PMID- 17443673
OWN - NLM
STAT- MEDLINE
DCOM- 20070816
LR  - 20201002
IS  - 0021-9541 (Print)
IS  - 0021-9541 (Linking)
VI  - 212
IP  - 2
DP  - 2007 Aug
TI  - Thapsigargin induces biphasic fragmentation of mitochondria through 
      calcium-mediated mitochondrial fission and apoptosis.
PG  - 498-508
AB  - Mitochondrial fission and fusion are the main components mediating the dynamic 
      change of mitochondrial morphology observed in living cells. While many protein 
      factors directly participating in mitochondrial dynamics have been identified, 
      upstream signals that regulate mitochondrial morphology are not well understood. 
      In this study, we tested the role of intracellular Ca(2+) in regulating 
      mitochondrial morphology. We found that treating cells with the ER Ca(2+)-ATPase 
      inhibitor thapsigargin (TG) induced two phases of mitochondrial fragmentation. 
      The initial fragmentation of mitochondria occurs rapidly within minutes dependent 
      on an increase in intracellular Ca(2+) levels, and Ca(2+) influx into 
      mitochondria is necessary for inducing mitochondrial fragmentation. The initial 
      mitochondrial fragmentation is a transient event, as tubular mitochondrial 
      morphology was restored as the Ca(2+) level decreased. We were able to block the 
      TG-induced mitochondrial fragmentation by inhibiting mitochondrial fission 
      proteins DLP1/Drp1 or hFis1, suggesting that increased mitochondrial Ca(2+) acts 
      upstream to activate the cellular mitochondrial fission machinery. We also found 
      that prolonged incubation with TG induced the second phase of mitochondrial 
      fragmentation, which was non-reversible and led to cell death as reported 
      previously. These results suggest that Ca(2+) is involved in controlling 
      mitochondrial morphology via intra-mitochondrial Ca(2+) signaling as well as the 
      apoptotic process.
FAU - Hom, Jennifer R
AU  - Hom JR
AD  - Department of Pharmacology and Physiology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York 14642, USA.
FAU - Gewandter, Jennifer S
AU  - Gewandter JS
FAU - Michael, Limor
AU  - Michael L
FAU - Sheu, Shey-Shing
AU  - Sheu SS
FAU - Yoon, Yisang
AU  - Yoon Y
LA  - eng
GR  - DK073858/DK/NIDDK NIH HHS/United States
GR  - HL33333/HL/NHLBI NIH HHS/United States
GR  - DK061991/DK/NIDDK NIH HHS/United States
GR  - R01 DK061991/DK/NIDDK NIH HHS/United States
GR  - R21 DK073858/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Fis1 protein, rat)
RN  - 0 (Mitochondrial Proteins)
RN  - 67526-95-8 (Thapsigargin)
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - EC 3.6.5.5 (Dnm1l protein, rat)
RN  - EC 3.6.5.5 (Dynamins)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Calcium/*metabolism
MH  - Cell Line
MH  - Cytochromes c/metabolism
MH  - Cytosol/metabolism
MH  - Dynamins/genetics/metabolism
MH  - Endoplasmic Reticulum/drug effects/enzymology
MH  - Enzyme Inhibitors/*pharmacology
MH  - Hepatocytes/*drug effects/metabolism/pathology
MH  - Mitochondria, Liver/*drug effects/metabolism/pathology
MH  - Mitochondrial Membranes/*drug effects/metabolism/pathology
MH  - Mitochondrial Proteins/genetics/metabolism
MH  - Rats
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/*antagonists & 
      inhibitors/metabolism
MH  - Signal Transduction/drug effects
MH  - Thapsigargin/*pharmacology
MH  - Time Factors
MH  - Transfection
EDAT- 2007/04/20 09:00
MHDA- 2007/08/19 09:00
CRDT- 2007/04/20 09:00
PHST- 2007/04/20 09:00 [pubmed]
PHST- 2007/08/19 09:00 [medline]
PHST- 2007/04/20 09:00 [entrez]
AID - 10.1002/jcp.21051 [doi]
PST - ppublish
SO  - J Cell Physiol. 2007 Aug;212(2):498-508. doi: 10.1002/jcp.21051.