A 4–base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome

Coo, I.F.M. de; Renier, W.O.; Ruitenbeek, W.; Laak, H.J. ter; Bakker, M.; Oost, B.A. van; Smeets, Hubert J.M.

doi:10.1002/1531-8249(199901)45:1<130::aid-art21>3.3.co;2-q

Cited by 69 publications

(76 citation statements)

References 15 publications

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“…Mitochondria are thought to contribute to aging through the accumulation of mtDNA mutations and net production of ROS. Mitochondrial DNA mutations, mitochondrial abnormalities, and mitochondrial respiratory chain-deficient cells are also present in age-related neurodegenerative diseases such as PD and AD (De Coo et al, 1999;Coskun et al, 2004;Smigrodzki et al, 2004;Parker and Parks, 2005;Bender et al, 2006Reeve et al, 2008). The types of mtDNA deletions in the substantia nigra neurons from patients with PD and age-matched controls were found to be similar to those that occur in patients with Kearns-Sayre, Twinkle, or multiple-deletion disorder (Reeve et al, 2008).…”

Section: Mitochondrial Dna Mutations and Neurodegenerationmentioning

confidence: 83%

Mitochondrial Dysfunction in Neurodegenerative Diseases

Johri

Beal

2012

J Pharmacol Exp Ther

615

429

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Neurodegenerative diseases are a large group of disabling disorders of the nervous system, characterized by the relative selective death of neuronal subtypes. In most cases, there is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases. More recently, evidence has emerged for impaired mitochondrial dynamics (shape, size, fission-fusion, distribution, movement etc.) in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Here, we provide a concise overview of the major findings in recent years highlighting the importance of healthy mitochondria for a healthy neuron.

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Section: Mitochondrial Dna Mutations and Neurodegenerationmentioning

confidence: 83%

Mitochondrial Dysfunction in Neurodegenerative Diseases

Johri

Beal

2012

J Pharmacol Exp Ther

615

429

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“…A heteroplasmic G290D mutation in the cytochrome b gene of patient P3 (80% mutated mtDNA in muscle) was previously found to be associated with impaired assembly of complex III and progressive exercise intolerance (15)(16)(17). In another patient, P4, a 4-base-pair deletion generating truncated cytochrome b (85% mutated mtDNA in muscle) was associated with Parkinsonism/MELAS overlap syndrome (18). In both patients, complex III was severely reduced or even below the detection limit; complexes IV and V were found at normal levels (Fig.…”

Section: Resultsmentioning

confidence: 98%

Significance of Respirasomes for the Assembly/Stability of Human Respiratory Chain Complex I

Schägger

Coo

Bauer

et al. 2004

Journal of Biological Chemistry

291

221

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We showed that the human respiratory chain is organized in supramolecular assemblies of respiratory chain complexes, the respirasomes. The mitochondrial complexes I (NADH dehydrogenase) and III (cytochrome c reductase) form a stable core respirasome to which complex IV (cytochrome c oxidase) can also bind. An analysis of the state of respirasomes in patients with an isolated deficiency of single complexes provided evidence that the formation of respirasomes is essential for the assembly/stability of complex I, the major entry point of respiratory chain substrates. Genetic alterations leading to a loss of complex III prevented respirasome formation and led to the secondary loss of complex I. Therefore, primary complex III assembly deficiencies presented as combined complex III/I defects. This dependence of complex I assembly/stability on respirasome formation has important implications for the diagnosis of mitochondrial respiratory chain disorders.

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“…Mitochondrial cyt b is part of the respiratory enzyme complex III, which catalyzes electron transfer from succinate and NAD + -linked dehydrogenases to cytochrome c. Mutations in mitochondrial cyt b have been associated with several human diseases, including progressive exercise intolerance and complex III deficiency (31), myoglobinuria (32), Leber's hereditary optic neuropathy (33), ischemic cardiomyopathy (25), parkinsonism/ mitochondrial encephalopathy, lactate acidosis, and stroke-like episodes (34), and severe hypertrophic cardiomyopathy (35). All of these reported cases of cyt b mutations were heteroplasmic (f70-80% mutant genes in affected organs only), suggesting that they were somatic in origin.…”

Section: Discussionmentioning

confidence: 99%

CD4+ T-Cell Response to MitochondrialCytochrome bin Human Melanoma

Voo

Zeng

et al. 2006

Cancer Research

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Mitochondrial DNA (mtDNA) is highly susceptible to mutations due to the low level of DNA repair and the presence of a high level of reactive oxygen species in the organelle. Although mtDNA mutations have been implicated in degenerating diseases, aging, and cancer, very little is known about the role of T cells in immunosurveillance for mtDNA aberrations. Here, we describe T-cell recognition of a peptide translated from an alternative open reading frame of the mitochondrial cytochrome b (cyt b) gene in melanoma cells established from a patient. To understand how the cyt b gene is transcribed and translated in tumor cells, we found that cyt b-specific CD4 + T cells only recognized protein fractions derived from cytoplasm and not from mitochondria. However, T-cell recognition of tumor cells could be inhibited by treatment of tumor cells with rhodamine 6G inhibitor, which depletes mitochondria. These findings suggest that cyt b mRNA is leaked out of the mitochondria and then translated in the cytoplasm for presentation to CD4 + T cells. The cyt b cDNAs from this patient contain highly heteroplasmic transition mutations compared with control cell lines, suggesting a compromise of mitochondrial integrity that may have contributed to melanoma induction or progression. These findings provide the first example of a mitochondrial immune target for CD4 + T cells and therefore have implications for the immunosurveillance of mitochondrial aberrations in cancer patients.

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A 4–base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome

Cited by 69 publications

References 15 publications

Mitochondrial Dysfunction in Neurodegenerative Diseases

Mitochondrial Dysfunction in Neurodegenerative Diseases

Significance of Respirasomes for the Assembly/Stability of Human Respiratory Chain Complex I

CD4+ T-Cell Response to MitochondrialCytochrome bin Human Melanoma

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