Targeted Mitochondrial COQ 10 Delivery Attenuates Antiretroviral-Drug-Induced Senescence of Neural Progenitor Cells

Martina Velichkovska, Bapurao Surnar, Madhavan Nair, Shanta Dhar, Michal Toborek

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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 Q 10 (CoQ 10 ) 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, CoQ 10 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 CoQ 10 .

Original languageEnglish (US)
Pages (from-to)724-736
Number of pages13
JournalMolecular Pharmaceutics
Volume16
Issue number2
DOIs
StatePublished - Feb 4 2019

Keywords

  • CoQ
  • HIV
  • aging
  • antiretroviral therapy
  • mitochondria
  • oxidative stress
  • progenitor cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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