Maternally inherited myopathy and cardiomyopathy: association with mutation in mitochondrial DNA tRNALeu(UUR)

Zeviani, Massimo; Gellera, Cinzia; Antozzi, Carlo; Rimoldi, M.; Morandi, Lucia; Tiranti, Valeria; DiDonato, Stefano; Villani, Flavio

doi:10.1016/0140-6736(91)90136-d

Cited by 356 publications

(118 citation statements)

References 11 publications

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“…In earlier investigations, the cardiomyopathy appeared to only become clinically and histologically apparent, when the degree of combined respiratory chain and mtDNA-insults exceeded a threshold of less than 30% residual COX/SDH activity. 9,30 This threshold was however not reached by the high-dose DOXO-EMCH group, explaining the lack of clinical manifestations.…”

Section: Table III -Lack Of Mitochondrial Effects Of Doxorubicin and mentioning

confidence: 95%

The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

Lebrecht

Geist

Ketelsen

et al. 2006

Intl Journal of Cancer

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Doxorubicin causes a chronic cardiomyopathy in which genetic and functional lesions of mitochondria accumulate in the longterm and explain in part the delayed onset of heart dysfunction. DOXO-EMCH a 6-maleimidocaproyl hydrazone derivative of doxorubicin, is an albumin binding prodrug which has entered clinical trials because of its superior antitumor and toxicological profile. In the present work, we examined the chronic cardiotoxicity of DOXO-EMCH in direct comparison with doxorubicin. Rats (11 weeks of age) were treated with intravenous doxorubicin (0.8 mg/kg weekly for 7 weeks), an equimolar dose of DOXO-EMCH (1.1 mg/kg), or with 3.3 mg/kg of DOXO-EMCH. Controls received saline. Animals were euthanized at 48th week. Rats exposed to doxorubicin had a severe clinical, and histopathological cardiomyopathy with depressed myocardial activity of cytochrome c-oxidase (COX, 26% of controls), reduced expression of the mtDNA-encoded COX II subunit, decreased mtDNA copy numbers (46% of controls), and high levels of malondialdehyde and superoxide (787% of controls). All parameters were highly correlated with myocardial damage. Both DOXO-EMCH groups did not differ from controls with regard to clinical symptomatology, mortality and mitochondrial enzymes, although the myocardia of the high-dose group had slightly increased histopathological abnormalities, depressed mtDNA copies (74% of controls) and elevated superoxide levels (347% of controls). Doxorubicin-exposed hearts and to a lesser extent the myocardia of both DOXO-EMCH groups contained mtDNA-deletions. In summary both DOXO-EMCH doses were superior over doxorubicin with respect to clinical and histopathological evidence of cardiomyopathy, myocardial COX-activity, COX II expression, mtDNA-content, mtDNA mutation loads and superoxide production in rats. ' 2006 Wiley-Liss, Inc.Key words: doxorubicin prodrug; mitochondria cytochrome oxidase; DNA mitochondrial; reactive oxygen species Doxorubicin is an antineoplastic anthracycline that is widely used in the treatment of leukemia and lymphoma, breast and ovarian carcinoma and many other solid tumors. Bone marrow suppression with maximum toxicity after 7-10 days and a rapid recovery thereafter generally limits the escalation of single doses. Cumulative doses of doxorubicin exceeding 500 mg/m 2 in contrast, are curtailed by a late-onset and irreversible cardiotoxicity. The antitumor potency and toxicological profile of anthracyclines has been the impetus for a diligent search for more effective and less toxic anthracycline analogues, and 2,000 derivatives have been developed during the past 20 years.2 Despite these efforts, daunorubicin, epirubicin, idarubicin, pirarubicin, zorubicin, aclarubicin and carminomycin have not satisfactorily improved the therapeutic index of anthracyclines in clinical practice. 3To improve the therapeutic potential of doxorubicin, we have developed a macromolecular prodrug in which doxorubicin is derivatized at its C-13 keto-position with a thiol-binding spacer molecule (i.e., 6-maleimidocaproyl ...

