Mitochondrial tRNAlle mutation in fatal cardiomyopathy

Taniike, Masako; Fukushima, Hisao; Yanagihara, Itaru; Tsukamoto, Hiroko; Tanaka, Junya; Fujimura, Harutoshi; Nagai, Toshisaburo; Sano, Takuya; Yamaoka, Kiyoshi; Inui, Koji; Okada, Shintaro

doi:10.1016/s0006-291x(05)80773-9

Cited by 161 publications

(65 citation statements)

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“…To demonstrate the reliable isolation of respiration-deficient clones, we carried out nuclear transfer from 0 HeLa cells to respiration-deficient fibroblasts containing 90% mtDNA with a pathogenic mutation (A to G) in tRNA Ile at 4,269 derived from a patient with fatal cardiomyopathy (14,15). Then we examined the content of the mtDNA with the tRNA Ile 4,269 mutation in all 12 nuclear hybrid clones by analysis of the SspI restriction pattern of the PCR products as described previously (15).…”

Section: Resultsmentioning

confidence: 99%

“…TIG3S was used as a positive control of mitochondrial respiratory function in nuclear transfer experiments. As a negative control, we used a respiration-deficient fibroblast line CM derived from a 18-year-old patient with fatal cardiomyopathy with a tRNA Ile 4,269 pathogenic mtDNA mutation (14,15), which was obtained from Dr. S. Okada, the Department of Pediatrics, Osaka University Medical School. The 0 HeLa cells are resistant to 20 M 6-thioguanine and 2 mM Oua (6).…”

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confidence: 99%

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Nuclear-recessive Mutations of Factors Involved in Mitochondrial Translation Are Responsible for Age-related Respiration Deficiency of Human Skin Fibroblasts

Isobe¹,

Ito²,

Hosaka³

et al. 1998

Journal of Biological Chemistry

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We addressed the question of whether both mitochondrial and cytoplasmic translation activities decreased simultaneously in human skin fibroblasts with the age of the donors and found that the age-related reduction was limited to mitochondrial translation. Then, to determine which genome, mitochondrial or nuclear, was responsible for this age-related, mitochondria-specific reduction, pure nuclear transfer was carried out from mitochondrial DNA (mtDNA)-less HeLa cells to four fibroblast lines, two from aged subjects, one from a fetus, and one from a patient with cardiomyopathy, and their nuclear hybrid clones were isolated. A normal fibroblast line from the fetus and a respiration-deficient fibroblast line from the patient were used as a positive and a negative control, respectively. Subsequently, the mitochondrial translation and respiration properties of the nuclear hybrid clones were compared. A negative control experiment showed that this procedure could be used to isolate even nuclear hybrids expressing overall mitochondrial respiration deficiency, whereas no respiration deficiencies were observed in any nuclear hybrids irrespective of whether their mtDNAs were exclusively derived from aged or fetal donors. These observations suggest that nuclear-recessive mutations of factors involved in mitochondrial translation but not mtDNA mutations are responsible for age-related respiration deficiency of human fibroblasts.It has been presumed that somatic mutations accumulate in mitochondrial DNA (mtDNA) much faster than in nuclear DNA because mitochondria are highly oxygenic organelles due to their function in producing energy, mtDNA lacks histones protecting it from mutagenic damage, and its repair systems are limited (1). Therefore, it has been proposed that the accumulation of various somatic mutations in mtDNA and the resultant decrease in mitochondrial respiratory function could be involved in aging processes in mammals (2-4). There have been many reports that the respiration capacity of mitochondria in highly oxidative tissues decreases during aging (4). Moreover, the accumulation of somatic and pathogenic mtDNA mutations, which have been shown to cause various kinds of mitochondrial encephalomyopathies (5-8), was also shown to increase with age in normal subjects (9, 10). However, as the nuclear genome encodes most mitochondrial proteins including factors necessary for replication and expression of the mitochondrial genome, it is possible that only mutations in the nuclear genome contribute to the age-related decline of mitochondrial respiratory function. In fact, there is no convincing evidence that mtDNA somatic mutations are responsible for this age-related phenotype.Previously, we observed age-related reduction of cytochrome c oxidase (COX) 1 activity and mitochondrial translation in cultured human skin fibroblasts isolated from donors of various ages (0 -97 years), and in studies on their mtDNA transfer to mtDNA-less ( 0 ) HeLa cells, we showed that mtDNA mutations were not responsible for the observed age...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Nuclear-recessive Mutations of Factors Involved in Mitochondrial Translation Are Responsible for Age-related Respiration Deficiency of Human Skin Fibroblasts

Isobe¹,

Ito²,

Hosaka³

et al. 1998

Journal of Biological Chemistry

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“…Goto et al also reported that three of forty MELASpatients (7.5%), who all had mutations of transfer RNALeu(UUR) 3 ,243 , presenting cardiomyopathy (14). Some cases diagnosed with non-autosomal idiopathic cardiomyopathy were reported to have mitochondrial DNAmutations, and these were termed mitochondrial cardiomyopathy (1)(2)(3)(15)(16)(17). On the other hand, the gene responsible for familial hypertrophic cardiomyopathy was reported to be localized on chromosome 14.…”

