Direct, DNA Pol-γ-Independent Effects of Nucleoside Reverse Transcriptase Inhibitors on Mitochondrial Bioenergetics (original) (raw)
Related papers
2004
In this investigation we demonstrate that various nucleoside reverse transcriptase inhibitors (NRTIs) and their corresponding nucleotides can cause a direct, DNA polymerase-g-independent, inhibition of respiration, membrane potential, and calcium loading capacity in isolated rat heart mitochondria in vitro. Both AZT and d4T also increased total adenine phosphate energy charge in H9c2 rat cardiac myocytes in cell culture. These results demonstrate that the various NRTI nucleosides and nucleotides are capable, at sufficiently high concentrations, of directly affecting mitochondrial bioenergetics in vitro, which may enhance the toxicity observed in vivo previously attributed to inhibition of DNA polymerase-g.
Cardiomyopathy with Mitochondrial Damage Associated with Nucleoside Reverse-Transcriptase Inhibitors
New England Journal of Medicine, 2002
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Absence of a universal mechanism of mitochondrial toxicity by nucleoside analogs
Antimicrobial agents and …, 2007
Nucleoside analogs are associated with various mitochondrial toxicities, and it is becoming increasingly difficult to accommodate these differences solely in the context of DNA polymerase gamma inhibition. Therefore, we examined the toxicities of zidovudine (AZT) (10 and 50 M; 2.7 and 13.4 g/ml), didanosine (ddI) (10 and 50 M; 2.4 and 11.8 g/ml), and zalcitabine (ddC) (1 and 5 M; 0.21 and 1.1 g/ml) in HepG2 and H9c2 cells without the presumption of mitochondrial DNA (mtDNA) depletion. Ethidium bromide (EtBr) (0.5 g/ml; 1.3 M) was used as a positive control. AZT treatment resulted in metabolic disruption (increased lactate and superoxide) and increased cell mortality with decreased proliferation, while mtDNA remained unchanged or increased (HepG2 cells; 50 M AZT). ddC caused pronounced mtDNA depletion in HepG2 cells but not in H9c2 cells and increased mortality in HepG2 cells, but no significant metabolic disruption in either cell type. ddI caused a moderate depletion of mtDNA in both cell types but showed no other effects. EtBr exposure resulted in metabolic disruption, increased cell mortality with decreased cell proliferation, and mtDNA depletion in both cell types. We conclude that nucleoside analogs display unique toxicities within and between culture models, and therefore, care should be taken when generalizing about the mechanisms of nucleoside reverse transcriptase inhibitor toxicity. Additionally, mtDNA abundance does not necessarily correlate with metabolic disruption, especially in cell culture; careful discernment is recommended in this regard.
Journal of Infectious Diseases, 2005
Background. Nucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described. Methods. We examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks. Results. We observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator-activated receptor-g coactivator-1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues. Conclusions. Independent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase-g, whereas disruption of expression of lipid metabolism genes offers an explanation for NRTI-induced lipoatrophy.
Antiviral Therapy, 2010
Background The metabolism of pyrimidine deoxynucleosides and nucleoside reverse transcriptase inhibitors has been studied in growing cells. However, many of these drugs are associated with mitochondrial toxicities observed in non-replicating tissues, such as in the heart, where their metabolism has not been investigated. Methods The aims of this study were twofold. The first was to investigate the metabolism of the thymidine analogues 3’-azido-3'deoxythymidine (AZT) and 2’,3’-didehydrodideoxy-thymidine (d4T), and the deoxycytidine (dCyd) analogues 2’-deoxy-3’-thiacytidine (3TC) and 2’,3’-dideoxycytidine (ddC) with regard to phosphorylation and breakdown. The second was to investigate their potential effects, singly or in combination with AZT, on metabolism of the naturally occurring deoxynucleosides in the perfused rat heart and in isolated heart mitochondria. Results The analogue d4T was not metabolized in perfused heart or in isolated mitochondria, and had no effect on either ...
Cardiovascular Toxicology, 2005
Hearts from 1-yr-old Erythrocebus patas monkeys were examined after in utero and 6-wk-postbirth exposure to antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs). Protocols were modeled on those given to human immunodeficiency virus (HIV)-1-infected pregnant women. NRTIs were administered daily to the dams for the last 20% or 50% of gestation, and to the infants for 6 wk after birth. Exposures included: no drug (n = 4); Zidovudine, 3'-azido-3'-deoxythymidine (AZT; n = 4); AZT/Lamivudine, (-)-b-L-2', 3'-Dideoxy-3'-thiacytidine (Epivir, 3TC) (n = 4); AZT/Didanosine (Videx, ddI) (n = 4); and Stavudine (Zerit, d4T)/3TC (n = 4). Echocardiograms and clinical chemistry showed no drug-related changes, but the d4T/3TC-exposed fetuses at 6 and 12 mo had increased white cell counts (p < 0.05). At 1 yr of age, oxidative phosphorylation (OXPHOS) enzyme activities were similar in heart mitochondria from all groups. Mitochondrial pathology, that included clones of damaged mitochondria (p < 0.05), was found in hearts of all 1-yr drugexposed infants. Levels of mtDNA were elevated (p < 0.05) in hearts of all NRTI-exposed monkeys in the following order: control < d4T/3TC < AZT < AZT/3TC < AZT/ddI. The clinical status of NRTI-exposed infants, as evidenced by behavior, clinical chemistry, OXPHOS activity and echocardiogram, was normal. However, extensive mitochondrial damage with clusters of similarappearing damaged heart mitochondria observed by electron microscopy, and an increase in mtDNA quantity, that persisted at 1 yr of age, suggest the potential for cardiotoxicity later in life.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2010
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.