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Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors

Kees Brinkman, MD, PhD
Section Editor
John G Bartlett, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Since the introduction of potent antiretroviral therapy (ART), the life expectancy of HIV-infected patients has improved enormously. However, the chronic administration of antiretroviral medications has led to the recognition of long-term complications of these therapies [1,2]. Mitochondrial toxicity is recognized as a major adverse effect of nucleoside analogue treatment and can lead to myopathy, peripheral neuropathy, and hepatic steatosis with lactic acidosis, which can be life-threatening.

The induction of mitochondrial dysfunction by nucleoside reverse transcriptase inhibitors (NRTIs) will be discussed here. The use of NRTIs for the treatment of HIV infection is discussed separately. (See "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient".)


The main function of mitochondria is oxidative phosphorylation in which fatty acids and pyruvate are used as substrates to produce energy in the form of adenosine triphosphate (ATP). Normally there is tight coupling between oxidation and phosphorylation (OXPHOS) that is governed by normal mitochondrial enzymes, such as the cytochrome oxidases and other enzymes of the respiratory chain system. OXPHOS is also responsible for neutralization of free radicals and beta-oxidation of free fatty acids.

Mitochondria also play an important role in the generation of reactive oxygen species (ROS), which are produced physiologically during oxidative phosphorylation. Oxidative stress can occur if there is an imbalance between the production of ROS and cellular antioxidant defenses [3]. Mitochondrial DNA polymerase is a target of oxidative damage [4].


Nucleoside analogues are effective in inhibiting HIV replication due to their high affinity for the viral enzyme reverse transcriptase (a viral DNA polymerase) [5-7]. However, NRTIs can also bind to other human DNA-polymerases, like DNA polymerase beta (necessary for repair of nuclear DNA) and mitochondrial DNA polymerase gamma, which is exclusively responsible for the replication of mitochondrial DNA (mtDNA).

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Literature review current through: Dec 2017. | This topic last updated: Aug 16, 2017.
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