MOLECULAR BASIS OF MITOCHONDRIAL MYOPATHIES: POLYPEPTIDE ANALYSIS IN COMPLEX-1 DEFICIENCY

doi:10.1016/S0140-6736(88)91296-2

The Lancet

Volume 331, Issue 8584, 5 March 1988, Pages 500-503

https://doi.org/10.1016/S0140-6736(88)91296-2 Get rights and content

Abstract

Clinical and biochemical data are reported for three patients with mitochondrial myopathy. One patient presented only with exercise-induced muscle weakness, whereas the other two showed signs of multisystem disease. Polarographic determination of oxygen uptake in skeletal muscle mitochondria suggested complex-I (nicotinamide adenine dinucleotide [reduced] ubiquinone oxidoreductase) deficiency. Sodium dodecyl sulphate polyacrylamide gel electrophoresis and immunoblotting with antibody to the holoenzyme of complex-I and specific antibodies to certain of the Fe-S subunits of complex-I showed a relatively normal profile in the least affected patient and a generalised reduction in the intensities of all crossreacting bands in the other two patients. The most severely affected patient also showed a disproportionate and pronounced reduction in the 24 K Fe-S subunit. Clinical severity of muscle involvement correlated with the biochemical deficiency as determined polarographically and with the immunoblot appearances.

