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Thapsigargin induces biphasic fragmentation of mitochondria through calcium‐mediated mitochondrial fission and apoptosis
Author(s) -
Hom Jennifer R.,
Gewandter Jennifer S.,
Michael Limor,
Sheu SheyShing,
Yoon Yisang
Publication year - 2007
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21051
Subject(s) - mitochondrial fission , mitochondrial apoptosis induced channel , microbiology and biotechnology , mitochondrion , thapsigargin , fragmentation (computing) , mitochondrial fusion , apoptosis , mitochondrial permeability transition pore , dna fragmentation , mitochondrial dna , biology , atp–adp translocase , dnaja3 , intracellular , programmed cell death , chemistry , inner mitochondrial membrane , biochemistry , ecology , gene
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. J. Cell. Physiol. 212: 498–508, 2007. © 2007 Wiley‐Liss, Inc.