TY - JOUR
T1 - Extracellular vesicles secreted in response to cytokine exposure increase mitochondrial oxygen consumption in recipient cells
AU - Russell, Ashley E.
AU - Jun, Sujung
AU - Sarkar, Saumyendra
AU - Geldenhuys, Werner J.
AU - Lewis, Sara E.
AU - Rellick, Stephanie L.
AU - Simpkins, James W.
N1 - Funding Information:
This work was supported by NIH Grants P20 GM109098, P01 AG027956, T32 AG052375 and U54 GM104942. Imaging experiments and image analysis were performed in the West Virginia University Imaging Facilities which have been supported by the WVU Cancer Institute and NIH grants P20RR016440 and P30RR032138/P30GM103488. Experiments were also performed in the West Virginia University Flow Cytometry and Single Cell Core Facility, which is supported by the following National Institutes of Health and the Institutional Development Awards (IDeA) grants U57GM104942 (WV CTSI), P30GM103488 (CoBRE), P20GM109098 (Stroke CoBRE) and P20GM103434 (INBRE).
Publisher Copyright:
© 2019 Russell, Jun, Sarkar, Geldenhuys, Lewis, Rellick and Simpkins.
PY - 2019/1/29
Y1 - 2019/1/29
N2 - Extracellular vesicles (EVs) are small, membrane-bound nanoparticles released from most, if not all cells, and can carry functionally active cargo (proteins, nucleic acids) which can be taken up by neighboring cells and mediate physiologically relevant effects. In this capacity, EVs are being regarded as novel cell-to-cell communicators, which may play important roles in the progression of neurodegenerative diseases, like Alzheimer’s disease (AD). Aside from the canonical physical hallmarks of this disease [amyloid β (Aβ) plaques, neurofibrillary tangles, and widespread cell death], AD is characterized by chronic neuroinflammation and mitochondrial dysfunction. In the current study, we sought to better understand the role of tumor necrosis factor-alpha (TNF-α), known to be involved in inflammation, in mediating alterations in mitochondrial function and EV secretion. Using an immortalized hippocampal cell line, we observed significant reductions in several parameters of mitochondrial oxygen consumption after a 24-h exposure period to TNF-α. In addition, after TNF-α exposure we also observed significant upregulation of two microRNAs (miRNAs; miR-34a and miR-146a) associated with mitochondrial dysfunction in secreted EVs. Despite this, when naïve cells are exposed to EVs isolated from TNF-α treated cells, mitochondrial respiration, proton leak, and reactive oxygen species (ROS) production are all significantly increased. Collectively these data indicate that a potent proinflammatory cytokine, TNF-α, induces significant mitochondrial dysfunction in a neuronal cell type, in part via the secretion of EVs, which significantly alter mitochondrial activity in recipient cells.
AB - Extracellular vesicles (EVs) are small, membrane-bound nanoparticles released from most, if not all cells, and can carry functionally active cargo (proteins, nucleic acids) which can be taken up by neighboring cells and mediate physiologically relevant effects. In this capacity, EVs are being regarded as novel cell-to-cell communicators, which may play important roles in the progression of neurodegenerative diseases, like Alzheimer’s disease (AD). Aside from the canonical physical hallmarks of this disease [amyloid β (Aβ) plaques, neurofibrillary tangles, and widespread cell death], AD is characterized by chronic neuroinflammation and mitochondrial dysfunction. In the current study, we sought to better understand the role of tumor necrosis factor-alpha (TNF-α), known to be involved in inflammation, in mediating alterations in mitochondrial function and EV secretion. Using an immortalized hippocampal cell line, we observed significant reductions in several parameters of mitochondrial oxygen consumption after a 24-h exposure period to TNF-α. In addition, after TNF-α exposure we also observed significant upregulation of two microRNAs (miRNAs; miR-34a and miR-146a) associated with mitochondrial dysfunction in secreted EVs. Despite this, when naïve cells are exposed to EVs isolated from TNF-α treated cells, mitochondrial respiration, proton leak, and reactive oxygen species (ROS) production are all significantly increased. Collectively these data indicate that a potent proinflammatory cytokine, TNF-α, induces significant mitochondrial dysfunction in a neuronal cell type, in part via the secretion of EVs, which significantly alter mitochondrial activity in recipient cells.
KW - Extracellular vesicles
KW - MicroRNAs
KW - Mitochondria
KW - Neuroinflammation
KW - TNF-α
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U2 - 10.3389/fncel.2019.00051
DO - 10.3389/fncel.2019.00051
M3 - Article
C2 - 30837842
AN - SCOPUS:85064197932
SN - 1662-5102
VL - 13
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
M1 - 51
ER -