish maternal from Mendelian inheritance include the following:


The number of affected individuals in subsequent generations should be higher than in autosomal dominant disease, again, were it not for the “threshold effect” (see below).


Inheritance is maternal, as in X-linked diseases, but children of both sexes are affected.


Because there are hundreds or thousands of copies of mtDNA in each cell, the phenotypic expression of a mitochondrially encoded gene depends on the relative proportions of mutant and wild-type mtDNAs within a cell; this is termed the “threshold effect.”


Because mitochondria replicate more often than do nuclei, the relative proportion of mutant and wild-type mtDNAs may change within a cell cycle.


At the time of cell division, the proportion of mutant and wild-type mtDNAs in the two daughter cells can shift, thus giving them different genotypes and, possibly, different phenotypes, a phenomenon called mitotic segregation.

Maternal inheritance has been documented in diseases due to point mutations of mtDNA, while most diseases due to mtDNA deletions or duplications are sporadic.

The genetic classification of mitochondrial diseases divides them into three groups

Defects of mtDNA include point mutations and deletions or duplications. From a biochemical point of view, these disorders will be associated with dysfunction of the respiratory chain because all 13 subunits encoded by mtDNA are subunits of respiratory chain complexes. Diseases due to point mutations are transmitted by maternal inheritance, and the number has rapidly increased during the past few years. The main syndromes include MERRF; MELAS (Table 42-1); Leber's hereditary optic neuropathy (LHON), a disorder causing blindness in young adult men; and neurogenic atrophy, ataxia and retinitis pigmentosa (NARP), which, depending on the relative proportion of mutant mitochondrial genomes in tissues, can cause a multisystem disorder in young adults or a devastating encephalomyopathy of childhood, termed Leigh's syndrome. Diseases due to deletions or duplications are usually sporadic, for reasons that are not completely clear. They include, besides KSS (Table 42-1), isolated progressive external ophthalmoplegia and Pearson's syndrome, a usually fatal infantile disorder dominated by sideroblastic anemia and exocrine pancreas dysfunction.

Defects of nuclear DNA also cause mitochondrial diseases. As mentioned above, the vast majority of mitochondrial proteins are encoded by nDNA, synthesized in the cytoplasm and “imported” into the mitochondria, through a complex series of steps. Defects of genes encoding the proteins themselves or controlling the importation machinery will cause mitochondrial diseases, which will be transmitted by Mendelian inheritance. From a biochemical point of view, all areas of mitochondrial metabolism can be affected (see below).

Defects of communication between nDNA and mtDNA can also cause mitochondrial diseases. The nDNA controls many functions of the mtDNA, including its replication. It is, therefore, conceivable that mutations of nuclear genes controlling these functions could cause alterations in the mtDNA. Two human diseases have been attributed to this mechanism [9,12,13]. The first is associated with multiple mtDNA deletions and is characterized clinically by ophthalmoplegia, weakness of limb and respiratory muscles and early death. Transmission is usually autosomal dominant, and it is assumed that a mutation in a nuclear gene makes the mtDNA prone to develop deletions. In fact, linkage analyses in a few large pedigrees have mapped the affected genes to two different loci, one on chromosome 3 and the other on chromosome 10, showing that these disorders are genetically heterogeneous [9,12,13]. The second disease is associated with mtDNA depletion in one or more tissues, more commonly in muscle. Depending on the tissue affected and the severity of the mtDNA decrease, the clinical picture can be a rapidly fatal congenital myopathy, a slightly more benign myopathy of childhood or a fatal hepatopathy. Transmission appears to be autosomal recessive or dominant, and it is postulated that an nDNA mutation may impair mtDNA replication. As expected, all subunits encoded by mtDNA are markedly decreased in the affected tissues.

The biochemical classification of mitochondrial DNA is based on the five major steps of mitochondrial metabolism

These steps are illustrated in Figure 42-3 and divide mitochondrial diseases into five groups: (i) defects of mitochondrial transport, (ii) defects of substrate utilization, (iii) defects of the Krebs cycle, (iv) defects of oxidation—phosphorylation coupling and (v) defects of the respiratory chain.

All disorders except those in group 5 are due to defects of nDNA and are transmitted by Mendelian inheritance. Disorders of the respiratory chain can be due to defects of nDNA, mtDNA or intergenomic communication. Usually, mutations of nDNA cause isolated, severe defects of individual respiratory complexes, whereas mutations in mtDNA or defects of intergenomic communication cause variably severe, multiple deficiencies of respiratory chain complexes. The description that follows is based on the biochemical classification.

