Antiretroviral Therapy–Induced Mitochondrial Toxicity: Potential Mechanisms Beyond Polymerase-γ Inhibition

Selvaraj, Shanmugapriya; Ghebremichael, Musie; Li, Min; Foli, Yram; Langs-Barlow, Allison; Ogbuagu, Arit; Barakat, Lydia; Tubridy, Elizabeth; Edifor, Regina; Lam, Wing; Cheng, Yung‐Chi; Paintsil, Elijah

doi:10.1038/clpt.2014.64

Cited by 42 publications

(40 citation statements)

References 48 publications

(51 reference statements)

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“…Therefore, deficiencies in TK2 or dGK activity are likely responsible for the observed mtDNA depletion in these HIV patients, independent of mtDNA polymerase inhibition (Fig. 7), in line with a recent report showing that antiviral therapy caused depletion of both ribonucleotide and deoxynucleotide pools in HIV patients (12).…”

Section: Discussionsupporting

confidence: 89%

“…The mechanism underlying the mitochondrial toxic effects of these types of nucleoside analogs has been postulated to occur via the inhibition of mitochondrial DNA (mtDNA) polymerase by the triphosphates of these analogs. However, recent studies using peripheral blood mononuclear cells from HIV-infected individuals treated with antiviral agents showed that depletion of both ribonucleotide and deoxynucleotide pools may be responsible for the observed mitochondrial toxicity independent of mtDNA polymerase inhibition (12). Other studies suggest that inhibition of mitochondrial TK2 and dGK may be a major contributing factor in nucleoside analog-induced mitochondrial toxicity, and the symptoms of AIDS patients treated with AZT or ddI resemble those reported for MDS patients (5,6,10,11).…”

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confidence: 99%

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Zidovudine Induces Downregulation of Mitochondrial Deoxynucleoside Kinases: Implications for Mitochondrial Toxicity of Antiviral Nucleoside Analogs

Sun

Eriksson

Wang

2014

Antimicrob Agents Chemother

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Mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) catalyze the initial phosphorylation of deoxynucleosides in the synthesis of the DNA precursors required for mitochondrial DNA (mtDNA) replication and are essential for mitochondrial function. Antiviral nucleosides are known to cause toxic mitochondrial side effects. Here, we examined the effects of 3=-azido-2=,3=-dideoxythymidine (AZT) (zidovudine) on mitochondrial TK2 and dGK levels and found that AZT treatment led to downregulation of mitochondrial TK2 and dGK in U2OS cells, whereas cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) levels were not affected. The AZT effects on mitochondrial TK2 and dGK were similar to those of oxidants (e.g., hydrogen peroxide); therefore, we examined the oxidative effects of AZT. We found a modest increase in cellular reactive oxygen species (ROS) levels in the AZT-treated cells. The addition of uridine to AZT-treated cells reduced ROS levels and protein oxidation and prevented the degradation of mitochondrial TK2 and dGK. In organello studies indicated that the degradation of mitochondrial TK2 and dGK is a mitochondrial event. These results suggest that downregulation of mitochondrial TK2 and dGK may lead to decreased mitochondrial DNA precursor pools and eventually mtDNA depletion, which has significant implications for the regulation of mitochondrial nucleotide biosynthesis and for antiviral therapy using nucleoside analogs. N ucleoside analogs are widely used as antiviral and anticancer agents, and today Ͼ50% of the FDA-approved antiviral and anticancer drugs are nucleoside or nucleobase analogs. These analogs are administered as prodrugs that need to be activated by cellular enzymes to exert their therapeutic potential. Deoxynucleoside kinases catalyze the initial phosphorylation of nucleoside analogs; once phosphorylated, these nucleotides are trapped inside the cell and are further metabolized to their active forms, which interact with the final targets. There are four deoxynucleoside kinases in mammalian cells, i.e., cytosolic thymidine kinase 1 (TK1) and deoxycytidine kinase (dCK) and mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) (1, 2). Recent studies using TK1-and dCK-knockout mouse models indicate that cytosolic TK1 and dCK regulate hematopoiesis by linking salvage deoxynucleotide synthesis and replication stress (3, 4). The mitochondrial enzymes TK2 and dGK are vital for mitochondrial function, because deficiency in either causes severe mitochondrial DNA (mtDNA) depletion syndrome (MDS) in human patients and in TK2-knockout mouse models (5-8). TK2 has also been shown to play an important role in providing dTTP for nuclear DNA repair and thus genomic stability in quiescent cells (9).The nucleoside analogs used in antiviral and anticancer therapy are often associated with mitochondrial toxicity. Mitochondrial myopathy, cardiomyopathy, and lipodystrophy associated with anti-HIV treatment using zidovudine (AZT) or 2=,3=-dideoxyinosine (ddI) (didanosine) wer...

