PMID- 35159243
OWN - NLM
STAT- MEDLINE
DCOM- 20220408
LR  - 20220531
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 11
IP  - 3
DP  - 2022 Jan 27
TI  - Mitochondria Fusion upon SERCA Inhibition Prevents Activation of the NLRP3 
      Inflammasome in Human Monocytes.
LID - 10.3390/cells11030433 [doi]
LID - 433
AB  - Sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) is a crucial component of the 
      cellular machinery responsible for Ca(2+) homeostasis. The selective inhibition 
      of SERCA by thapsigargin (TG) leads to perturbations in Ca(2+) signaling, which 
      can trigger endoplasmic reticulum (ER) stress. The unfolded protein response 
      (UPR) pathway is activated in response to ER stress and induces an adaptive 
      response to preserve cell survival or committee cells to programmed death, 
      depending on stress duration and/or level. Early stages of ER stress stimulate 
      mitochondrial metabolism to preserve survival but under chronic ER stress 
      conditions, mitochondrial dysfunction is induced, which, in turn, can enhance 
      inflammation through NLRP3 inflammasome activation. This study was aimed at 
      investigating the role of SERCA inhibition on NLRP3 inflammasome activation in 
      human monocytes, which was evaluated in primary monocytes isolated from healthy 
      individuals and in the THP-1 human monocytic cell line. Findings obtained in both 
      THP-1 and primary monocytes demonstrate that SERCA inhibition triggered by TG 
      does not activate the NLRP3 inflammasome in these innate immune cells since IL-1beta 
      secretion was not affected. Results from THP-1 monocytes showing that SERCA 
      inhibition increases mitochondrial Ca(2+) content and fusion, in the absence of 
      changes in ROS levels and membrane potential, support the view that human 
      monocytes counteract ER stress that arises from inhibition of SERCA through 
      modulation of mitochondrial morphology towards mitochondria fusion, thus 
      preventing NLRP3 inflammasome activation. Overall, this work contributes to a 
      better understanding of the molecular mechanisms that modulate the activity of 
      the NLRP3 inflammasome leading to sterile inflammation, which are still poorly 
      understood.
FAU - Pereira, Ana Catarina
AU  - Pereira AC
AUID- ORCID: 0000-0002-3269-0865
AD  - CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative 
      Biomedicine and Biotechnology, University of Coimbra, Rua Larga-Faculdade de 
      Medicina, 1 degrees andar-Polo I Universidade de Coimbra, 3004-504 Coimbra, Portugal.
AD  - Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
AD  - CACC-Clinical Academic Center of Coimbra, 3004-561 Coimbra, Portugal.
FAU - Madeira, Nuno
AU  - Madeira N
AUID- ORCID: 0000-0001-5009-8841
AD  - Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
AD  - CACC-Clinical Academic Center of Coimbra, 3004-561 Coimbra, Portugal.
AD  - CIBIT-Coimbra Institute for Biomedical Imaging and Translational Research, 
      University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.
AD  - Department of Psychiatry, CHUC-UC-Centro Hospitalar e Universitario de Coimbra, 
      3004-561 Coimbra, Portugal.
FAU - Morais, Sofia
AU  - Morais S
AD  - Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
AD  - CACC-Clinical Academic Center of Coimbra, 3004-561 Coimbra, Portugal.
AD  - Department of Psychiatry, CHUC-UC-Centro Hospitalar e Universitario de Coimbra, 
      3004-561 Coimbra, Portugal.
FAU - Macedo, Antonio
AU  - Macedo A
AUID- ORCID: 0000-0003-2180-2718
AD  - Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
AD  - CACC-Clinical Academic Center of Coimbra, 3004-561 Coimbra, Portugal.
AD  - Department of Psychiatry, CHUC-UC-Centro Hospitalar e Universitario de Coimbra, 
      3004-561 Coimbra, Portugal.
FAU - Cruz, Maria Teresa
AU  - Cruz MT
AUID- ORCID: 0000-0001-9846-6754
AD  - CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative 
      Biomedicine and Biotechnology, University of Coimbra, Rua Larga-Faculdade de 
      Medicina, 1 degrees andar-Polo I Universidade de Coimbra, 3004-504 Coimbra, Portugal.
AD  - CACC-Clinical Academic Center of Coimbra, 3004-561 Coimbra, Portugal.
AD  - Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
FAU - Pereira, Claudia M F
AU  - Pereira CMF
AD  - CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative 
      Biomedicine and Biotechnology, University of Coimbra, Rua Larga-Faculdade de 
      Medicina, 1 degrees andar-Polo I Universidade de Coimbra, 3004-504 Coimbra, Portugal.
AD  - Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
AD  - CACC-Clinical Academic Center of Coimbra, 3004-561 Coimbra, Portugal.
LA  - eng
GR  - CENTRO-01-0145-FEDER-000012/European Regional Development Fund (ERDF)/
GR  - SFRH/BD/148653/2019/Fundacao para a Ciencia e a Tecnologia/
GR  - POCI-01-0145-FEDER-028214 (MAM4BD) and POCI-01-0145-FEDER-029369 and 
      UIDB/04539/2020 and UIDP/04539/2020/Fundacao para a Ciencia e a Tecnologia/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220127
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (NLRP3 protein, human)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
SB  - IM
MH  - Humans
MH  - *Inflammasomes/metabolism
MH  - Inflammation/metabolism
MH  - Mitochondria/metabolism
MH  - *Mitochondrial Dynamics
MH  - Monocytes/metabolism
MH  - *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - *Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors
MH  - Thapsigargin/pharmacology
PMC - PMC8833979
OTO - NOTNLM
OT  - calcium homeostasis
OT  - endoplasmic reticulum (ER) stress
OT  - immune system
OT  - mitochondria dynamics
OT  - sterile inflammation
COIS- The authors declare no conflict of interest.
EDAT- 2022/02/16 06:00
MHDA- 2022/04/09 06:00
PMCR- 2022/01/27
CRDT- 2022/02/15 01:04
PHST- 2021/12/27 00:00 [received]
PHST- 2022/01/18 00:00 [revised]
PHST- 2022/01/25 00:00 [accepted]
PHST- 2022/02/15 01:04 [entrez]
PHST- 2022/02/16 06:00 [pubmed]
PHST- 2022/04/09 06:00 [medline]
PHST- 2022/01/27 00:00 [pmc-release]
AID - cells11030433 [pii]
AID - cells-11-00433 [pii]
AID - 10.3390/cells11030433 [doi]
PST - epublish
SO  - Cells. 2022 Jan 27;11(3):433. doi: 10.3390/cells11030433.