Targeted Mitochondrial COQ10 Delivery Attenuates Antiretroviral-Drug-Induced Senescence of Neural Progenitor Cells.,Molecular Pharmaceutics

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Targeted Mitochondrial COQ10 Delivery Attenuates Antiretroviral-Drug-Induced Senescence of Neural Progenitor Cells.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-01-11 , DOI: 10.1021/acs.molpharmaceut.8b01014
Martina Velichkovska , Bapurao Surnar , Madhavan Nair ₁ , Shanta Dhar , Michal Toborek

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HIV infection is associated with symptoms of accelerated or accentuated aging that are likely to be driven not only by HIV itself but also by the toxicity of long-term use of antiretroviral drugs. Therefore, it is crucially important to understand the mechanisms by which antiretroviral drugs may contribute to aging. The aim of this study was to investigate the hypothesis that antiretroviral drugs cause increased reactive oxygen species (ROS) generation that results in mitochondrial dysfunction and culminates in promoting cellular senescence. In addition, we applied targeted nanoparticle (NP)-based delivery to specifically enrich mitochondria with coenzyme Q10 (CoQ10) in order to enhance antioxidant protection. The studies employed neural progenitor cells (NPCs), as differentiation of these cells into mature neurons is affected both during HIV infection and in the aging process. Exposure of cultured NPCs to various combinations of HIV antiretroviral therapy (ART) induced a more than 2-fold increase in mitochondrial ROS generation and mitochondrial membrane potential, a more than 50% decrease in oxygen consumption and ATP levels, a 60% decrease in SIRT3 expression, and a 42% decrease in cell proliferation relative to control levels. These alterations were accompanied by a 37% increase in beta-galactosidase staining and a shortening of the telomere length to more than half of the length of controls as assessed by quantitative telomere-FISH labeling, indicating accelerated NPC senescence in response to ART exposure. Importantly, CoQ10 delivered by targeted nanoparticles effectively attenuated these effects. Overall, these results indicate that ART promotes cellular senescence by causing mitochondrial dysfunction, which can be successfully reversed by supplementation with mitochondria-targeted CoQ10.

中文翻译：

靶向线粒体 COQ10 递送减弱了抗逆转录病毒药物诱导的神经祖细胞衰老。

HIV 感染与加速或加重衰老的症状有关，这些症状可能不仅由 HIV 本身驱动，而且由长期使用抗逆转录病毒药物的毒性驱动。因此，了解抗逆转录病毒药物可能导致衰老的机制至关重要。本研究的目的是调查抗逆转录病毒药物导致活性氧 (ROS) 生成增加，从而导致线粒体功能障碍并最终促进细胞衰老的假设。此外，我们应用基于靶向纳米颗粒 (NP) 的递送来特异性地用辅酶 Q10 (CoQ10) 丰富线粒体，以增强抗氧化保护。这些研究使用了神经祖细胞 (NPC)，因为这些细胞向成熟神经元的分化在 HIV 感染和衰老过程中都会受到影响。培养的 NPC 暴露于 HIV 抗逆转录病毒疗法 (ART) 的各种组合导致线粒体 ROS 生成和线粒体膜电位增加 2 倍以上，耗氧量和 ATP 水平降低 50% 以上，SIRT3 降低 60%表达，并且细胞增殖相对于对照水平降低了 42%。这些改变伴随着 37% 的 β-半乳糖苷酶染色增加和端粒长度缩短至超过通过定量端粒-FISH 标记评估的对照长度的一半，表明 NPC 加速衰老以响应 ART 暴露。重要的是，靶向纳米颗粒递送的辅酶 Q10 有效地减弱了这些影响。

更新日期：2018-12-28

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