Defects of mitochondrial transport interfere with the movement of molecules across the inner mitochondrial membrane, which is tightly regulated by specific translocation systems. The carnitine cycle is shown in Figure 42-2 and is responsible for the translocation of acyl-CoA thioesters from the cytosol into the mitochondrial matrix. The carnitine cycle involves four elements: the plasma membrane carnitine-transporter system, CPT I, the carnitine—acyl carnitine translocase system in the inner mitochondrial membrane and CPT II. Genetic defects have been described for each of these four steps, as discussed previously [4,68].

Defects of substrate utilization. Pyruvate dehydrogenase (PDH) deficiency can cause alterations of pyruvate metabolism, as can defects of pyruvate carboxylase, as discussed earlier. Over 200 patients have been described with a disturbance of the PDH complex (PDHC) [9]. The clinical picture includes several phenotypes ranging from a severe, devastating metabolic disease in the neonatal period to a benign, recurrent syndrome in older children. There is considerable overlap clinically and biochemically with other disorders (see below).

The PDHC catalyzes the irreversible conversion of pyruvate to acetyl-CoA (Fig. 42-3) and is dependent on thiamine and lipoic acid as cofactors (see Chap. 35). The complex has five enzymes: three subserving a catalytic function and two subserving a regulatory role. The catalytic components include PDH, E1; dihydrolipoyl transacetylase, E2; and dihydrolipoyl dehydrogenase, E3. The two regulatory enzymes include PDH-specific kinase and phospho-PDH-specific phosphatase. The multienzyme complex contains nine protein subunits, including protein X. Protein X anchors the E3 component to the E2 core of the complex. The E1 α subunit is encoded by a gene on the short arm of the X chromosome and a gene on chromosome 4. The E1 β subunit is encoded by a gene on chromosome 3, the E2 component is encoded by a gene on chromosome 11 and the E3 component is encoded by a gene on chromosome 7. Biochemical defects have been documented for the E1 α subunit, E2 (one case), E3 (six cases), protein X (two cases) and the phospho-PDH-specific phosphatase (four cases). The great majority of cases involve a mutation defect of the E1 α subunit. Both genders are equally represented despite the location of the E1 α-subunit gene on the X chromosome.

The most devastating phenotype of PDH deficiency presents in the newborn period. The majority of patients are male and critically ill with a severe metabolic acidosis. There is an elevated blood or CSF lactate concentration and associated elevations of pyruvate and alanine. These patients have seizures, failure to thrive, optic atrophy, microcephaly and dysmorphic features. Multiple brain abnormalities have been described, including dysmyelination of the cortex, cystic degeneration of the basal ganglia, ectopic olivary nuclei, hydrocephalus and partial or complete agenesis of the corpus callosum. A less devastating phenotype presents in early infancy. These patients demonstrate the histopathological features of Leigh's syndrome. Other patients affected in infancy survive with a chronic neurodegenerative syndrome manifested by mental retardation, microcephaly, recurrent seizures, spasticity, ataxia and dystonia.

Mutations involving the E1 α subunit behave clinically like an X-linked dominant condition. These mutations usually are lethal in boys during early infancy. The clinical spectrum in the heterozygous girl is more varied, ranging from a devastating condition in early infancy to a mild chronic encephalopathy with mental retardation. The least symptomatic woman may give birth to affected male and female progeny and pose a significant problem in clinical diagnosis and genetic counseling.

Treatment is largely symptomatic, and the prognosis ranges from dismal to guarded. Thiamine, lipoic acid, ketogenic diet and physostigmine have been tried in different concentrations and doses with equivocal results. Some patients with periodic ataxia resulting from PDHC deficiency may respond to acetazolamide.

Glutaric aciduria type II, which is a defect of β-oxidation, may affect muscle exclusively or in conjunction with other tissues. Glutaric aciduria type II, also termed multiple acyl-CoA dehydrogenase deficiency (Fig. 42-2), usually causes respiratory distress, hypoglycemia, hyperammonemia, systemic carnitine deficiency, nonketotic metabolic acidosis in the neonatal period and death within the first week. A few patients with onset in childhood or adult life showed lipid-storage myopathy, with weakness or premature fatigue [4,6]. Short-chain acyl-CoA deficiency (Fig. 42-2) was described in one woman with proximal limb weakness and exercise intolerance. Muscle biopsy showed marked accumulation of lipid droplets. Although no other tissues were studied, the defect appeared to be confined to skeletal muscle, suggesting the existence of tissue-specific isozymes [9,12,13].

