A new type of mitochondrial DNA deletion in patients with encephalomyopathy

Miyabayashi, Shigeaki; Hanamizu, H.; Endo, Hitoshi; Tada, Keiya; Horai, Satoshi

doi:10.1007/bf01799954

Cited by 21 publications

(10 citation statements)

References 16 publications

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“…8). Evidence of the involvement of mtDNA mutations in the pathogenesis of diabetes mellitus was reported in two pedigrees with maternally transmitted diabetes mellitus and deafness, one pedigree had a 10.4-kilobase large scale mtDNA deletion (21), which seemed to be very similar to that reported in patients with Leigh syndrome (22), and the other had a mitochondrial encephalopathy, lactic acidosis, and strokelike episode (MELAS)-specific mitochondrial tRNA Leu(UUR) mutation at nucleotide position 3243 (23). The former mutation was subsequently shown to be derived from partially duplicated mtDNA through rearrangement (41).…”

Section: Discussionsupporting

confidence: 61%

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Mitochondrial DNA Is Required for Regulation of Glucose-stimulated Insulin Secretion in a Mouse Pancreatic Beta Cell Line, MIN6

Soejima

Inoue

Takai

et al. 1996

Journal of Biological Chemistry

145

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To determine whether mtDNA and mitochondrial respiratory function in pancreatic beta cells are necessary for the phenotypic expression of glucose-stimulated insulin secretion, we used a cultured mouse pancreatic beta cell line, MIN6, and two derivative lines, mtDNA knockout MIN6 ( 0 MIN6) and mtDNA repopulated cybrid MIN6. The MIN6 cells retain the property of glucose-stimulated insulin secretion, but their mtDNA knockout induced the loss of mitochondrial transcription, translation, and respiration activity, without inhibition of transcription of the insulin gene or loss of succinate dehydrogenase activity, indicating that the observed mitochondrial dysfunction in 0 MIN6 cells was not due to a cytotoxic side effect derived from the mtDNA knockout. Moreover, the mtDNA depletion also inhibited both the glucose-stimulated increase in the intracellular free Ca 2؉ content and the elevation of insulin secretion. The possibility of the involvement of nuclear genome-encoded factors in this process was excluded by the observation that the missing sensitivity to extracellular glucose stimulation in 0 MIN6 cells was restored reversibly by repopulation with foreign mtDNA and isolating cybrid MIN6 clones. Therefore, these findings provide unambiguous evidence for the involvement of the mitochondrial dysfunction induced by mtDNA impairment in developing pathogeneses of some forms of diabetes mellitus.

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Section: Discussionsupporting

confidence: 61%

“…Similar mutations had been described in patients with Leigh syndrome (22). Then, the point mutation in the tRNA Leu(UUR) gene at position 3243, which had been observed in about 90% of patients with mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS), was identified in more than 1% of patients with diabetes mellitus (23)(24)(25)(26).…”

mentioning

confidence: 54%

Mitochondrial DNA Is Required for Regulation of Glucose-stimulated Insulin Secretion in a Mouse Pancreatic Beta Cell Line, MIN6

Soejima

Inoue

Takai

et al. 1996

Journal of Biological Chemistry

145

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“…Assay of mitochondrial respiratory transfer enzymes. The activities of respiratory transfer enzymes, such as NADH-cytochrome c reductase, succinate dehydrogenase, succinate cytochrome c reductase and cytochrome c oxidase were assayed using freshly purified mitochondria from skeletal muscle biopsy specimens, as described by Miyabayashi et al [15].…”

Section: Methodsmentioning

confidence: 99%

Pancreatic beta-cell secretory defect associated with mitochondrial point mutation of the tRNALEU(UUR) gene: a study in seven families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)