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Section: Table III -Lack Of Mitochondrial Effects Of Doxorubicin and mentioning

confidence: 95%

The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

Lebrecht

Geist

Ketelsen

et al. 2006

Intl Journal of Cancer

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“…A number of recent reports have indicated that mutations in either the DNA or transfer RNA species of mitochondria may be directly associated with development of cardiomyopathy in humans (8,11,13,21) as well as in mice (1). While it is unclear whether the PhIP-induced adducts in the hearts of treated animals specifically involve the mitochondria or the nuclei, or both, the question of whether or not a similar situation might exist with regard to this environmental compound of such obvious potential impact has hitherto not been addressed.…”

Section: Introductionmentioning

confidence: 99%

Chronic Administration of the Mutagenic Heterocyclic Amine 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine Induces Cardiac Damage with Characteristic Mitochondrial Changes in Fischer Rats

et al. 1996

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Fischer-344 rats of both sexes were administered the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo [4,5-b ]pyridine (PhIP) for 52 wk at the dietary level of 400 ppm. Light microscopic and ultrastructural investigation of the myocardium revealed prominent changes in all PhIP-treated male and female animals investigated. These were characterized by a diffuse proliferation of markedly enlarged mitochondria, with abundant cristae and often containing lamellar bodies as inclusions. PhIP is well known to cause DNA adducts in the rat heart, and there are numerous reports of mutations in mitochondrial DNA in both humans and experimental animals being associated with very similar lesions to those observed in the present study. The results thus suggest that this heterocyclic amine induces cardiac damage by the same mechanism.

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“…COX deficiency has been documented in disorders caused by mutations in mtDNA-encoded tRNA genes, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS; tRNA Leu(UUR) ) and mtDNA disorders caused by large deletions of mtDNA such as Kearns-Sayre syndrome. Usually these disorders present with multiple respiratory chain enzyme deficiencies including COX deficiency (11)(12)(13). Several types of isolated COX deficiency have been described including Leigh disease and a fatal infantile form presenting as a myopathy or cardiomyopathy (14,15).…”

mentioning

confidence: 99%

A Pathogenic 15-Base Pair Deletion in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit III Results in the Absence of Functional Cytochrome c Oxidase

Hoffbuhr¹,

Davidson²,

Filiano³

et al. 2000

Journal of Biological Chemistry

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A 15-base pair, in-frame, deletion (9480del15) in the mitochondrial DNA (mtDNA)-encoded cytochrome c oxidase subunit III (COX III) gene was identified previously in a patient with recurrent episodes of myoglobinuria and an isolated COX deficiency. Transmitochondrial cell lines harboring 0, 97, and 100% of the 9480del15 deletion were created by fusing human cells lacking mtDNA ( 0 cells) with platelet and lymphocyte fractions isolated from the patient. The COX III gene mutation resulted in a severe respiratory chain defect in all mutant cell lines. Cells homoplasmic for the mutation had no detectable COX activity or respiratory ATP synthesis, and required uridine and pyruvate supplementation for growth, a phenotype similar to 0 cells. The cells with 97% mutated mtDNA exhibited severe reductions in both COX activity (6% of wild-type levels) and rates of ATP synthesis (9% of wild-type). The COX III polypeptide in the mutant cells, although translated at rates similar to wild-type, had reduced stability. There was no evidence for assembly of COX

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Maternally inherited myopathy and cardiomyopathy: association with mutation in mitochondrial DNA tRNALeu(UUR)

Cited by 356 publications

References 11 publications

The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

Chronic Administration of the Mutagenic Heterocyclic Amine 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine Induces Cardiac Damage with Characteristic Mitochondrial Changes in Fischer Rats

A Pathogenic 15-Base Pair Deletion in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit III Results in the Absence of Functional Cytochrome c Oxidase

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