Defects of the Krebs cycle. Fumarase deficiency was reported in three children with mitochondrial encephalomyopathy. Two of them had developmental delay since early infancy, microcephaly, hypotonia and cerebral atrophy; one died at 8 months of age. The third patient was a 3.5-year-old, mentally retarded girl. The laboratory hallmark of the disease is the excretion of large amounts of fumaric acid and, to a lesser extent, succinic acid in the urine. The enzyme defect has been found in muscle, liver and cultured skin fibroblasts [9,12,13].

Defects of oxidation—phosphorylation coupling. The best known example of such a defect is Luft's disease, or nonthyroidal hypermetabolism. Only two patients with this condition have been reported. Family history was noncontributory in both cases. Symptoms started in childhood or early adolescence with fever, heat intolerance, profuse perspiration, resting tachypnea and dyspnea, polydipsia, polyphagia and mild weakness. The basal metabolic rate was markedly increased in both patients, but all tests of thyroid function were normal. Muscle biopsies showed ragged red fibers and proliferation of capillaries. Other tissues were morphologically normal. Studies of oxidative phosphorylation in isolated muscle mitochondria from both patients showed maximal respiratory rate even in the absence of ADP, an indication that respiratory control was lost. Respiration proceeded at a high rate independently of phosphorylation, and energy was lost as heat, causing hypermetabolism and hyperthermia [13].

Abnormalities of the respiratory chain are usually identified based on polarographic studies showing differential impairment in the ability of isolated intact mitochondria to use different substrates. For example, defective respiration with NAD-dependent substrates, such as pyruvate and malate, but normal respiration with FAD-dependent substrates, such as succinate, suggests an isolated defect of complex I (Fig. 42-3). However, defective respiration with both types of substrates in the presence of activity of normal cytochrome c oxidase, also termed complex IV, localizes the lesions to complex III (Fig. 42-3).

Polarographic studies can be complemented by measurement of reduced-minus-oxidized spectra of cytochromes, showing decreased amounts of reducible cytochromes a and a3 in patients with complex IV deficiency and of reducible cytochrome b in many, but not all, patients with complex III deficiency (Fig. 42-3). Finally, electron transport through discrete portions of the respiratory chain can be measured directly. Thus, an isolated defect of NADH—cytochrome c reductase activity suggests a problem within complex I, while a simultaneous defect of NADH and succinate—cytochrome c reductase activities points to a biochemical error in complex III (Fig. 42-3). The function of complex III alone can be tested by measuring the activity of reduced coenzyme Q—cytochrome c reductase.

Abnormalities of the respiratory chain: defects of complex I. These have been described in about 25 patients and seem to cause two major clinical syndromes: pure myopathy, with exercise intolerance and myalgia presenting in childhood or adult life, and multisystem disorder. Patients with multisystem disorder were not clinically homogeneous: some had a fatal infantile form of the disease, causing severe congenital lactic acidosis, hypotonia, seizures, respiratory insufficiency and death before age 3 months; others had a less severe encephalomyopathy with onset in childhood or adult life and characterized by the association, in various proportions, of the following signs and symptoms: exercise intolerance, weakness, ophthalmoplegia, pigmentary retinopathy, optic atrophy, sensorineural hearing loss, dementia, cerebellar ataxia and pyramidal signs [1214]. This clinical heterogeneity is hardly surprising when one considers the large number of proteins comprising complex I, but the molecular defect in most patients is not known (Fig. 42-3).

Abnormalities of the respiratory chain: defects of complex II. These have not been fully characterized in the few reported patients, and the diagnosis has often been based solely on a decrease of succinate—cytochrome c reductase activity (Fig. 42-3). The clinical picture is characterized by severe infantile myopathy, with lactic acidosis in two cases and encephalomyopathy in three cases [3,5,7,11]. However, partial complex II deficiency was documented in muscle and cultured fibroblasts from two sisters with clinical and neuroradiological evidence of Leigh's syndrome, and molecular genetic analysis showed that both patients were homozygous for a point mutation in the flavoprotein subunit of the complex [15]. This is the first documentation of a molecular defect in the nuclear genome associated with a respiratory chain disorder.

Abnormalities of the respiratory chain: coenzyme Q10 (CoQ10) deficiency. This disorder is characterized, based on four patients described thus far, by a triad of symptoms in muscle: (i) exercise intolerance and recurrent myoglobinuria; (ii) CNS dysfunction, with seizures or mental retardation; and (iii) ragged red fibers and markedly increased lipid droplets in the muscle biopsy. Biochemical analysis of muscle shows a partial block at the level of complex III. This syndrome is important to consider in the differential diagnosis of recurrent myoglobinurias because patients benefit considerably from CoQ10 administration [16,17].

