Open AccessMCU-knockdown attenuates high glucose-induced inflammation through regulating MAPKs/NF-κB pathways and ROS production in HepG2 cells
Author(s) -
Ghodratollah Panahi,
Parvin Pasalar,
Mina Zare,
Gaudenzio Meneghesso,
Reza Meshkani
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0196580
Subject(s) - mitochondrial ros , mitochondrion , microbiology and biotechnology , reactive oxygen species , oxidative stress , gene knockdown , biology , calcium , glucose uptake , inflammation , phosphorylation , protein kinase b , proinflammatory cytokine , chemistry , insulin , biochemistry , apoptosis , endocrinology , immunology , organic chemistry
Mitochondrial Ca 2+ is a key regulator of organelle physiology and the excessive increase in mitochondrial calcium is associated with the oxidative stress. In the present study, we investigated the molecular mechanisms linking mitochondrial calcium to inflammatory and coagulative responses in hepatocytes exposed to high glucose (HG) (33mM glucose). Treatment of HepG2 cells with HG for 24 h induced insulin resistance, as demonstrated by an impairment of insulin-stimulated Akt phosphorylation. HepG2 treatment with HG led to an increase in mitochondrial Ca 2+ uptake, while cytosolic calcium remained unchanged. Inhibition of MCU by lentiviral-mediated shRNA prevented mitochondrial calcium uptake and downregulated the inflammatory (TNF-α, IL-6) and coagulative (PAI-1 and FGA) mRNA expression in HepG2 cells exposed to HG. The protection from HG-induced inflammation by MCU inhibition was accompanied by a decrease in the generation of reactive oxygen species (ROS). Importantly, MCU inhibition in HepG2 cells abrogated the phosphorylation of p38, JNK and IKKα/IKKβ in HG treated cells. Taken together, these data suggest that MCU inhibition may represent a promising therapy for prevention of deleterious effects of obesity and metabolic diseases.