et al. 1994

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Recent evidence suggests possible linkage between diabetes mellitus and mitochondrial gene mutation. We surveyed mitochondrial tRNA(LEU(UUR)) (3243) mutation in 7 mitochondrial encephalomyopathy, lactic acidosis and stroke-like episode (MELAS) families and identified 24 mutated subjects (7 MELAS probands and 17 non-MELAS relatives) as well as 11 non-mutant family members. An OGTT in the 24 mutant relatives revealed 14 diabetic subjects, 3 with impaired glucose tolerance and 7 with normal glucose tolerance and all non-mutant family members as having normal glucose tolerance. Insulinogenic index was significantly reduced in the mutant diabetic subjects and those with impaired and normal glucose tolerance in comparison with the normal control subjects and the non-mutant members. Urinary 24-h C-peptide immunoreactivity excretion was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance, compared with the control subjects and the non-mutant family members. Plasma C-peptide immunoreactivity 6 min after glucagon injection was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance compared with the control subjects and the non-mutant family members. Si, an index of insulin sensitivity of the four mutant subjects was within normal range. Islet cell antibodies were negative in sera of eight mutated diabetic subjects, 2 and 6 with impaired and normal glucose tolerance, respectively. Diabetic retinopathy and nephropathy were demonstrated in 7 (50%) and 12 (85.7%) of 14 mutant diabetic subjects, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…It has been suggested that mitochondrial diseases should be considered in cases of progressive sensorineural hearing loss, especially with the coexistence of multisystem involvement. 42 A 10.4‐kb mtDNA deletion has been identified in association with maternally transmitted diabetes and deafness, without ophthalmoplegia or mitochondrial myopathies, which was the hallmark of mtDNA deletion syndromes. 43 Other studies have identified mutations in the tRNA(Leu)(UUR) gene in a large pedigree with maternally inherited dia‐ betes mellitus type II and deafness.…”

Section: Historical Perspectives and Review Of The Literaturementioning

confidence: 99%

Effects of Dietary Restriction and Antioxidants on Presbyacusis

2000

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Objectives/Hypothesis: The premise of this study is that the membrane hypothesis of aging, also known as the mitochondrial clock theory of aging, is the basis for presbyacusis. Furthermore, it is proposed that treatment with antioxidants or dietary restriction can attenuate age-related hearing loss. Many studies have demonstrated a reduction in blood flow to specific tissues, including the cochlea, with aging. Hypoperfusion leads to the formation of reactive oxygen metabolites (ROM). ROM are highly toxic molecules that directly affect tissues including inner ear structures. In addition, ROM can damage mitochondrial DNA (mtDNA), resulting in the production of specific mtDNA deletions (mtDNA del 4977 [human] or mtDNA del 4834 [rat]; also known as the common aging deletion]. Previous corroborating data suggest that the common aging deletion mtDNA 4834 may be associated not only with aging but also with presbyacusis, thus further strengthening the basis of the current studies. In this study, experiments provide compelling evidence that long-term treatment with compounds that block or scavenge reactive oxygen metabolites attenuate age-related hearing loss and reduce the impact of associated deleterious changes at the molecular level. Study Design: Prospective randomized study. Methods: One hundred thirty rats were randomly assigned to one of six groups with appropriate controls. Animals were divided into the following treatment arms: group 1, 30% caloric restriction; group 2, vitamin E oversupplementation; group 3, vitamin C oversupplementation; group 4, melatonin treatment; group 5, lazaroid treatment; and group 6, placebo. In addition, 10 animals were used to determine the appropriate caloric restriction. All subjects underwent baseline and every-3-month testing until their health failed (range, 18 -28 mo; average, 25 mo). This testing included auditory sensitivity studies using auditory brainstem response (ABR) testing, as well as tissue analysis for mtDNA deletions using molecular biological techniques. At the conclusion of the study, animals underwent a final ABR test and were tested for mtDNA deletions in brain and inner ear tissues, and the opposite ear was used for histological analysis. Results: Results indicated that the 30%-caloricrestricted group maintained the most acute auditory sensitivities, the lowest quantity of mtDNA deletions, and the least amount of outer hair cell loss. The antioxidant-treated subjects had improved auditory sensitivities, and a trend for fewer mtDNA deletions was observed compared with the placebo subjects. The placebo subjects had the poorest auditory sensitivity, the most mtDNA deletions, and the greatest degree of outer hair cell loss. Conclusions: Intervention designed to reduce reactive oxygen metabolite damage appears to protect against age-related hearing loss specifically and aging in general. This is reflected by an overall reduction in mtDNA deletions. These data also suggest that the common aging deletion appears to be associated with presbyacusis, as demonstrated b...

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A new type of mitochondrial DNA deletion in patients with encephalomyopathy

Cited by 21 publications

References 16 publications

Mitochondrial DNA Is Required for Regulation of Glucose-stimulated Insulin Secretion in a Mouse Pancreatic Beta Cell Line, MIN6

Mitochondrial DNA Is Required for Regulation of Glucose-stimulated Insulin Secretion in a Mouse Pancreatic Beta Cell Line, MIN6

Pancreatic beta-cell secretory defect associated with mitochondrial point mutation of the tRNALEU(UUR) gene: a study in seven families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)

Effects of Dietary Restriction and Antioxidants on Presbyacusis

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