Kearns‐Sayre syndrome and complex II deficiency

Rivner, Michael H.; Shamsnia, Morteza; Swift, Thomas R.; Trefz, J.; Roesel, Raffaello; Carter, A. L.; Yanamura, Wayne; Hommes, F. A.

doi:10.1212/wnl.39.5.693

Cited by 71 publications

(22 citation statements)

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“…Severe deficiency of succinate dehydrogenase or succinate:ubiquinone oxidoreductase (complex II), with milder abnormalities of other mitochondrial activities, has been described in only three other patients, two of whom appear to have disorders that differ from our patient. The first had Kearns-Sayre syndrome, with low activity of complex II but normal cross-reacting material, and elevated complex I activity (32). The second had an encephalopathy in addition to progressive muscle weakness (33).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins.

Hall¹,

Henriksson²,

Lewis³

et al. 1993

J. Clin. Invest.

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Recently, we described a patient with severe exercise intolerance and episodic myoglobinuria, associated with marked impairment of succinate oxidation and deficient activity of succinate dehydrogenase and aconitase in muscle mitochondria ( 1 ). We now report additional enzymatic and immunological characterization of mitochondria. In addition to severe deficiency of complex II, manifested by reduction of succinate dehydrogenase and succinate:coenzyme Q oxidoreductase activities to 12 and 22% of normal, respectively, complex III activity was reduced to 37% and rhodanese to 48% of normal. Furthermore, although complex I activity was not measured, immunoblot analysis of complex I showed deficiency of the 39-, 24-, 13-, and 9-kD peptides with lesser reductions of the 51-and 18-kD peptides. Immunoblots of complex III showed markedly reduced levels of the mature Rieske protein in mitochondria and elevated levels of its precursor in the cytosol, suggesting deficient uptake into mitochondria. Immunoreactive aconitase was also low. These data, together with the previous documentation of low amounts of the 30-kD iron-sulfur protein and the 13.5-kD subunit of complex II, compared to near normal levels of the 70-kD protein suggest a more generalized abnormality of the synthesis, import, processing, or assembly of a group of proteins containing iron-sulfur clusters. (J. Clin. Invest. 1993. 92:2660-2666.) Key words: myoglobinuria -electron transport * nicotinamide adenine dinucleotide (reduced form) dehydrogenase * ubiquinol-cytochrome c reductase * thiosulfate sulfurtransferase

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Section: Resultsmentioning

confidence: 99%

Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins.

Hall¹,

Henriksson²,

Lewis³

et al. 1993

J. Clin. Invest.

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“…SDH deficiency has only recently been recognized (34)(35)(36) and aconitase deficiency has not previously been identified. Rivner and coworkers described a patient with Kearns-Sayre syndrome of ophthalmoplegia, retinal pigmentary degeneration, and heart block (34). In this patient, histochemical staining ofmuscle for SDH revealed a mixture ofintensely and poorly stained muscle fibers, unlike the generalized loss of muscle fiber staining for SDH found in our patient.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.

Haller¹,

Henriksson²,

Jorfeldt³

et al. 1991

J. Clin. Invest.

123

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We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39±5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (V02) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v 02 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7±2.1) despite normal oxygen carrying capacity and Hgb-02 PSO. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Q..: patient = 303 ml/min per kg, normal men 238±36) and the slope of increase in Q relative to V02 (i.e., A&Q/AVO2) from rest to exercise was exaggerated (A&Q/AVO2, patient = 29, normal men = 4.7±0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at the level of complex II of the mitochondrial respiratory chain. A defect in Complex H in skeletal muscle was confirmed by the finding ofdeficiency ofsuccinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle. (J. Clin.

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“…Although CII deficiencies (OMIM # 252011) are rare, they still demonstrate the typical clinical heterogeneity associated with mitochondrial diseases. Many CII disorders present in childhood as retinopathies [66] or as encephalopathies [67,68], namely Leigh Syndrome [69], with accompanying cardiomyopathy [70]. Conversely, adult onset CII disorders have also been reported [71].…”

Section: Oxphos Complex IImentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Nsiah-Sefaa

McKenzie

2016

Bioscience Reports

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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Kearns‐Sayre syndrome and complex II deficiency

Cited by 71 publications

References 0 publications

Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins.

Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins.

Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

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