Congratulations to Martina for her paper that was accepted in Molecular Pharmaceutics (If 4.556) an undergraduate student in the laboratory! The paper is a collaborative work with Dr. Dhar (BMB) and Dr. Nair (FIU).
Velichkovska M, Surnar B, Nair M, Dhar S, Toborek M. Targeted mitochondrial CoQ10 delivery attenuates antiretroviral-drug-induced senescence of neural progenitor cells. Mol Pharm. 2019 Feb 4;16(2):724-736. doi: 10.1021/acs.molpharmaceut.8b01014.
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 two-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 telomeres length shortened to more half of the length of controls as assessed by quantitative telomere-FISH labeling, indicating accelerated NPC senescence in response to ART exposure. Importantly, targeted nanoparticles delivered by CoQ10 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.