Dominantly inherited mitochondrial myopathy with multiple deletions of mitochondrial DNA

Servidei, Serenella; Zeviani, Massimo; Manfredi, Giovanni; Ricci, Enzo; Silvestri, Gabriella; Bertini, E.; Gellera, Cinzia; Mauro, Salvatore Di; Donate, S. Di; Tonali, P.

doi:10.1212/wnl.41.7.1053

Cited by 121 publications

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“…First and foremost, COX is a vital enzyme, without which oxidative metabolism cannot be carried to completion and mitochondrial ATP cannot be generated (33,34). Dysfunction of this enzyme jeopardizes health, and absence of this enzyme is incompatible with life (35,36). COX is a housekeeping enzyme present in almost every eukaryotic cell (with a few exceptions, such as mature, short lived red blood cells lacking in both nuclei and mitochondria).…”

Section: Table 2 3c Interactions Among All 10 Nucleus-encoded Cox Submentioning

confidence: 99%

Chromosome Conformation Capture of All 13 Genomic Loci in the Transcriptional Regulation of the Multisubunit Bigenomic Cytochrome c Oxidase in Neurons

Dhar

Ongwijitwat

Wong‐Riley

2009

Journal of Biological Chemistry

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Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain composed of 13 subunits; three are mitochondria-encoded, and 10 are nucleus-inscribed on nine different chromosomes within the mammalian genome. The transcriptional regulation of such a multisubunit, multichromosomal, and bigenomic enzyme is mechanistically challenging. Transcription factories have been proposed as one mechanism by which genes from different genomic loci congregate to transcribe functionally related genes, and chromosome conformation capture (3C) is a means by which such interactions can be revealed. Thus far, however, only loci from the same chromosome or at most two chromosomes have been co-localized by 3C. The present study used 3C to test our hypothesis that not only the 10 genomic loci from nine chromosomes encoding the 10 nuclear subunits of COX, but also genes from three chromosomes encoding mitochondrial transcription factors A and B (Tfam, Tfb1m, and Tfb2m) critical for the transcription of the three mitochondria-encoded COX subunit genes all occupy common intranuclear sites in the murine neuronal nuclei. The pairing of various COX subunit genes and Tf genes indicates that interactions are present among all of them. On the other hand, genes for a non-mitochondrial protein (calreticulin) as well as a mitochondrial enzyme (citrate synthase) did not interact with COX genes. Furthermore, interactions between COX subunit and Tf genes were up-regulated by depolarizing stimulation and down-regulated by impulse blockade in primary neurons. Thus, a viable mechanism is in place for a synchronized, coordinated transcriptional regulation of this multisubunit, bigenomic COX enzyme in neurons.Cytochrome c oxidase (COX) 2 or complex IV of the mitochondrial electron transport chain is made up of three subunits encoded in the mitochondrial genome and 10 nucleus-encoded subunits located on nine different chromosomes (1-3). The 10 nucleus-encoded COX subunits are 4, 5a, 5b, 6a, 6b, 6c, 7a, 7b, 7c, and 8a. Subunits 4, 6a, 6b, 7a, and 8a each has a ubiquitous isoform and a tissue-specific isoform. Transcription of all ubiquitously expressed subunits in neurons are coordinately regulated according to the cell's ATP requirement (4). Transcriptional regulators of COX in rats, mice, and humans include NRF-1 and NRF-2 (nuclear respiratory factors 1 and 2) (5-8).In particular, both NRF-1 and NRF-2 activate the transcription of all 10 nucleus-encoded COX subunits and modulate the level of transcription in response to changing cellular energy demands in neurons (9 -14). Additionally, NRF-1 and NRF-2 indirectly activate the three mitochondria-encoded COX subunit genes by regulating Tfam, Tfb1m, and Tfb2m (mitochondrial transcription factors A, B1, and B2) critical for mitochondrial DNA transcription and replication (15-18). Transcriptional coactivators, such as PGC-1␣ (peroxisome proliferator-activated receptor ␥-coactivator 1␣) (19,20), also play an important role in stimulating COX transcription in the presence of upstream signals i...

