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Kadenbach, Bernhard; Frank, Viola; Rieger, T.; Napiwotzki, Jörg

doi:10.1023/a:1006819416358

Cited by 20 publications

(3 citation statements)

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“…Cytochrome c oxidase controls mitochondrial energy metabolism (50,51) by acting as a sensor of extramitochondrial ATP/ADP (52). A low ATP/ ADP ratio, as is expected in the complex III mutants, may increase complex IV driven respiration.…”

Section: Discussionmentioning

confidence: 99%

Mutations in Mitochondrial Complex III Uniquely Affect Complex I in Caenorhabditis elegans

Suthammarak

Morgan

Sedensky

2010

Journal of Biological Chemistry

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Mitochondrial supercomplexes containing complexes I, III, and IV of the electron transport chain are now regarded as an established entity. Supercomplex I⅐III⅐IV has been theorized to improve respiratory chain function by allowing quinone channeling between complexes I and III. Here, we show that the role of the supercomplexes extends beyond channeling. Mutant analysis in Caenorhabditis elegans reveals that complex III affects supercomplex I⅐III⅐IV formation by acting as an assembly or stabilizing factor. Also, a complex III mtDNA mutation, ctb-1, inhibits complex I function by weakening the interaction of complex IV in supercomplex I⅐III⅐IV. Other complex III mutations inhibit complex I function either by decreasing the amount of complex I (isp-1), or decreasing the amount of complex I in its most active form, the I⅐III⅐IV supercomplex (isp-1;ctb-1). ctb-1 suppresses a nuclear encoded complex III defect, isp-1, without improving complex III function. Allosteric interactions involve all three complexes within the supercomplex and are necessary for maximal enzymatic activities.A solid-state model (1) of the mitochondrial respiratory chain within the mitochondrial membrane was proposed a half-century ago. In this model, the respiratory complexes are assembled into multicomplex structures, supercomplexes. Supercomplexes are capable of substrate channeling and thus facilitate transfer of electrons from one complex to the next (2). This is in contrast to the random collision model (3), which proposes that the complexes of the mitochondrial respiratory chain are embedded in the inner mitochondrial membrane as separate entities. Individual complexes are functionally connected to each other by the small, mobile electron carriers, coenzyme Q, and cytochrome c. The random collision model became more generally accepted as kinetic studies demonstrated homogenous pool behavior of coenzyme Q (4), rates of electron transfer that did not require substrate channeling, and the successful isolation of individual respiratory complexes that were enzymatically active (3, 5). However, supercomplex structures containing complexes I, III, and IV, have been investigated by blue native polyacrylamide gel electrophoresis (BN-PAGE), 3 sucrose gradient centrifugation, and single particle analysis (6, 7). A recent study by convincingly showed that supercomplexes are functional units capable of consuming oxygen when provided appropriate electron donors. They concluded that supercomplexes are in fact the functional respiratory unit of the mitochondrion in vivo. Schagger and Pfeiffer (9) demonstrated that supercomplex I⅐III⅐IV appears on blue native gels (BNGs) with increasing stoichiometries of complex IV. They termed these entities S0 -S4, where the numeral denotes the number of complex IVs within the supercomplex.Supercomplexes provide a logical explanation for combined deficiencies of the electron transport chain (ETC) observed in patients. It is estimated that ϳ30% of all ETC disorders involve multiple complexes (10). Combined I⅐IV deficie...

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Section: Discussionmentioning

confidence: 99%

Mutations in Mitochondrial Complex III Uniquely Affect Complex I in Caenorhabditis elegans

Suthammarak

Morgan

Sedensky

2010

Journal of Biological Chemistry

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“…However, allosteric activators or inhibitors could remain in effect under these conditions. Modulators of COX have been identified and are thought to be an important regulatory mechanism of this enzyme complex (41,42). In addition, evidence that acute exercise increases skeletal muscle citrate synthase activity well before mRNA transcription and protein synthesis increases has been reported (43,44).…”

Section: Discussionmentioning

confidence: 99%

Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

Stump

Short

Bigelow

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

419

369

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Mitochondria are the primary site of skeletal muscle fuel metabolism and ATP production. Although insulin is a major regulator of fuel metabolism, its effect on mitochondrial ATP production is not known. Here we report increases in vastus lateralis muscle mitochondrial ATP production capacity (32-42%) in healthy humans (P < 0.01) i.v. infused with insulin (1.5 milliunits͞kg of fat-free mass per min) while clamping glucose, amino acids, glucagon, and growth hormone. Increased ATP production occurred in association with increased mRNA levels from both mitochondrial (NADH dehydrogenase subunit IV) and nuclear [cytochrome c oxidase (COX) subunit IV] genes (164 -180%) encoding mitochondrial proteins (P < 0.05). In addition, muscle mitochondrial protein synthesis, and COX and citrate synthase enzyme activities were increased by insulin (P < 0.05). Further studies demonstrated no effect of low to high insulin levels on muscle mitochondrial ATP production for people with type 2 diabetes mellitus, whereas matched nondiabetic controls increased 16 -26% (P < 0.02) when four different substrate combinations were used. In conclusion, insulin stimulates mitochondrial oxidative phosphorylation in skeletal muscle along with synthesis of gene transcripts and mitochondrial protein in human subjects. Skeletal muscle of type 2 diabetic patients has a reduced capacity to increase ATP production with high insulin levels.cytochrome c oxidase ͉ NADH dehydrogenase subunit IV ͉ amino acids ͉ citrate synthase

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“…Each controls mitochondrial energy metabolism (22,23). COX IV does so through an allosteric mechanism when the extramitochondrial ATP/ADP ratio is high.…”

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confidence: 99%

Complex I Function Is Defective in Complex IV-deficient Caenorhabditis elegans

Suthammarak

Yang

Morgan

et al. 2009

Journal of Biological Chemistry

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Cytochrome c oxidase (COX) is hypothesized to be an important regulator of oxidative phosphorylation. However, no animal phenotypes have been described due to genetic defects in nuclear-encoded subunits of COX. We knocked down predicted homologues of COX IV and COX Va in the nematode Caenorhabditis elegans. Animals treated with W09C5.8 (COX IV) or Y37D8A.14 (COX Va) RNA interference had shortened lifespans and severe defects in mitochondrial respiratory chain function. Amount and activity of complex IV, as well as supercomplexes that included complex IV, were decreased in COXdeficient worms. The formation of supercomplex I:III was not dependent on COX. We found that COX deficiencies decreased intrinsic complex I enzymatic activity, as well as complex I-III enzymatic activity. However, overall amounts of complex I were not decreased in these animals. Surprisingly, intrinsic complex I enzymatic activity is dependent on the presence of complex IV, despite no overall decrease in the amount of complex I. Presumably the association of complex I with complex IV within the supercomplex I:III:IV enhances electron flow through complex I. Our results indicate that reduction of a single subunit within the electron transport chain can affect multiple enzymatic steps of electron transfer, including movement within a different protein complex. Patients presenting with multiple defects of electron transport may, in fact, harbor a single genetic defect.

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Cited by 20 publications

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Mutations in Mitochondrial Complex III Uniquely Affect Complex I in Caenorhabditis elegans

Mutations in Mitochondrial Complex III Uniquely Affect Complex I in Caenorhabditis elegans

Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

Complex I Function Is Defective in Complex IV-deficient Caenorhabditis elegans

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