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

Abstract

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

Age-related increases in oxidatively damaged proteins of mouse kidney mitochondrial electron transport chain complexes

“…The positive correlation between the increase in oxidative modification and the decrease in coupled and overall complex activity suggests that this modification affects either the substrate binding or the electron transfer ability of SDHA, or both. This is consistent with the observation that deficiency in and mutation of SDH subunits are known to cause severe diseases in humans and may thus support the argument that modifications in SDHA can lead to structural and functional changes similar to those caused by genetic mutations [34,35]. Thus, we show for the first time that the increase of in vivo oxidative modification of SDHA subunit directly correlates to an age-associated functional deficiency in CII.…”

Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

“…14 Respiratory chain activities in isolated mitochondria from vastus lateralis muscle from patient 2 were measured as described previously. 15,16 Cell culture Cultured skin fibroblasts from patient 1 and her mother were maintained as previously described. 17 …”

Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms

“…In patient 3-MM, a novel tRNAtrp mutation was associated with deficiency of multiple respiratory chain complexes, especially complex IV (52). Two patients had a mitochondrial myopathy with deficiency of multiple iron-sulfur cluster containing enzymes, particularly the tricarboxylic acid (TCA) cycle enzymes succinate dehydrogenase and aconitase, due to a mutation in the ISCU gene (20,21,40). The main clinical feature in all patients was severe exercise intolerance with prominent exertional dyspnea provoked by low-intensity exercise that had been present since childhood.…”

“…Exaggerated exercise ventilation is indicated by markedly elevated V E/V O2, V E/V CO2, and RER. While lactic acidosis likely contributes to exercise hyperventilation, the fact that ventilation normalizes during recovery from exercise despite increasing metabolic acidosis strongly indicates that additional, exercise-specific mechanisms are responsible for this distinctive pattern of exercise ventilation.hyperventilation; lactic acidosis; metaboreflex; exercise; oxidative phosphorylation EXERTIONAL DYSPNEA WAS FIRST described as a symptom that limited exercise in mitochondrial myopathy (MM) in patients with a familial disorder studied by Linderholm and coworkers in the 1960s (36, 38), a disease now recognized to be attributable to a mutation in the iron-sulfur cluster scaffold (ISCU) gene (40, 42) and associated with deficiency of multiple iron-sulfur proteins, including succinate dehydrogenase and aconitase (20,21). Exertional dyspnea has since been described as a dominant feature of exercise intolerance in other mitochondrial myopathies that severely restrict muscle oxidative phosphorylation (3a, 22).…”

“…hyperventilation; lactic acidosis; metaboreflex; exercise; oxidative phosphorylation EXERTIONAL DYSPNEA WAS FIRST described as a symptom that limited exercise in mitochondrial myopathy (MM) in patients with a familial disorder studied by Linderholm and coworkers in the 1960s (36, 38), a disease now recognized to be attributable to a mutation in the iron-sulfur cluster scaffold (ISCU) gene (40, 42) and associated with deficiency of multiple iron-sulfur proteins, including succinate dehydrogenase and aconitase (20,21). Exertional dyspnea has since been described as a dominant feature of exercise intolerance in other mitochondrial myopathies that severely restrict muscle oxidative phosphorylation (3a, 22).…”