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ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV

We have previously demonstrated mitochondrial dysfunction in aging CD4 T cells from antiretroviral therapy (ART)-controlled people living with HIV (PLWH). However, the underlying mechanisms by which CD4 T cells develop mitochondrial dysfunction in PLWH remain unclear. In this study, we sought to elu...

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Autores principales: Schank, Madison, Zhao, Juan, Wang, Ling, Nguyen, Lam Ngoc Thao, Zhang, Yi, Wu, Xiao Y., Zhang, Jinyu, Jiang, Yong, Ning, Shunbin, El Gazzar, Mohamed, Moorman, Jonathan P., Yao, Zhi Q.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10224005/
https://www.ncbi.nlm.nih.gov/pubmed/37243148
http://dx.doi.org/10.3390/v15051061
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author Schank, Madison
Zhao, Juan
Wang, Ling
Nguyen, Lam Ngoc Thao
Zhang, Yi
Wu, Xiao Y.
Zhang, Jinyu
Jiang, Yong
Ning, Shunbin
El Gazzar, Mohamed
Moorman, Jonathan P.
Yao, Zhi Q.
author_facet Schank, Madison
Zhao, Juan
Wang, Ling
Nguyen, Lam Ngoc Thao
Zhang, Yi
Wu, Xiao Y.
Zhang, Jinyu
Jiang, Yong
Ning, Shunbin
El Gazzar, Mohamed
Moorman, Jonathan P.
Yao, Zhi Q.
author_sort Schank, Madison
collection PubMed
description We have previously demonstrated mitochondrial dysfunction in aging CD4 T cells from antiretroviral therapy (ART)-controlled people living with HIV (PLWH). However, the underlying mechanisms by which CD4 T cells develop mitochondrial dysfunction in PLWH remain unclear. In this study, we sought to elucidate the mechanism(s) of CD4 T cell mitochondrial compromise in ART-controlled PLWH. We first assessed the levels of reactive oxygen species (ROS), and we observed significantly increased cellular and mitochondrial ROS levels in CD4 T cells from PLWH compared to healthy subjects (HS). Furthermore, we observed a significant reduction in the levels of proteins responsible for antioxidant defense (superoxide dismutase 1, SOD1) and ROS-mediated DNA damage repair (apurinic/apyrimidinic endonuclease 1, APE1) in CD4 T cells from PLWH. Importantly, CRISPR/Cas9-mediated knockdown of SOD1 or APE1 in CD4 T cells from HS confirmed their roles in maintaining normal mitochondrial respiration via a p53-mediated pathway. Reconstitution of SOD1 or APE1 in CD4 T cells from PLWH successfully rescued mitochondrial function as evidenced by Seahorse analysis. These results indicate that ROS induces mitochondrial dysfunction, leading to premature T cell aging via dysregulation of SOD1 and APE1 during latent HIV infection.
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spelling pubmed-102240052023-05-28 ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV Schank, Madison Zhao, Juan Wang, Ling Nguyen, Lam Ngoc Thao Zhang, Yi Wu, Xiao Y. Zhang, Jinyu Jiang, Yong Ning, Shunbin El Gazzar, Mohamed Moorman, Jonathan P. Yao, Zhi Q. Viruses Article We have previously demonstrated mitochondrial dysfunction in aging CD4 T cells from antiretroviral therapy (ART)-controlled people living with HIV (PLWH). However, the underlying mechanisms by which CD4 T cells develop mitochondrial dysfunction in PLWH remain unclear. In this study, we sought to elucidate the mechanism(s) of CD4 T cell mitochondrial compromise in ART-controlled PLWH. We first assessed the levels of reactive oxygen species (ROS), and we observed significantly increased cellular and mitochondrial ROS levels in CD4 T cells from PLWH compared to healthy subjects (HS). Furthermore, we observed a significant reduction in the levels of proteins responsible for antioxidant defense (superoxide dismutase 1, SOD1) and ROS-mediated DNA damage repair (apurinic/apyrimidinic endonuclease 1, APE1) in CD4 T cells from PLWH. Importantly, CRISPR/Cas9-mediated knockdown of SOD1 or APE1 in CD4 T cells from HS confirmed their roles in maintaining normal mitochondrial respiration via a p53-mediated pathway. Reconstitution of SOD1 or APE1 in CD4 T cells from PLWH successfully rescued mitochondrial function as evidenced by Seahorse analysis. These results indicate that ROS induces mitochondrial dysfunction, leading to premature T cell aging via dysregulation of SOD1 and APE1 during latent HIV infection. MDPI 2023-04-26 /pmc/articles/PMC10224005/ /pubmed/37243148 http://dx.doi.org/10.3390/v15051061 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Schank, Madison
Zhao, Juan
Wang, Ling
Nguyen, Lam Ngoc Thao
Zhang, Yi
Wu, Xiao Y.
Zhang, Jinyu
Jiang, Yong
Ning, Shunbin
El Gazzar, Mohamed
Moorman, Jonathan P.
Yao, Zhi Q.
ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV
title ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV
title_full ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV
title_fullStr ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV
title_full_unstemmed ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV
title_short ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV
title_sort ros-induced mitochondrial dysfunction in cd4 t cells from art-controlled people living with hiv
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10224005/
https://www.ncbi.nlm.nih.gov/pubmed/37243148
http://dx.doi.org/10.3390/v15051061
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