Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs

Feng, Joy Y.; Johnson, Allison A.; Johnson, Kenneth A.; Anderson, Karen S.

doi:10.1074/jbc.m101156200

Cited by 129 publications

(114 citation statements)

References 45 publications

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“…Polymerase g exonuclease is inefficient in removing these drugs. 38 Earlier studies have demonstrated the efficient removal of NA from the 3 0 terminus in the presence of p53. 39,40 p53 in mitochondria can play an important function as an external proofreader in the removal of 3 0 -terminal NAs, thus decreasing their potential for chain termination (manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

p53 in mitochondria enhances the accuracy of DNA synthesis

et al. 2008

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Mitochondrial localization of p53 was observed in stressed and unstressed cells. p53 is involved in DNA repair and apoptosis. It exerts physical and functional interactions with mitochondrial DNA and DNA polymerase c (pol c). The functional cooperation of p53 and pol c during DNA synthesis was examined in the mitochondrial fraction of p53-null H1299 cells, as the source of pol c. The results show that p53 may affect the accuracy of DNA synthesis in mitochondria: (1) the excision of a misincorporated nucleotide increases in the presence of (a) recombinant wild-type p53 (wtp53); (b) cytoplasmic fraction of LCC2 cells expressing endogenous wtp53 (but not specifically pre-depleted fraction); (c) cytoplasmic extract of H1299 cells overexpressing wtp53, but not exonuclease-deficient mutant p53-R175H. (2) Mitochondrial extracts of HCT116(p53 þ / þ ) cells display higher exonuclease activity compared with that of HCT116(p53À/À) cells. Addition of exogenous p53 complements the HCT116(p53À/À) mitochondrial extract mispair excision. Furthermore, the misincorporation was lower in the mitochondrial fraction of HCT116(p53 þ / þ ) cells as compared with that of HCT116(p53À/À) cells. The tumor suppressor protein p53 represents a central factor for the maintenance of genome stability and for the suppression of cancer. 1 p53 is present at low levels in unstressed cells, but after exposure to various stress signals, the protein is stabilized and activated by a series of post-translational modifications. p53 is involved in the induction of cell-cycle arrest and apoptosis through transcriptional activation of target genes. 2 p53 displays multicompartmental functions in the cell. Interestingly, in response to multiple death stimuli, mitochondrial p53 targeting occurs in a wide spectrum of cell types, where it elicits a series of responses that can promote an apoptosis through a transcription-independent mechanism. 3,4 Several lines of evidence support a connection between p53 and mitochondrion. Mitochondrial p53 levels are proportional to total p53 levels, and a small fraction of protein is associated with mitochondrial DNA (mtDNA) in the absence of exogenous stress, thus implying a non-apoptotic function for mitochondrial p53. 5 Furthermore, translocation of p53 to mitochondria was observed in various cells (e.g., MCF-7 and HCT116) independent of apoptosis. 6 p53 may be a component of a stress response pathway that involves the upregulation of mitochondrial repair in mouse liver and cancer cells, suggesting the potential role of p53 in maintaining mtDNA stability. 7,8 Mitochondrial DNA, a 16.5-kb circular double-stranded molecule, is replicated by an assembly of enzymes and proteins consisting of DNA polymerase g (pol g), ssDNAbinding protein, DNA helicase and various accessory proteins and transcription factors. 9 Mitochondrial DNA is prone to mutations, as it is localized near the inner mitochondrial membrane in which reactive oxygen species are generated. In addition, mtDNA lacks histone protection and highly efficient DNA repair...

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Section: Discussionmentioning

confidence: 99%

p53 in mitochondria enhances the accuracy of DNA synthesis

et al. 2008

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“…Unwanted interactions of NRTIs with host molecules such as DNA polymerase ␥, the mitochondrial DNA polymerase, can lead to off-target effects (35)(36)(37). Because SAMHD1, the newly identified antiviral host factor, interacts with and hydrolyzes cellular dNTPs, which chemically mimic NRTI-TPs, we tested whether SAMHD1 influences the antiviral efficacy of NRTIs by directly hydrolyzing NRTI-TPs.…”

Section: Discussionmentioning

confidence: 99%

Anti-HIV Host Factor SAMHD1 Regulates Viral Sensitivity to Nucleoside Reverse Transcriptase Inhibitors via Modulation of Cellular Deoxyribonucleoside Triphosphate (dNTP) Levels

Amie

Daly

Noble

et al. 2013

Journal of Biological Chemistry

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Background: SAMHD1 is an enzyme that maintains low dNTP concentrations in macrophages. Results: Depletion of SAMHD1 decreases HIV-1 sensitivity to nucleoside reverse transcriptase inhibitors (NRTIs) in macrophages, but does not significantly alter sensitivity in T cells. Conclusion: SAMHD1 expression levels in macrophages directly impact the efficacy of NRTIs by modulating cellular dNTP concentrations. Significance: SAMHD1 controls HIV-1 sensitivity to NRTIs.

