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Published on: May 5, 2022
Methamphetamine causes mitrochondrial oxidative damage in human T lymphocytes leading to functional impairment
Raghava Potula1, Brian J Hawkins, Jonathan M Cenna
1Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. Raghava.Potula@tuhs.temple.edu
Abstract:
Methamphetamine (METH) abuse is known to be associated with an inordinate rate of infections. Although many studies have described the association of METH exposure and immunosuppression, so far the underlying mechanism still remains elusive. In this study, we present evidence that METH exposure resulted in mitochondrial oxidative damage and caused dysfunction of primary human T cells. METH treatment of T lymphocytes led to a rise in intracellular calcium levels that enhanced the generation of reactive oxygen species. TCR-CD28 linked calcium mobilization and subsequent uptake by mitochondria in METH-treated T cells correlated with an increase in mitochondrion-derived superoxide. Exposure to METH-induced mitochondrial dysfunction in the form of marked decrease in mitochondrial membrane potential, increased mitochondrial mass, enhanced protein nitrosylation and diminished protein levels of complexes I, III, and IV of the electron transport chain. These changes paralleled reduced IL-2 secretion and T cell proliferative responses after TCR-CD28 stimulation indicating impaired T cell function. Furthermore, antioxidants attenuated METH-induced mitochondrial damage by preserving the protein levels of mitochondrial complexes I, III, and IV. Altogether, our data indicate that METH can cause T cell dysfunction via induction of oxidative stress and mitochondrial injury as underlying mechanism of immune impairment secondary to METH abuse.
Insights
Methamphetamine (METH) abuse impairs T cell function by causing mitochondrial oxidative damage. This study reveals METH-induced mitochondrial injury as a key mechanism behind immune suppression in METH users.
Area of Science:
- Immunology
- Toxicology
- Cell Biology
Background:
- Methamphetamine (METH) abuse is linked to increased infections, suggesting immune system impairment.
- The precise mechanisms underlying METH-induced immunosuppression remain unclear.
- Previous research indicates a potential association between METH exposure and compromised immune responses.
Purpose of the Study:
- To investigate the effects of METH on primary human T cells.
- To elucidate the role of mitochondrial dysfunction and oxidative stress in METH-induced T cell impairment.
- To identify potential therapeutic targets for mitigating METH's immunotoxic effects.
Main Methods:
- T lymphocytes were treated with METH in vitro.
- Intracellular calcium levels, reactive oxygen species (ROS) generation, and mitochondrial superoxide production were measured.
- Mitochondrial function markers, including membrane potential and electron transport chain complex levels, were assessed.
- T cell proliferation and IL-2 secretion following TCR-CD28 stimulation were evaluated.
- The impact of antioxidants on METH-induced mitochondrial damage was examined.
Main Results:
- METH treatment increased intracellular calcium and ROS production in T cells.
- METH exposure led to increased mitochondrial superoxide, decreased mitochondrial membrane potential, and elevated mitochondrial mass.
- Protein levels of electron transport chain complexes I, III, and IV were diminished in METH-treated cells.
- Antioxidants protected against METH-induced mitochondrial damage and preserved electron transport chain complex levels.
- METH exposure resulted in reduced IL-2 secretion and impaired T cell proliferation.
Conclusions:
- METH exposure induces oxidative stress and mitochondrial injury in human T cells.
- Mitochondrial dysfunction is a significant mechanism underlying METH-induced T cell impairment and immune suppression.
- Targeting oxidative stress and mitochondrial damage may offer therapeutic strategies for METH abuse-related immune dysfunction.
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