TY - JOUR
T1 - Targeted Mitochondrial COQ 10 Delivery Attenuates Antiretroviral-Drug-Induced Senescence of Neural Progenitor Cells
AU - Velichkovska, Martina
AU - Surnar, Bapurao
AU - Nair, Madhavan
AU - Dhar, Shanta
AU - Toborek, Michal
N1 - Funding Information:
Supported in part by the National Institutes of Health (NIH), grants HL126559, DA039576, MH098891, MH072567, DA040537, and DA044579. M.V. would like to thank Drs. Diana Avila, Luc Bertrand, and Marta Skowronska for technical support and Dr. Richard Myers for encouragement and academic support.
PY - 2019/2/4
Y1 - 2019/2/4
N2 - 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 .
AB - 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 .
KW - CoQ
KW - HIV
KW - aging
KW - antiretroviral therapy
KW - mitochondria
KW - oxidative stress
KW - progenitor cells
UR - http://www.scopus.com/inward/record.url?scp=85061013168&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061013168&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.8b01014
DO - 10.1021/acs.molpharmaceut.8b01014
M3 - Article
C2 - 30592424
AN - SCOPUS:85061013168
VL - 16
SP - 724
EP - 736
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 2
ER -