2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13-15 September 2000, Toronto, Canada

PRIMARY AND SECONDARY CAUSES OF MITOCHONDRIAL DYSFUNCTION

Antiviral Therapy 2000; 5(Suppl. 5):5 (abstract no. O5)

AHV Schapira
University Department of Clinical Neurosciences, Royal Free and University College Medical School and Institute of Neurology, University College London, London, UK

Mitochondria playa pivotal role in two critical cell functions. They are the source of ATP generation by oxidative phosphorylation, and they are the final common pathway for a number of initiators of apoptosis. Mitochondria have their own DNA and are therefore the source of a number of molecular genetic defects resulting in human disease. Mitochondrial dysfunction may also be a consequence of a variety of nuclear genomic abnormalities. Finally, mitochondria are the target of a number of endogenous and exogenous toxins, several of which have been documented as resulting in human disease. Intriguing interactions between mitochondrial DNA and the environment, including drugs, are now emerging. MtDNA mutations causing human disease include rearrangements (macro- and micro-deletions), point mutations of transfer RNAs, ribosomal RNAs and protein coding genes, and mtDNA depletion. The spectrum of phenotypic expression is vast, including myopathy, encephalopathy, diabetes mellitus, deafness, lipomatosis and cardiomyopathy. Replication of mtDNA is undertaken by DNA polymerase-γ, and this enzyme is inhibited by nucleotide-analogue reverse transcriptase inhibitors (NRTIs). The agents include the 2,3-dideoxy analogues that lack the hydroxyl radical in the 3 position and are incorporated into DNA but prevent elongation of the DNA strand. Thus, these drugs can induce mtDNA depletion and result in mitochondrial respiratory chain and oxidative phosphorylation deficits. These effects were first observed in zidovudine-treated patients who developed a myopathy with ragged red fibres and low mtDNA levels. Other drugs may have similar actions and be responsible for some of the side-effects seen with combination therapy.

000913
O5

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