Thapsigargin induces biphasic fragmentation of mitochondria through calcium-mediated mitochondrial fission and apoptosis

Jennifer R. Hom, Jennifer S. Gewandter, Limor Michael, Shey Shing Sheu, Yisang Yoon

Research output: Contribution to journalArticle

92 Scopus citations

Abstract

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 Ca2+ in regulating mitochondrial morphology. We found that treating cells with the ER Ca2+-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 Ca2+ levels, and Ca2+ 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 Ca2+ 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 Ca2+ is involved in controlling mitochondrial morphology via intra-mitochondrial Ca2+ signaling as well as the apoptotic process.

Original languageEnglish (US)
Pages (from-to)498-508
Number of pages11
JournalJournal of Cellular Physiology
Volume212
Issue number2
DOIs
StatePublished - Aug 2007
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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