Mitochondrial myopathies: clinical defects

Ja, Morgan-Hughes; Jm, Cooper; Holt, Ian; Harding, A E; Schapira, Anthony H.V.; Jb, Clark

doi:10.1042/bst0180523

Cited by 12 publications

(2 citation statements)

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“…Thus, thirteen essential subunits of the OXPHOS, including seven subunits of complex I (NADH:ubiquinone oxidoreductase), one subunit of complex III (ubiquinol:cytochrome c oxidoreductase), three subunits of complex IV (cytochrome c oxidase) and two subunits of complex V (ATP synthase), as well as the major part of the mitochondrial translation system (two rRNAs and 22 tRNAs), are encoded by the mitochondrial genome (1). Decreased OXPHIOS capacities, as a result of homoor heteroplasmic single base substitutions or large scale deletions ofthe mtDNA, have been recently associated with a broad spectrum of clinical manifestations, including blindness, deafness, dementia, movement disorders, weakness, cardiac failure, diabetes, dystonia, renal dysfunction and liver disease (2)(3)(4)(5)(6)(7)(8). The severity of patient's symptoms caused by OXPHOS defects varies, depending on the nature ofthe mutation, the percentage of mutant mtDNAs in different tissues and the relative reliance of the affected organ systems on mitochondrial energy production (2).…”

Section: Introductionmentioning

confidence: 99%

Transfection of mitochondria: strategy towards a gene therapy of mitochondrial DNA diseases

Seibel¹,

Trappe²,

Villani³

et al. 1995

Nucl Acids Res

156

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Successes in classical gene therapies have been achieved by placing a corrected copy of a defective nuclear gene in cells. A similar gene replacement approach for a mutant mitochondrial genome is invariably linked to the use of a yet unavailable mitochondrial transfection vector. Here we show that DNA coupled covalently to a short mitochondrial leader peptide (chimera) can enter mitochondria via the protein import pathway, opening a new way for gene-, antisense-RNA- or antisense-DNA-delivery in molecular therapies. The import behavior of the purified chimera, composed of the amino-terminal leader peptide of the rat ornithine transcarbamylase (OTC) and a double stranded DNA molecule (17 bp or 322 bp), was tested by incubating with coupled and 'energized' rat liver mitochondria in the presence of reticulocyte lysate. The chimera was translocated with a high efficiency into the matrix of mitochondria utilizing the protein import pathway, independent from the size of its passenger DNA.

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Section: Introductionmentioning

confidence: 99%

Transfection of mitochondria: strategy towards a gene therapy of mitochondrial DNA diseases

Seibel¹,

Trappe²,

Villani³

et al. 1995

Nucl Acids Res

156

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“…This complexity has hampered progress in studies on many aspects of the structure and mechanism of action of this enzyme complex (Yagi, 1991). However, such studies have taken on a greater significance in recent years since there has been an increasing number of reports on human mitochondrial diseases involving structural and functional defects at the level of this enzyme complex (Morgan-Hughes et al, 1990; Wallace et al, 1988). It has been recently suggested that Parkinson's and Huntington's diseases might also 1 Abbreviations: Q, quinone; UQ, ubiquinone; NDH-1 or complex I, energy-transducing NADH-quinone oxidoreductase; NDH-2, NADHquinone oxidoreductase lacking energy coupling site; complex III, ubiquinol-cytochrome c oxidoreductase; bp, base pairs; FP, IP, and HP, respectively, the flavoprotein, the iron-sulfur protein, and the hydrophobic protein fractions of complex I; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; PCR, polymerase chain reaction; PVDF, poly(vinylidene difluoride).…”

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confidence: 99%

The NADH-binding subunit of the energy-transducing NADH-ubiquinone oxidoreductase of Paracoccus denitrificans: gene cloning and deduced primary structure

Matsuno‐Yagi²,

Yagi³

1991

Biochemistry

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The NADH dehydrogenase complex isolated from Paracoccus denitrificans is composed of approximately 10 unlike polypeptides and contains noncovalently bound FMN, non-heme iron, and acid-labile sulfide [Yagi, T. (1986) Arch. Biochem. Biophys. 250, 302-311]. The NADH-binding subunit (Mr = 50,000) of this enzyme complex was identified by direct photoaffinity labeling with [32P]NADH [Yagi, T., & Dinh, T.M. (1990) Biochemistry 29, 5515-5520]. Primers were synthesized on the basis of the N-terminal amino acid sequence of this polypeptide, and these primers were used to synthesize an oligonucleotide probe by the polymerase chain reaction. This probe was utilized to isolate the gene encoding the NADH-binding subunit from a genomic library of P. denitrificans. The nucleotide sequence of the gene and the deduced amino acid sequence of the entire NADH-binding subunit were determined. The NADH-binding subunit has 431 amino acid residues and a calculated molecular weight of 47,191. The encoded protein contains a putative NAD(H)-binding and an iron-sulfur cluster-binding consensus sequence. The deduced amino acid sequence of the Paracoccus NADH-binding subunit shows remarkable similarity to the alpha subunit of the NAD-linked hydrogenase of Alcaligenes eutrophus H16. When partial DNA sequencing of the regions surrounding the gene encoding the NADH-binding subunit was carried out, sequences homologous to the 24-, 49-, and 75-kDa polypeptides of bovine complex I were detected, suggesting that the structural genes of the Paracoccus NADH dehydrogenase complex constitute a gene cluster.

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Exercise Intolerance and Mitochondriopathies

Desnuelle¹,

Paquis²

1999

Exercise Intolerance and Muscle Contracture

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Mitochondrial myopathies: clinical defects

Cited by 12 publications

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Transfection of mitochondria: strategy towards a gene therapy of mitochondrial DNA diseases

Transfection of mitochondria: strategy towards a gene therapy of mitochondrial DNA diseases

The NADH-binding subunit of the energy-transducing NADH-ubiquinone oxidoreductase of Paracoccus denitrificans: gene cloning and deduced primary structure

Exercise Intolerance and Mitochondriopathies

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