Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy

Ozawa, Takayuki; Tanaka, Masashi; Sugiyama, Satoru; Hattori, Kazuki; Itō, Takayuki; Ohno, Kinji; Takahashi, Akira; Sato, Wataru; Takada, Goro; Mayumi, Bunji; Yamamoto, Kayoko; Adachi, Kenzō; Koga, Yoshinori; Toshima, Hironori

doi:10.1016/0006-291x(90)92166-w

Cited by 163 publications

(40 citation statements)

References 17 publications

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“…The occurrence of mtDNA deletions is a common phenomenon, and normal tissue homogenates contain a mean concentration of 1% of any particular deletion mutation (40). Nonetheless, the number and type of mtDNA deletions vary greatly in different tissues and organs depending on age and the presence of distinct hereditary or acquired pathological conditions (20,25,55).…”

Section: Discussionmentioning

confidence: 99%

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Fukushima¹,

Fiocchi²

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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Fukushima, Kouhei, and Claudio Fiocchi. Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients. Am J Physiol Gastrointest Liver Physiol 286: G804-G813, 2004; 10.1152/ajpgi.00398.2003.-Ulcerative colitis (UC) is a condition characterized by chronic inflammation targeted at the epithelial layer. In addition to being involved in immune phenomena, UC epithelial cells exhibit decreased oxidation of butyrate, downregulation of oxidative pathway regulatory genes, and overexpression of mitochondrial (mt) genes. We investigated whether these events, which translate an altered energy metabolism, are associated with an abnormal pattern of mtDNA deletions. Highly purified colonocytes were isolated from surgically resected control, involved and uninvolved inflammatory bowel disease mucosa. The frequency, type, and number of mtDNA deletions were assessed by PCR amplification, Southern blot analysis, and cloning and sequencing of amplified DNA fragments. The 4977 mtDNA deletion was less frequent in UC than control and Crohn's disease (CD) epithelium, regardless of patient age. Several other deletions were detected, but all were less common in UC than control and CD cells. The frequency, variety, and number of mtDNA deletions were invariably lower in colonocytes isolated from inflamed mucosa than in autologous cells from noninflamed mucosa. In conclusion, in the absence of inflammation, UC colonocytes exhibit an mtDNA deletion pattern similar to that of control cells, indicating a normal response to physiological levels of oxidative stress. In active inflammation, when oxidative stress increases, the frequency, variety, and number of mtDNA deletions decrease. Because comparable abnormalities are absent in active CD, the mtDNA deletion pattern of active UC suggests that colonocytes respond uniquely to inflammation-associated stress in this condition. epithelium; energy metabolism ALTHOUGH THE ETIOLOGY OF ULCERATIVE colitis (UC) is still uncertain, colonic epithelial cells (EC) have long been considered central to its pathophysiology. In addition to the restriction of the inflammatory process and associated dysplastic changes to the epithelial lining (43), there is abundant experimental evidence pointing to colonocytes as likely targets and mediators of key pathogenic events. Detection of circulating colon antibodies and cytotoxic mononuclear cells in UC patients initially suggested that colonocytes could be targets of autoimmune reactivity (6, 49). Subsequent studies demonstrated that in UC, EC express high levels of human leukocyte antigen D-related antigens (48), secrete abnormal mucin glycoconjugates (41), produce increased amounts of cytokines and chemokines (4,42,57), express costimulatory molecules (39), display autoantigens recognized exclusively by UC tissueeluted antibodies (53), and fail to mediate induction of suppressor T cells (36). Additional reports demonstrated cyclooxygenase 2 and NF-B activation (46, 51), as well as an increased rate of EC apoptosis in UC (...