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Complex I is the first protein component of the mitochondrial respiratory chain and as such plays a crucial role in ATP production and mitochondrial function in general. Mitochondrial dysfunction has been identified in a number of neurodegenerative diseases. In some of these the mitochondrial abnormality is primary and in others secondary. Mitochondrial toxins are capable of producing relatively selective neuronal cell death and have been used to produce models of human neurodegenerative diseases e.g. 1-methyl 4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) for Parkinson's disease, and 3-nitropropionic acid for Huntington's disease. Annonacin, an ingredient of local soursop, is a Complex I inhibitor and has been incriminated as the cause of a parkinsonian tauopathy disorder in Guadeloupe. A systematic analysis has identified several environmentally available potent lipophilic Complex I inhibitors that can induce neuronal cell death in striatal cultures and somatodendritic redistribution of tau protein. It is possible that these compounds may contribute to the pathogenesis of neurodegenerative disorders, although further work must be done to confirm their potential participation in pathogenesis.
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Their role has only been reinforced by the discovery of several genetic causes for PD and an understanding of their mechanism of action. Defects of the mitochondrial respiratory chain and, in particular, complex I deficiency were traditionally associated with mitochondrial myopathies.152,153 The first link between mitochondria and PD came with the identification of the deficiency of mitochondrial respiratory chain protein complex I activity in substantia nigra from patients with PD.154–156
Possibility of transkingdom gene therapy for Complex I diseases
2006, Biochimica et Biophysica Acta - Bioenergetics
Citation Excerpt :
However, it seems likely that animal models of Parkinson's disease (PD) may be suitable for this purpose. Complex I deficiency in the brain of a patient with PD was first described in 1989 [54]. Numerous studies have followed which indicated involvement of complex I in early events of neurodegeneration in sporadic PD.
Defects of complex I are involved in many human mitochondrial diseases, and therefore we have proposed to use the NDI1 gene encoding a single subunit NADH dehydrogenase of Saccharomyces cerevisiae for repair of respiratory activity. The yeast NDI1 gene was successfully introduced into mammalian cell lines. The expressed NDI1 protein was correctly targeted to the matrix side of the inner mitochondrial membranes, was fully functional and restored the NADH oxidase activity to the complex I-deficient cells. The NDI1-transduced cells were more resistant to complex I inhibitors and diminished production of reactive oxygen species induced by rotenone. It was further shown that the NDI1 protein can be functionally expressed in tissues such as skeletal muscles and the brain of rodents, which scarcely induced an inflammatory response. The use of NDI1 as a potential molecular therapy for complex I-deficient diseases is briefly discussed, including the proposed animal model.
Genomic structure of the human NDUFS8 gene coding for the iron-sulfur TYKY subunit of the mitochondrial NADH:ubiquinone oxidoreductase
1998, Gene
The structural organization of the NDUFS8 gene coding for the TYKY subunit of the human mitochondrial NADH:ubiquinone oxidoreductase (Complex I) has been determined by sequencing of a genomic fragment cloned from a cosmid library. The NDUFS8 gene is located on chromosome 11q13 immediately downstream of the ALDH7 isoform gene. It spans about 6 kb and contains seven exons ranging in size from 51 to 186 bp. Three CCAAT box sequence motifs are present upstream of the transcription start. Sp1 and NRF1 binding site motifs are present in the first intron. Expression of the gene is ubiquitous but predominant in heart and skeletal muscle. Immunodetection of the TYKY subunit in placental mitochondria after two-dimensional gel electrophoresis revealed that the mature protein has a molecular mass of 22 kDa and a pI in the range of 4.9–5.0.
Human xenomitochondrial cybrids: Cellular models of mitochondrial complex I deficiency
1998, Journal of Biological Chemistry
The subunits forming the mitochondrial oxidative phosphorylation system are coded by both nuclear and mitochondrial genes. Recently, we attempted to introduce mtDNA from non-human apes into a human cell line lacking mtDNA (ρ°), and succeeded in producing human-common chimpanzee, human-pigmy chimpanzee, and human-gorilla xenomitochondrial cybrids (HXC). Here, we present a comprehensive characterization of oxidative phosphorylation function in these cells. Mitochondrial complexes II, III, IV, and V had activities indistinguishable from parental human or non-human primate cells. In contrast, a complex I deficiency was observed in all HXC. Kinetic studies of complex I using decylubiquinone or NADH as limiting substrates showed that the V _max was decreased in HXC by approximately 40%, and the K _mfor the NADH was significantly increased (3-fold, p < 0.001). Rotenone inhibition studies of intact cell respiration and pyruvate-malate oxidation in permeabilized cells showed that 3 nm rotenone produced a mild effect in control cells (0–10% inhibition) but produced a marked inhibition of HXC respiration (50–75%). Immunoblotting analyses of three subunits of complex I (ND1, 75 and 49 kDa) showed that their relative amounts were not significantly altered in HXC cells. These results establish HXC as cellular models of complex I deficiency in humans and underscore the importance of nuclear and mitochondrial genomes co-evolution in optimizing oxidative phosphorylation function.
Cloning of the human mitochondrial 51 kDa subunit (NDUFV1) reveals a 100% antisense homology of its 3'UTR with the 5'UTR of the γ-interferon inducible protein (IP-30) precursor: Is this a link between mitochondrial myopathy and inflammation?
1998, Biochemical and Biophysical Research Communications
We report the cloning of the genomic and cDNA of the human 51 kDa subunit (NDUFV1) of mitochondrial complex I. The 6 kbp NDUFV1 gene is composed of 10 exons. All intron-exon boundaries comply to the consensus sequence for splice donor and acceptor sites. Within the 5′ flanking region we identified a putative binding site for NRF-2, a GATA- and GC-box element. Canonical TATA- or CCAAT-boxes were absent, the transcriptional start site, however, lies within a CpG island, which is consistent with the “housekeeping” function of the gene. Within the coding sequence we detected consensus motifs for NADH, FMN, and iron-sulfur binding sites. The amino acid sequence homology between human and cow is 96.9%. Surprisingly we found a 48 bp long complete antisense homology between the 3′UTR of the NDUFV1-mRNA and the 5′UTR of the mRNA for the γ-interferon inducible protein precursor (IP-30). This finding is intriguing since both genes lie on different chromosomes. The exact function of IP-30 is not yet known, but it may play a role in γ-interferon mediated immune reactions. The NDUFV1-mRNA might act as an antisense suppresser, thus restraining translation of IP-30 in tissues with high energy demand. This finding could be a molecular link between complex I deficiency and inflammatory myopathy which have been repeatedly described to occur together.

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MOLECULAR BASIS OF MITOCHONDRIAL MYOPATHIES: POLYPEPTIDE ANALYSIS IN COMPLEX-1 DEFICIENCY

Abstract

Trends Neurosci

J Biol Chem

J Biol Chem

Arch Biochem Biophys

The mitochondrial myopathies

Mitochondrial myopathies

Ann Neurol

Sequence and organisation of the human mitochondrial genome

Nature

Functional assignment of the products of the unidentified reading frames of human mitochondrial DNA

Mitochondrial inheritance in a mitochondrially mediated disease

N Engl J Med

Maternally inherited mitochondrial myopathy and myoclonic epilepsy

Ann Neurol

Mitochondrial myopathies: deficiencies localised to Complex I and Complex III of the mitochondrial respiratory chain

Biochem Soc Trans

The mitochondrial myopathies. Defects of the mitochondrial respiratory chain and oxidative phosphorylation