AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress

Koczor, Christopher A.; Jing, Zhe; Fields, Earl; Russ, Rodney; Ludaway, Tomika; Lewis, William

doi:10.1152/physiolgenomics.00045.2015

Cited by 25 publications

(17 citation statements)

References 41 publications

(66 reference statements)

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“…It has been recently found that NRTIs altered nDNA methylation [41], and downregulated PPARγ and mtDNA-encoded genes expression [42]. Moreover, ethidium bromide, a DNA intercalating agent that provokes mtDNA depletion, reduced 3T3-L1 MT-CO1 and PPARγ mRNA levels [4].…”

Section: Resultsmentioning

confidence: 99%

Pharmacologic concentrations of linezolid modify oxidative phosphorylation function and adipocyte secretome

Llobet

Bayona‐Bafaluy

Pacheu-Grau³

et al. 2017

Redox Biology

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The oxidative phosphorylation system is important for adipocyte differentiation. Therefore, xenobiotics inhibitors of the oxidative phosphorylation system could affect adipocyte differentiation and adipokine secretion. As adipokines impact the overall health status, these xenobiotics may have wide effects on human health. Some of these xenobiotics are widely used therapeutic drugs, such as ribosomal antibiotics. Because of its similarity to the bacterial one, mitochondrial translation system is an off-target for these compounds. To study the influence of the ribosomal antibiotic linezolid on adipokine production, we analyzed its effects on adipocyte secretome. Linezolid, at therapeutic concentrations, modifies the levels of apolipoprotein E and several adipokines and proteins related with the extracellular matrix. This antibiotic also alters the global methylation status of human adipose tissue-derived stem cells and, therefore, its effects are not limited to the exposure period. Besides their consequences on other tissues, xenobiotics acting on the adipocyte oxidative phosphorylation system alter apolipoprotein E and adipokine production, secondarily contributing to their systemic effects.

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Section: Resultsmentioning

confidence: 99%

Pharmacologic concentrations of linezolid modify oxidative phosphorylation function and adipocyte secretome

Llobet

Bayona‐Bafaluy

Pacheu-Grau³

et al. 2017

Redox Biology

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“…Thus, it is conceivable to expect that the potential cumulative side effects of NRTIs may lead to long-term tissue damage in the population aging with HIV/AIDS (13)(14)(15). In that regard, long-term therapy with zidovudine has been associated with a toxic mitochondrial myopathy (16) and myocyte mitochondrial dysfunction with increased ROS production, confirmed by both in vitro and in vivo studies (2,3,10,11,17,18).…”

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confidence: 89%

Zidovudine-Mediated Autophagy Inhibition Enhances Mitochondrial Toxicity in Muscle Cells

Lin

Stankov

Hegermann

et al. 2019

Antimicrob Agents Chemother

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Nucleoside reverse transcriptase inhibitors (NRTI), such as zidovudine (AZT), are constituents of HIV-1 therapy and are used for the prevention of mother-to-child transmission. Prolonged thymidine analogue exposure has been associated with mitochondrial toxicities to heart, liver, and skeletal muscle. We hypothesized that the thymidine analogue AZT might interfere with autophagy in myocytes, a lysosomal degradation pathway implicated in the regulation of mitochondrial recycling, cell survival, and the pathogenesis of myodegenerative diseases. The impact of AZT and lamivudine (3TC) on C2C12 myocyte autophagy was studied using various methods based on LC3-green fluorescent protein overexpression or LC3 staining in combination with Western blotting, flow cytometry, and confocal and electron microscopy. Lysosomal and mitochondrial functions were studied using appropriate staining for lysosomal mass, acidity, cathepsin activity, as well as mitochondrial mass and membrane potential in combination with flow cytometry and confocal microscopy. AZT, but not 3TC, exerted a significant dose- and time-dependent inhibitory effect on late stages of autophagosome maturation, which was reversible upon mTOR inhibition. Inhibition of late autophagy at therapeutic drug concentrations led to dysfunctional mitochondrial accumulation with membrane hyperpolarization and increased reactive oxygen species (ROS) generation and, ultimately, compromised cell viability. These AZT effects could be readily replicated by pharmacological and genetic inhibition of myocyte autophagy and, most importantly, could be rescued by pharmacological stimulation of autophagolysosomal biogenesis. Our data suggest that the thymidine analogue AZT inhibits autophagy in myocytes, which in turn leads to the accumulation of dysfunctional mitochondria with increased ROS generation and compromised cell viability. This novel mechanism could contribute to our understanding of the long-term side effects of antiviral agents.

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“…Mitochondria promote the abundance of SAM in both embryonic and post-natal growth conditions [100]. In heart, oxidative stress increases SAM abundance and promotes DNA methylation associated with pathological remodeling [101]. …”

Section: Dna Methylationmentioning

confidence: 99%

Epigenetic regulation in heart failure

Kim

Morales

Gillette

et al. 2016

Current Opinion in Cardiology

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Purpose of review To provide an overview, highlighting recent findings, of a major mechanism of gene regulation and its relevance to the pathophysiology of heart failure. Recent findings The syndrome of heart failure is a complex and highly prevalent condition, one in which the heart undergoes substantial structural remodeling. Triggered by a wide range of disease-related cues, heart failure pathophysiology is governed by both genetic and epigenetic events. Epigenetic mechanisms, such as chromatin/DNA modifications and non-coding RNAs, have emerged as molecular transducers of environmental stimuli to control gene expression. Here, we emphasize metabolic milieu, aging, and hemodynamic stress as they impact the epigenetic landscape of the myocardium. Summary Recent studies in multiple fields, including cancer, stem cells, development, and cardiovascular biology, have uncovered biochemical ties linking epigenetic machinery and cellular energetics and mitochondrial function. Elucidation of these connections will afford molecular insights into long-established epidemiological observations. With time, exploitation of the epigenetic machinery therapeutically may emerge with clinical relevance.

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AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress

Cited by 25 publications

References 41 publications

Pharmacologic concentrations of linezolid modify oxidative phosphorylation function and adipocyte secretome

Pharmacologic concentrations of linezolid modify oxidative phosphorylation function and adipocyte secretome

Zidovudine-Mediated Autophagy Inhibition Enhances Mitochondrial Toxicity in Muscle Cells

Epigenetic regulation in heart failure

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