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Section: Discussionmentioning

confidence: 99%

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Fukushima¹,

Fiocchi²

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In the last few years mitochondrial (mt)DNA deletions 1 or transfer (t)RNA point mutations [2][3][4][5][6][7][8][9][10] have been identified in cardiomyopathies phenotypically characterized by hypertrophy, atrio-ventricular block, or congestive heart failure. 11 Although some cardiomyopathies associated with mtDNA defects have been reported as clinically isolated disorders, [2][3][4] they may also be associated with peripheral myopathies [5][6][7] or with multisystem syndromes; 9 -11 in these latter cases, cardiac involvement may be the major determinant of poor outcomes.…”

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confidence: 99%

Mitochondrial DNA Mutations and Mitochondrial Abnormalities in Dilated Cardiomyopathy

Arbustini

Diegoli

Fasani

et al. 1998

The American Journal of Pathology

219

140

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Mitochondrial (mt)DNA defects , both deletions and tRNA point mutations , have been associated with cardiomyopathies. The aim of the study was to determine the prevalence of pathological mtDNA mutations and to assess associated defects of mitochondrial enzyme activity in dilated cardiomyopathy (DCM) patients with ultrastructural abnormalities of cardiac mitochondria. In a large cohort of 601 DCM patients we performed conventional light and electron microscopy on endomyocardial biopsy samples. Cases with giant organelles , angulated , tubular , and concentric cristae , and crystalloid or osmiophilic inclusion bodies were selected for mtDNA analysis. Mutation screening techniques , automated DNA sequencing, restriction enzyme digestion , and densitometric assays were performed to identify mtDNA mutations, assess heteroplasmy , and quantify the amount of mutant in myocardial and blood DNA. Of 601 patients (16 to 63 years; mean , 43.5 ؎ 12.7 years) , 85 had ultrastructural evidence of giant organelles , with abnormal cristae and inclusion bodies; 19 of 85 (22.35%) had heteroplasmic mtDNA mutations (9 tRNA, 5 rRNA , and 4 missense , one in two patients) that were not found in 111 normal controls and in 32 DCM patients without the above ultrastructural mitochondrial abnormalities. In all cases , the amount of mutant was higher in heart than in blood. In hearts of patients that later underwent transplantation , cytochrome c oxidase (Cox) activity was significantly lower in cases with mutations than in those without or controls (P ‫؍‬ 0.0008). NADH dehydrogenase activity was only slightly reduced in cases with mutations (P ‫؍‬ 0.0388) , whereas succinic dehydrogenase activity did not significantly differ between DCM patients with mtDNA mutations and those without or controls. The present study represents the first attempt to detect a morphological, easily identifiable marker to guide mtDNA mutation screening. Pathological mtDNA mutations are associated with ultrastructurally abnormal mitochondria, and reduced Cox activity in a small subgroup of non-otherwise-defined, idiopathic DCMs, in which mtDNA defects may constitute the basis for, or contribute to, the development of congestive heart failure. (Am J Pathol 1998, 153:1501-1510)

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“…Total DNAwas extracted from the biopsied brachiobiceps muscle by the phe- nol/chloroform method as reported elsewhere (8). A mitochondrial DNAfragment of 800 bp (nucleotide position 2,881 to 3,680) was amplified using PCR primers, L288 (5?-CTACTATACT CAATTATCC-3') and H366 (5?-GAGTTTGATGCTCACCCTGA-3). Thirty cycles were performed with the following conditions: 15 seconds of denaturation at 94°C, 15 seconds of annealing at 50°C, and 80 seconds of primer extension at 72°C.…”

Section: Case Reportmentioning

confidence: 99%

“…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%

“…Onthe other hand, mutations of mitochondrial DNAcontribute to the pathogenesis of somecases of hypertrophic or dilated cardiomyopathy (1)(2)(3). Mitochondrial encephalomyopathies include three distinct clinical subgroups ; 1) mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)(4), 2) myoclonus epilepsy associated with ragged-red fibers (MERRF), and 3) chronic progressive external ophthalmoplegia (CPEO) including KearnsSayre syndrome (KSS).…”

Section: Introductionmentioning

confidence: 99%

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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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Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy

Cited by 163 publications

References 17 publications

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Mitochondrial DNA Mutations and Mitochondrial Abnormalities in Dilated Cardiomyopathy

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

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