Oxidative Stress Induces Mitochondrial Compromise in CD4 T Cells From Chronically HCV-Infected Individuals
Abstract
We have previously shown that chronic Hepatitis C virus (HCV) infection can induce DNA damage and immune dysfunctions with excessive oxidative stress in T cells. Furthermore, evidence suggests that HCV contributes to increased susceptibility to metabolic disorders. However, the underlying mechanisms by which HCV infection impairs cellular metabolism in CD4 T cells remain unclear. In this study, we evaluated mitochondrial mass and intracellular and mitochondrial reactive oxygen species (ROS) production by flow cytometry, mitochondrial DNA (mtDNA) content by real-time qPCR, cellular respiration by seahorse analyzer, and dysregulated mitochondrial-localized proteins by Liquid Chromatography-Mass Spectrometry (LC-MS) in CD4 T cells from chronic HCV-infected individuals and health subjects. Mitochondrial mass was decreased while intracellular and mitochondrial ROS were increased, expressions of master mitochondrial regulators peroxisome proliferator-activated receptor 1 alpha (PGC-1α) and mitochondrial transcription factor A (mtTFA) were down-regulated, and oxidative stress was increased while mitochondrial DNA copy numbers were reduced. Importantly, CRISPR/Cas9-mediated knockdown of mtTFA impaired cellular respiration and reduced mtDNA copy number. Furthermore, proteins responsible for mediating oxidative stress, apoptosis, and mtDNA maintenance were significantly altered in HCV-CD4 T cells. These results indicate that mitochondrial functions are compromised in HCV-CD4 T cells, likely via the deregulation of several mitochondrial regulatory proteins.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 08, 2021
- Source ID
- 10.3389/fimmu.2021.760707
Entities
People
- Dechao Cao
- Jinyu Zhang
- Jonathan P. Moorman
- Juan Zhao
- Lam Ngoc Thao Nguyen
- Ling Wang
- Madison Schank
- Mohamed El Gazzar
- Shunbin Ning
- Sushant Khanal
- Xiao Y. Wu
- Xindi Dang
- Yi Zhang
- Zhi Q Yao
Organizations
- American Diabetes Association
- National Institutes of Health
- United States Department of Defense
- United States Department of Veterans Affairs