Methamphetamine causes mitrochondrial oxidative damage in human T lymphocytes leading to functional impairment.
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.
Potula
Raghava
R
Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. Raghava.Potula@tuhs.temple.edu
Hawkins
Brian J
BJ
Cenna
Jonathan M
JM
Fan
Shongshan
S
Dykstra
Holly
H
Ramirez
Servio H
SH
Morsey
Brenda
B
Brodie
Michael R
MR
Persidsky
Yuri
Y
D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000633:toxicity; D003600:Cytosol / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004734:Energy Metabolism / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000276:immunology; D008694:Methamphetamine / Q000633:toxicity*; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects* / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000697:Central Nervous System Stimulants; D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D008694:Methamphetamine; D002118:Calcium