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Balcarek 2010

From Bioblast
Publications in the MiPMap
Balcarek K, Venhoff N, Deveaud C, Beauvoit B, Bonnet J, Kirschner J, Venhoff AC, Lebrecht D, Walker UA. (2010) Role of pyrimidine depletion in the mitochondrial cardiotoxicity of nucleoside analogue reverse transcriptase inhibitors. J Acquir Immune Defic Syndr. 55:550-7.

Β» PMID: 20827217

Balcarek K, Venhoff N, Deveaud C, Beauvoit B, Bonnet J, Kirschner J, Venhoff AC, Lebrecht D, Walker UA. (2010) J Acquir Immune Defic Syndr.

Abstract: OBJECTIVE: Long-term antiretroviral treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) may result in a cardiomyopathy due to mitochondrial DNA (mtDNA) depletion. An intact mitochondrial function is required for the synthesis of intramyocardial pyrimidine nucleotides, which in turn are building blocks of mtDNA. We investigated if NRTI-related cardiomyopathy can be prevented with pyrimidine precursors. METHODS: Mice were fed with zidovudine or zalcitabine with or without simultaneous Mitocnol, a dietary supplement with high uridine bioavailability. Myocardia were examined after 9 weeks. RESULTS: Both NRTI induced a cardiomyopathy with mitochondrial enlargement, a disrupted cristal architecture on electron microscopy and diminished myocardial mtDNA copy numbers. The myocardial mtDNA-encoded cytochrome c-oxidase I subunit was impaired more profoundly than the nucleus-encoded cytochrome c-oxidase IV subunit. The myocardial formation of reactive oxygen species and mtDNA mutations was enhanced in zidovudine and zalcitabine treated animals. Mitocnol attenuated or normalized all myocardial pathology when given with both NRTI, but by itself had no intrinsic effects and no apparent adverse effects. CONCLUSIONS: Zidovudine and zalcitabine induce a mitochondrial cardiomyopathy, which is antagonized with uridine supplementation, implicating pyrimidine pool depletion in its pathogenesis. Pyrimidine pool replenishment may be exploited clinically because uridine is well tolerated.


β€’ O2k-Network Lab: FR Pessac Diolez P


Labels: MiParea: mtDNA;mt-genetics, nDNA;cell genetics, Pharmacology;toxicology 


Organism: Mouse  Tissue;cell: Heart