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Section: Table 2 3c Interactions Among All 10 Nucleus-encoded Cox Submentioning

confidence: 99%

Chromosome Conformation Capture of All 13 Genomic Loci in the Transcriptional Regulation of the Multisubunit Bigenomic Cytochrome c Oxidase in Neurons

Dhar

Ongwijitwat

Wong‐Riley

2009

Journal of Biological Chemistry

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“…Some patients have duplications of mtDNA as well as deletions (Poulton et al 1989). Subsequently, multiple mtDNA deletions have been described in familial cases Servidei et al 1991), and nuclear gene defects predisposing to multiple deletions have been documented (Nishino et al 1999;Kaukonen et al 2000;Van Goethem et al 2001;Spelbrink et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Genotype and phenotype analyses in 136 patients with single large-scale mitochondrial DNA deletions

et al. 2008

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We examined 136 patients with mitochondrial DNA (mtDNA) deletion. Clinical diagnoses included chronic progressive external ophthalmoplegia (94 patients); Kearns-Sayre syndrome (KSS; 33 patients); Pearson's marrow-pancreas syndrome (six patients); and Leigh syndrome, Reye-like syndrome, and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (one patient). The length and location of deletion were highly variable. Only one patient had deletion within the so-called shorter arc between the two origins of mtDNA replication. The length of deletion and the number of deleted transfer ribonucleic acid (tRNAs) showed a significant relationship with age at onset. Furthermore, KSS patients had longer and larger numbers of deleted tRNAs, which could be risk factors for the systemic involvement of single mtDNA deletion diseases. We found 81 patterns of deletion. Direct repeats of 4 bp or longer flanking the breakpoints were found in 96 patients (70.5%) and those of 10 bp or longer in 49 patients (36.0%). We found two other common deletions besides the most common deletion (34 patients: 25.0%): the 2,310-bp deletion from nt 12113 to nt 14421 (11 patients: 8.0%) and the 7,664-bp deletion from nt 6330 to nt 13993 (ten patients: 7.3%). These deletions had incomplete direct repeats longer than 13 bp with one base mismatch.

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“…AD-PEO syndromes tend to be dominated by myopathy, but hearing loss, tremor, cataracts, have been described in Italian families (Servidei et al, 1991). Depression was an important feature in a large Finnish family (Suomalainen, 1997) and in an American family (Iannaccone et al, 1974), in which we later documented multiple mtDNA deletions in muscle.…”

Section: Defects Of Intergenomic Signalingmentioning

confidence: 69%

Mitochondrial disorders

DiMauro

Tanji

1997

Jap J Human Genet

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SummaryIn this minireview, we attempt to survey the three main group of mitochondrial disorders, defects of nuclear DNA, defects of mitochondrial DNA, and defects of intergenomic signaling, with emphasis on recent contributions and pathogenetic mechanisms. In so doing, we have tried to point out some of the numerous unsolved problems in genotype/phenotype correlation and to indicate future directions of research. Key Words mitochondria, mitochondrial DNA, intergenomic signaling, respiratory chain, mitochondrial encephalomyopathiesThe fascinating and still unfolding story of mitochondrial disorders is not only a "tale of two genomes," but also a tale of their sometimes less than harmonious interaction. Thus, we have to review succinctly three types of human diseases: 1) Defects of nuclear genes, inherited as mendelian traits; 2) Defects of mitochondrial genes, which can be sporadic conditions or maternally-inherited disorders; and 3) Defects of intergenomic communication, in which the still unknown culprits are nuclear genes and inheritance is mendelian. Though in our review we will consider these three groups in sequence, a unified biomolecular classification of the mitochondrial disorders, including acquired conditions, is offered in Table I. Because of the concise nature of these minireviews, we will limit references to the most recent contributions. Other references are provided in recent comprehensive reviews, including three chapters in a row in the 2nd edition of The

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Dominantly inherited mitochondrial myopathy with multiple deletions of mitochondrial DNA

Cited by 121 publications

References 0 publications

Chromosome Conformation Capture of All 13 Genomic Loci in the Transcriptional Regulation of the Multisubunit Bigenomic Cytochrome c Oxidase in Neurons

Chromosome Conformation Capture of All 13 Genomic Loci in the Transcriptional Regulation of the Multisubunit Bigenomic Cytochrome c Oxidase in Neurons

Genotype and phenotype analyses in 136 patients with single large-scale mitochondrial DNA deletions

Mitochondrial disorders

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