PMID- 26856873
OWN - NLM
STAT- MEDLINE
DCOM- 20170420
LR  - 20211204
IS  - 1674-8018 (Electronic)
IS  - 1674-800X (Print)
IS  - 1674-800X (Linking)
VI  - 7
IP  - 6
DP  - 2016 Jun
TI  - Homocysteine activates T cells by enhancing endoplasmic reticulum-mitochondria 
      coupling and increasing mitochondrial respiration.
PG  - 391-402
LID - 10.1007/s13238-016-0245-x [doi]
AB  - Hyperhomocysteinemia (HHcy) accelerates atherosclerosis by increasing 
      proliferation and stimulating cytokine secretion in T cells. However, whether 
      homocysteine (Hcy)-mediated T cell activation is associated with metabolic 
      reprogramming is unclear. Here, our in vivo and in vitro studies showed that 
      Hcy-stimulated splenic T-cell activation in mice was accompanied by increased 
      levels of mitochondrial reactive oxygen species (ROS) and calcium, mitochondrial 
      mass and respiration. Inhibiting mitochondrial ROS production and calcium signals 
      or blocking mitochondrial respiration largely blunted Hcy-induced T-cell 
      interferon gamma (IFN-gamma) secretion and proliferation. Hcy also enhanced endoplasmic 
      reticulum (ER) stress in T cells, and inhibition of ER stress with 
      4-phenylbutyric acid blocked Hcy-induced T-cell activation. Mechanistically, Hcy 
      increased ER-mitochondria coupling, and uncoupling ER-mitochondria by the 
      microtubule inhibitor nocodazole attenuated Hcy-stimulated mitochondrial 
      reprogramming, IFN-gamma secretion and proliferation in T cells, suggesting that 
      juxtaposition of ER and mitochondria is required for Hcy-promoted mitochondrial 
      function and T-cell activation. In conclusion, Hcy promotes T-cell activation by 
      increasing ER-mitochondria coupling and regulating metabolic reprogramming.
FAU - Feng, Juan
AU  - Feng J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Science, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China.
FAU - Lu, Silin
AU  - Lu S
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Science, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China.
FAU - Ding, Yanhong
AU  - Ding Y
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Science, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China.
FAU - Zheng, Ming
AU  - Zheng M
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Science, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China. zhengm@bjmu.edu.cn.
FAU - Wang, Xian
AU  - Wang X
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Science, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, China. xwang@bjmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160208
PL  - Germany
TA  - Protein Cell
JT  - Protein & cell
JID - 101532368
RN  - 0 (Phenylbutyrates)
RN  - 0 (Reactive Oxygen Species)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 7WY7YBI87E (4-phenylbutyric acid)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.7.11.1 (Ern1 protein, mouse)
RN  - EC 2.7.11.1 (PERK kinase)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - EC 3.1.- (Endoribonucleases)
RN  - SH1WY3R615 (Nocodazole)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Endoplasmic Reticulum/*metabolism
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Endoribonucleases/metabolism
MH  - Female
MH  - Homocysteine/*toxicity
MH  - Interferon-gamma/analysis
MH  - Metabolic Engineering
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria/*drug effects/metabolism
MH  - Nocodazole/pharmacology
MH  - Phenylbutyrates/pharmacology
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - T-Lymphocytes/cytology/drug effects/metabolism
MH  - eIF-2 Kinase/metabolism
PMC - PMC4887324
OTO - NOTNLM
OT  - T cell
OT  - endoplasmic reticulum stress
OT  - homocysteine
OT  - mitochondria
EDAT- 2016/02/10 06:00
MHDA- 2017/04/21 06:00
PMCR- 2016/02/08
CRDT- 2016/02/10 06:00
PHST- 2015/12/21 00:00 [received]
PHST- 2016/01/05 00:00 [accepted]
PHST- 2016/02/10 06:00 [entrez]
PHST- 2016/02/10 06:00 [pubmed]
PHST- 2017/04/21 06:00 [medline]
PHST- 2016/02/08 00:00 [pmc-release]
AID - 10.1007/s13238-016-0245-x [pii]
AID - 245 [pii]
AID - 10.1007/s13238-016-0245-x [doi]
PST - ppublish
SO  - Protein Cell. 2016 Jun;7(6):391-402. doi: 10.1007/s13238-016-0245-x. Epub 2016 
      Feb 8.