Fragmented mitochondria are sensitized to Bax insertion and activation during apoptosis

Craig Brooks, Sung Gyu Cho, Cong Yi Wang, Tianxin Yang, Zheng Dong

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Recent studies have shown mitochondrial fragmentation during cell stress and have suggested a role for the morphological change in mitochondrial injury and ensuing apoptosis. However, the underlying mechanism remains elusive. Here we demonstrate that mitochondrial fragmentation facilitates Bax insertion and activation in mitochondria, resulting in the release of apoptogenic factors. In HeLa cells, over-expression of mitofusins attenuated mitochondrial fragmentation during cisplatin- and azide-induced cell injury, which was accompanied by less apoptosis and less cytochrome c release from mitochondria. Similar effects were shown by inhibiting the mitochondrial fission protein Drp1 with a dominant negative mutant (dn-Drp1). Mitofusins and dn-Drp1 did not seem to significantly affect Bax translocation/accumulation to mitochondria; however, they blocked Bax insertion and activation in mitochondrial membrane. Consistently, in rat kidney proximal tubular cells, small interfering RNA knockdown of Drp1 prevented mitochondrial fragmentation during azide-induced ATP depletion, which was accompanied by less Bax activation, insertion, and oligomerization in mitochondria. These cells released less cytochrome c and AIF from mitochondria and showed significantly lower apoptosis. Finally, mitofusin-null mouse embryonic fibroblasts (MEF) had fragmented mitochondria. These MEFs were more sensitive to cisplatin-induced Bax activation, release of cytochrome c, and apoptosis. Together, this study provides further support for a role of mitochondrial fragmentation in mitochondrial injury and apoptosis. Mechanistically, mitochondrial fragmentation may sensitize the cells to Bax insertion and activation in mitochondria, facilitating the release of apoptogenic factors and consequent apoptosis.

Original languageEnglish (US)
Pages (from-to)C447-C455
JournalAmerican Journal of Physiology - Cell Physiology
Volume300
Issue number3
DOIs
StatePublished - Mar 1 2011

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Mitochondria
Apoptosis
Cytochromes c
Azides
Cisplatin
Wounds and Injuries
Mitochondrial Dynamics
Mitochondrial Proteins
Mitochondrial Membranes
HeLa Cells
Small Interfering RNA
Fibroblasts
Adenosine Triphosphate
Kidney

Keywords

  • Cytochrome c
  • Mitochondria outer membrane permeabilization
  • Mitochondrial dynamics

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

Fragmented mitochondria are sensitized to Bax insertion and activation during apoptosis. / Brooks, Craig; Cho, Sung Gyu; Wang, Cong Yi; Yang, Tianxin; Dong, Zheng.

In: American Journal of Physiology - Cell Physiology, Vol. 300, No. 3, 01.03.2011, p. C447-C455.

Research output: Contribution to journalArticle

Brooks, Craig ; Cho, Sung Gyu ; Wang, Cong Yi ; Yang, Tianxin ; Dong, Zheng. / Fragmented mitochondria are sensitized to Bax insertion and activation during apoptosis. In: American Journal of Physiology - Cell Physiology. 2011 ; Vol. 300, No. 3. pp. C447-C455.
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