Beyond the polymerase-γ theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity

Use of some HIV-1 nucleoside reverse transcriptase inhibitors (NRTI) is associated with severe adverse events. However, the exact mechanisms behind their toxicity has not been fully understood. Mitochondrial dysfunction after chronic exposure to specific NRTIs has predominantly been assigned to mitochondrial polymerase-γ inhibition by NRTIs. However, an increasing amount of data suggests that this is not the sole mechanism. Many NRTI induced adverse events have been linked to the incurrence of oxidative stress, although the causality of events leading to reactive oxygen species (ROS) production and their role in toxicity is unclear. In this study we show that short-term effects of first generation NRTIs, which are rarely discussed in the literature, include inhibition of oxygen consumption, decreased ATP levels and increased ROS production. Collectively these events affect fitness and longevity of C. elegans through mitohormetic signalling events. Furthermore, we demonstrate that these effects can be normalized by addition of the anti-oxidant N-acetylcysteine (NAC), which suggests that ROS likely influence the onset and severity of adverse events upon drug exposure.

部分人类免疫缺陷病毒1型（HIV-1）核苷类逆转录酶抑制剂（NRTI）的临床使用与严重不良反应事件密切相关。然而，该类药物毒性的确切分子机制尚未完全阐明。既往研究多认为，长期暴露于特定NRTI后引发的线粒体功能障碍，主要由NRTI对线粒体聚合酶γ（mitochondrial polymerase-γ）的抑制作用介导。但越来越多的实验数据表明，这并非其毒性作用的唯一机制。诸多NRTI诱导的不良反应事件与氧化应激的发生存在关联，尽管活性氧（ROS）生成相关的上游因果事件及其在毒性发生中的具体作用仍不明确。本研究证实，文献中鲜有探讨的第一代NRTI的短期效应包括：氧消耗抑制、ATP水平下降以及活性氧生成增加。上述事件通过线粒体兴奋信号通路共同影响秀丽隐杆线虫（C. elegans）的生存适应性与寿命。此外，本研究还证明，通过添加抗氧化剂N-乙酰半胱氨酸（NAC）可使上述效应得到逆转，这提示活性氧很可能会影响药物暴露后不良反应的发生时机与严重程度。