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Zidovudine Induces Downregulation of Mitochondrial Deoxynucleoside Kinases: Implications for Mitochondrial Toxicity of Antiviral Nucleoside Analogs

Sun

Eriksson

Wang

2014

Antimicrob Agents Chemother

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“…During the last decades, many studies have focused on the atherogenic effect of ART, especially PI-containing drugs [74]. ART could result in mitochondrial abnormalities by inhibiting the mitochondrial DNA polymerase, which would lead to respiratory chain dysfunction and reduction of cell energy [75]. Mitochondrial respiratory chain inhibition resulted in adipocyte abnormality, which is related to lipodystrophy syndrome and hyperlipemia [76].…”

Section: Discussionmentioning

confidence: 99%

Is the atherosclerotic process accentuated under conditions of HIV infection, antiretroviral therapy, and protease inhibitor exposure? Meta-analysis of the markers of arterial structure and function

Sun

Yuan

et al. 2015

Atherosclerosis

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“…Mitochondria have been closely linked to HIV infection, as a target of the deleterious effects of both HIV 2 and antiretroviral therapy (ART) 3 in relation to their involvement in the development of apoptosis. Mitochondrial and apoptotic alterations have been widely described in both naïve and treated patients in vivo 4, 5.…”

Section: Introductionmentioning

confidence: 99%

HIV‐1 promonocytic and lymphoid cell lines: an in vitro model of in vivo mitochondrial and apoptotic lesion

Morén

González‐Casacuberta

Álvarez-Fernández

et al. 2016

J Cellular Molecular Medi

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To characterize mitochondrial/apoptotic parameters in chronically human immunodeficiency virus (HIV‐1)‐infected promonocytic and lymphoid cells which could be further used as therapeutic targets to test pro‐mitochondrial or anti‐apoptotic strategies as in vitro cell platforms to deal with HIV‐infection. Mitochondrial/apoptotic parameters of U1 promonocytic and ACH2 lymphoid cell lines were compared to those of their uninfected U937 and CEM counterparts. Mitochondrial DNA (mtDNA) was quantified by rt‐PCR while mitochondrial complex IV (CIV) function was measured by spectrophotometry. Mitochondrial‐nuclear encoded subunits II–IV of cytochrome‐c‐oxidase (COXII‐COXIV), respectively, as well as mitochondrial apoptotic events [voltage‐dependent‐anion‐channel‐1(VDAC‐1)‐content and caspase‐9 levels] were quantified by western blot, with mitochondrial mass being assessed by spectrophotometry (citrate synthase) and flow cytometry (mitotracker green assay). Mitochondrial membrane potential (JC1‐assay) and advanced apoptotic/necrotic events (AnexinV/propidium iodide) were measured by flow cytometry. Significant mtDNA depletion spanning 57.67% (P < 0.01) was found in the U1 promonocytic cells further reflected by a significant 77.43% decrease of mitochondrial CIV activity (P < 0.01). These changes were not significant for the ACH2 lymphoid cell line. COXII and COXIV subunits as well as VDAC‐1 and caspase‐9 content were sharply decreased in both chronic HIV‐1‐infected promonocytic and lymphoid cell lines (<0.005 in most cases). In addition, U1 and ACH2 cells showed a trend (moderate in case of ACH2), albeit not significant, to lower levels of depolarized mitochondrial membranes. The present in vitro lymphoid and especially promonocytic HIV model show marked mitochondrial lesion but apoptotic resistance phenotype that has been only partially demonstrated in patients. This model may provide a platform for the characterization of HIV‐chronicity, to test novel therapeutic options or to study HIV reservoirs.

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Antiretroviral Therapy–Induced Mitochondrial Toxicity: Potential Mechanisms Beyond Polymerase-γ Inhibition

Cited by 42 publications

References 48 publications

Zidovudine Induces Downregulation of Mitochondrial Deoxynucleoside Kinases: Implications for Mitochondrial Toxicity of Antiviral Nucleoside Analogs

Zidovudine Induces Downregulation of Mitochondrial Deoxynucleoside Kinases: Implications for Mitochondrial Toxicity of Antiviral Nucleoside Analogs

Is the atherosclerotic process accentuated under conditions of HIV infection, antiretroviral therapy, and protease inhibitor exposure? Meta-analysis of the markers of arterial structure and function

HIV‐1 promonocytic and lymphoid cell lines: an in vitro model of in vivo mitochondrial and apoptotic lesion

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