Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation
Kazuhito Gotoh,
Takafumi Morisaki,
Daiki Setoyama,
Katsuhiko Sasaki,
Mikako Yagi,
Ko Igami,
Soichi Mizuguchi,
Takeshi Uchiumi,
Yoshinori Fukui,
Dongchon Kang
Affiliations
Kazuhito Gotoh
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Corresponding author
Takafumi Morisaki
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Daiki Setoyama
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Katsuhiko Sasaki
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Kyushu Pro Search Limited Liability Partnership, Fukuoka 819-0388, Japan
Mikako Yagi
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Ko Igami
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Kyushu Pro Search Limited Liability Partnership, Fukuoka 819-0388, Japan; Business Management Division, Clinical Laboratory Business Segment, LSI Medience Corporation, Tokyo, 101-8517, Japan
Soichi Mizuguchi
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Takeshi Uchiumi
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Yoshinori Fukui
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
Dongchon Kang
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Corresponding author
Summary: Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that p32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in p32-deficient DCs. We also found that p32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via p32-dependent PDH activity. p32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that p32 may serve as a therapeutic target for DC-related autoimmune diseases. : Although mitochondrial metabolic pathways are essential for DC activation, the precise molecular mechanism remains poorly understood. Gotoh et al. show that mitochondrial p32/C1qbp supports dendritic cell metabolism and maturation. In addition, mitochondrial p32 and pyruvate dehydrogenase activity are necessary for DC maturation in vitro and in vivo. Keywords: dendritic cell, mitochondria, p32/C1qbp, citrate, pyruvate dehydrogenase