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“…17 The DNC TG here offered an approach to evaluate NRTI toxicity in vivo and linked NRTI toxicity to mitochondrial import and nucleotide homeostasis. 4 For some time, our group [26][27][28] and others [29][30][31][32][33][34][35] have studied mechanisms of mitochondrial toxicity of NRTIs focusing on inhibition of DNA pol g (reviewed in Kaguni 36 ). NRTIs are firmly linked to altered mtDNA replication 10,37,38 through the DNA pol g hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

Lewis

Haase

Miller

et al. 2005

Laboratory Investigation

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Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals for AIDS with limiting mitochondrial side effects. The mitochondrial deoxynucleotide carrier (DNC) transports phosphorylated nucleosides for mitochondrial DNA replication and can transport phosphorylated NRTIs into mitochondria. Transgenic mice (TG) that exclusively overexpress DNC in the heart tested DNC's role in mitochondrial dysfunction from NRTIs. Two TG lines were created that overexpressed the human DNC gene in murine myocardium. Cardiac and mitochondrial structure and function were examined by magnetic resonance imaging, echocardiography, electrocardiography, transmission electron microscopy, and plasma lactate. Antiretroviral combinations (HAART) that contained NRTIs (stavudine (2 0 , 3 0 -didehydro-2 0 , 3 0 -deoxythymidine or d4T)/lamivudine/indinavir; or zidovudine (3 0 azido-3 0 -deoxythymidine or AZT)/lamivudine/indinavir; 35 days) were administered to simulate AIDS therapy. In parallel, a HAART combination without NRTIs (nevirapine/efavirenz/indinavir; 35 days) served as an NRTI-sparing, control regimen. Untreated DNC TGs exhibited normal cardiac function but abnormal mitochondrial ultrastructure. HAART that contained NRTIs caused cardiomyopathy in TGs with increased left ventricle mass and volume, heart rate variability, and worse mitochondrial ultrastructural defects. In contrast, treatment with an NRTI-sparing HAART regimen caused no cardiac changes. Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs. Keywords: deoxynucleotide; NRTI; AIDS; antiretroviral; mitochondrial import; DNC; cardiac; HIV The inner mitochondrial membrane contains transport proteins to move molecules into and out of the matrix. Members of the mitochondrial carrier family of proteins contain three conserved tandemrepeated sequences (B100 residues with two hydrophobic transmembrane a-helices and a hydrophilic segment thought to be an extramembranous loop 1 ). One of these proteins functions as a deoxynucleotide carrier (DNC) to import phosphorylated precursors of mitochondrial (mt-) DNA synthesis and has been characterized. 1-3 Toxicity to mitochondria from antiretroviral nucleoside reverse transcriptase inhibitors (NRTI) is an established side effect of AIDS therapy that limits effective treatment (reviewed in Lewis et al 4 ). Alternative combinations that are NRTI-sparing may be effective if toxicity is a significant clinical problem (reviewed in Joly et al 5 ).Since DNC provides a route for mitochondrial uptake of NRTIs including zidovudine (3 0 azido-3 0 -deoxythymidine or AZT) and stavudine (2 0 , 3 0 -didehydro-2 0 , 3 0 -deoxythymidine or d4T), its role in mitochondrial NRTI import and toxicity was addressed in vivo using transgenic mice (TG) and HAART treatment. One HAART regimen included NRTIs (with either an AZT or D4T 'backbone'). A second NRTI-sparing regimen was administered in parallel as a control.DNC ov...

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Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs

Cited by 129 publications

References 45 publications

p53 in mitochondria enhances the accuracy of DNA synthesis

p53 in mitochondria enhances the accuracy of DNA synthesis

Anti-HIV Host Factor SAMHD1 Regulates Viral Sensitivity to Nucleoside Reverse Transcriptase Inhibitors via Modulation of Cellular Deoxyribonucleoside Triphosphate (dNTP) Levels

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS

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