Native, not nitrated, cytochrome c and mitochondria-derived hydrogen peroxide drive osteoclast apoptosis

Merry Jo Oursler, Elizabeth W. Bradley, Sarah L. Elfering, Cecilia R Giulivi

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Two unresolved aspects of the role of mitochondria-derived cytochrome c in apoptosis are whether there is a separate pool of cytochrome c within mitochondria that participates in the activation of apoptosis and whether a chemically modified cytochrome c drives apoptosis. These questions were investigated using osteoclasts, because they are rich in mitochondria and because osteoclast apoptosis is critical in bone metabolism regulation. H 2O2 production was increased during culture, preceding cytochrome c release; both processes occurred anterior to apoptosis. With the addition of a mitochondrial uncoupler, H2O2 production and apoptosis were blocked, indicating the prominent role of mitochondria-derived H2O2. Trapping H2O2-derived hydroxyl radical decreased apoptosis. Cytosolic cytochrome c was originated from a single mitochondrial compartment, supporting a common pool involved in respiration and apoptosis, and it was chemically identical to the native form, with no indication of oxidative or nitrative modifications. Protein levels of Bcl-2 and Bc-xL were decreased before apoptosis, whereas expression of wild-type Bcl-2 repressed apoptosis, confirming that cytochrome c release is critical in initiating apoptosis. Cytosolic cytochrome c participated in activating caspase-3 and -9, both required for apoptosis. Collectively, our data indicate that the mitochondria-dependent apoptotic pathway is one of the major routes operating in osteoclasts.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume288
Issue number1 57-1
DOIs
StatePublished - Jan 2005

Keywords

  • Caspase
  • Free radicals
  • Nitric oxide
  • Reactive oxygen species

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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