Section: Case Reportmentioning

confidence: 99%

Mitochondrial Encephalomyopathy with A to G Transition of Mitochondrial Transfer RNALeU(uuR) 3,243 Presenting Hypertrophic Cardiomyopathy.

et al. 1995

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In a 24-year-old womanwith mitochondrial encephalomyopathy presenting hypertrophic cardiomyopathy, microscopical examination of myocardial biopsy specimen disclosed severe vacuolar degeneration of myocardium and aggregates of enlarged mitochondria with proliferated cristae. Limb muscle biopsy specimen showed "ragged-red fibers" light microscopically and enlarged abnormal mitochondria with markedly increased cristae ultrastructurally.Mitochondrial DNAanalysis by polymerase chain reaction (PCR) revealed an A-to-G transition in the mitochondrial transfer RNALeu(UUR) gene at nucleotide position 3,243 which is reported to be associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).However, the clinical features of this case, presenting mainly cardiac abnormalities, were not consistent with the typical MELAS. (Internal Medicine 34: 670-673, 1995)

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“…Examples of a missense mutation include Leber's hereditary optic neuropathy (LHON) (Newman, 1993) and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) (Holt et al, 1990). Synthetic mutations are mutations in the encoding region of tRNA, which include MELAS (Goto et al, 1990), MERRF (Shoffner et al, 1990), and maternally inherited cardiomyopathy (CM) (Taniike et al, 1992). Deletions in mtDNA have been found in the majority of CPEO and Kearns-Sayre syndrome (KSS) (Shanske et al, 1990).…”

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confidence: 99%

“…Since various diseases are caused by mutations in mtDNA as described above, a mitochondrial gene delivery leading to the repair of a mutation in mtDNA and/or complement normal mtDNA would be expected to serve as a novel strategy for curing a mitochondrial disease. ) (Goto et al, 1990) and bp 4269 (A to G; tRNA Ile ) (Taniike et al, 1992), respectively.…”

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Mitochondrial drug delivery and mitochondrial disease therapy – An approach to liposome-based delivery targeted to mitochondria

et al. 2007

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Recent progress in genetics and molecular biology has provided useful information regarding the molecular mechanisms associated with the mitochondrial diseases. Genetic approaches were initiated in the late 1980s to clarify the gene responsible for various mitochondrial diseases, and information concerning genetic mutations is currently used in the diagnosis of mitochondrial diseases. Moreover, it was also revealed that mitochondria play a central role in apoptosis, or programmed cell death, which is closely related to the loss of physiological functions of tissues. Therefore, drug therapies targeted to the mitochondria would be highly desirable. In spite of the huge amount of mechanism-based studies of mitochondrial diseases, effective therapies have not yet been established mainly because of the lack of an adequate delivery system. To date, numerous investigators have attempted to establish a mitochondrial drug delivery system. However, many problems remain to be overcome before a clinical application can be achieved. To fulfill a drug delivery targeted to mitochondria, we first need to establish a method to encapsulate various drugs, proteins, peptides, and genes into a drug carrier depending on their physical characteristics. Second, we need to target it to a specific cell. Finally, multi-processes of intracellular trafficking should be sophisticatedly regulated so as to release a drug carrier from the endosome to the cytosol, and thereafter to deliver to the mitochondria. In this review, we describe the current state of the development of mitochondrial drug delivery systems, and discuss the advantage and disadvantage of each system. Our current efforts to develop an efficient method for the packaging of macromolecules and regulating intracellular trafficking are also summarized.Furthermore, novel concept of "Regulation of intramitochondrial trafficking" is proposed herein as a future challenge to the development of a mitochondrial drug delivery system. Yamada, Y., et al 3 Keywords:Mitochondrial drug delivery; Mitochondrial protein therapy; Mitochondrial gene therapy; Transferrin and GALA system; multifunctional envelope-type nano device (MEND);Regulation of intramitochondrial trafficking. Yamada, Y., et al 4

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Mitochondrial tRNAlle mutation in fatal cardiomyopathy

Cited by 161 publications

References 10 publications

Nuclear-recessive Mutations of Factors Involved in Mitochondrial Translation Are Responsible for Age-related Respiration Deficiency of Human Skin Fibroblasts

Nuclear-recessive Mutations of Factors Involved in Mitochondrial Translation Are Responsible for Age-related Respiration Deficiency of Human Skin Fibroblasts

Mitochondrial Encephalomyopathy with A to G Transition of Mitochondrial Transfer RNALeU(uuR) 3,243 Presenting Hypertrophic Cardiomyopathy.

Mitochondrial drug delivery and mitochondrial disease therapy – An approach to liposome-based delivery targeted to mitochondria

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