Abnormalities of the respiratory chain: defects of complex III. These have a clinical picture that falls into one of two groups: (i) childhood- or adolescent-onset myopathy with or without involvement of extraocular muscles and (ii) encephalopathy with exercise intolerance, fixed weakness, pigmentary degeneration of the retina, sensorineural hearing loss, cerebellar ataxia, pyramidal signs and dementia [9,1214].

Biochemically, some patients show lack of reducible cytochrome b, whereas others have normal cytochrome spectra. In patients with a normal amount of reducible cytochrome b, the defect may involve the nonheme iron sulfur protein, also termed Rieske protein or coenzyme Q (Fig. 42-3).

In a young woman with complex III deficiency myopathy, the bioenergetic capacity of muscle was studied by [31P]-nuclear magnetic resonance (NMR). The ratio of phosphocreatine to inorganic phosphate concentration (PCr:Pi) was greatly reduced at rest, decreased further with mild exercise and returned to pre-exercise values very slowly. Treatment with menadione, vitamin K3, and ascorbate, vitamin C, two compounds whose redox potentials permit them to function between coenzyme Q and cytochrome c (Fig. 42-3), was associated with marked improvement of exercise capacity. NMR showed increased PCr:Pi ratios at rest and improved rates of recovery after exercise.

Abnormalities of the respiratory chain: defects of complex IV. These disorders, also termed cytochrome oxidase (COX) deficiency, have clinical phenotypes that fall into two main groups: one in which myopathy is the predominant or exclusive manifestation and another in which brain dysfunction predominates (Fig. 42-3). In the first group, the most common disorder is fatal infantile myopathy, causing generalized weakness, respiratory insufficiency and death before age 1 year. There is lactic acidosis and renal dysfunction, with glycosuria, phosphaturia and aminoaciduria, also termed DeToni-Fanconi-Debre syndrome. The association of myopathy and cardiopathy in the same patient and myopathy and liver disease in the same family has also been described [12].

In patients with pure myopathy, COX deficiency is confined to skeletal muscle, sparing heart, liver and brain. The amount of immunologically reactive enzyme protein is markedly decreased in muscle by enzyme-linked immunosorbent assay (ELISA) and by immunocytochemistry of frozen sections. Benign infantile mitochondrial myopathy, in contrast, has been described in a few children with severe myopathy and lactic acidosis at birth, who then improve spontaneously and are virtually normal by age 2 years. This condition is due to a reversible COX deficiency. The enzyme activity is markedly decreased, <19% of normal, in muscle biopsies taken soon after birth but returns to normal in the first year of life. Immunocytochemistry and immunotitration show normal amounts of enzyme protein in all muscle biopsies. This finding differs from the virtual lack of CRM in patients with fatal infantile myopathy and may represent a useful prognostic test. The selective involvement of one or more tissues and the reversibility of the muscle defect in the benign form suggest the existence of tissue-specific and developmentally regulated COX isoenzymes in humans [12].

Subacute necrotizing encephalomyelopathy, also termed Leigh's syndrome, typifies the second group of disorders of complex IV, dominated by involvement of the CNS. Leigh's syndrome usually starts in infancy or childhood and is characterized by psychomotor retardation, brainstem abnormalities and apnea [12]. The pathological hallmark consists of focal, symmetrical necrotic lesions from thalamus to pons, involving the inferior olives and the posterior columns of the spinal cord. Microscopically, these spongy brain lesions show demyelination, vascular proliferation and astrocytosis. In these patients, COX deficiency is generalized, including cultured fibroblasts in most, but not all, cases. This may provide a useful tool for prenatal diagnosis in at least some families. Immunological studies show CRM in all tissues. Partial defects of COX have been reported in patients with progressive external ophthalmoplegia and proximal myopathy and in patients with encephalomyopathy. However, the precise pathogenic significance of COX deficiency in these disorders remains uncertain [12].

Abnormalities of the respiratory chain: defects of complex V, mitochondrial ATPase, have been reported in two patients. One was a young woman with congenital, slowly progressive myopathy; the other was a 17-year-old boy who, at age 10 years, was found to have muscle carnitine deficiency [13]. Later, he developed a multisystem disorder characterized by weakness, dementia, ataxia, retinopathy and peripheral neuropathy. In both patients, respiration of isolated mitochondria was decreased with all substrates but returned to normal after addition of the uncoupling agent 1,4-dinitrophenol. This finding suggested that the biochemical defect involved the phosphorylative pathway rather than the respiratory chain. ATPase activity was decreased and responded poorly to dinitrophenol stimulation.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK27914


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