Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury

Pothana Saikumar, Zheng Dong, Yogi Patel, Kristi Hall, Ulrich Hopfer, Joel M. Weinberg, M. A. Venkatachalam

Research output: Contribution to journalArticle

239 Citations (Scopus)

Abstract

We investigated mechanisms of cell death during hypoxia/reoxygenation of cultured kidney cells. During glucose-free hypoxia, cell ATP levels declined steeply resulting in the translocation of Bax from cytosol to mitochondria. Concurrently, there was cytochrome c release and caspase activation. Cells that leaked cytochrome c underwent apoptosis after reoxygenation. ATP depletion induced by a mitochondrial uncoupler resulted in similar alterations even in the presence of oxygen. Moreover, inclusion of glucose during hypoxia prevented protein translocations and reoxygenation injury by maintaining intracellular ATP. Thus, ATP depletion, rather than hypoxia per se, was the cause of protein translocations. Overexpression of Bcl-2 prevented cytochrome c release and reoxygenation injury without ameliorating ATP depletion or Bax translocation. On the other hand, caspase inhibitors did not prevent protein translocations, but inhibited apoptosis during reoxygenation. Nevertheless, they could not confer long-term viability, since mitochondria had been damaged. Omission of glucose during reoxygenation resulted in continued failure of ATP production, and cell death with necrotic morphology. In contrast, cells expressing Bcl-2 had functional mitochondria and remained viable during reoxygenation even without glucose. Therefore, Bax translocation during hypoxia is a molecular trigger for cell death during reoxygenation. If ATP is available during reoxygenation, apoptosis develops; otherwise, death occurs by necrosis. By preserving mitochondrial integrity, BCL-2 prevents both forms of cell death and ensures cell viability.

Original languageEnglish (US)
Pages (from-to)3401-3415
Number of pages15
JournalOncogene
Volume17
Issue number26
DOIs
StatePublished - Dec 31 1998

Fingerprint

Cytochromes c
Adenosine Triphosphate
Wounds and Injuries
Cell Death
Protein Transport
Glucose
Mitochondria
Apoptosis
Caspase Inhibitors
Caspases
Hypoxia
Cytosol
Cultured Cells
Cell Survival
Necrosis
Oxygen
Kidney

Keywords

  • Bax
  • Bcl-2
  • Cell death
  • Cytochrome c
  • Hypoxia reoxygenation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Saikumar, P., Dong, Z., Patel, Y., Hall, K., Hopfer, U., Weinberg, J. M., & Venkatachalam, M. A. (1998). Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury. Oncogene, 17(26), 3401-3415. https://doi.org/10.1038/sj.onc.1202590

Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury. / Saikumar, Pothana; Dong, Zheng; Patel, Yogi; Hall, Kristi; Hopfer, Ulrich; Weinberg, Joel M.; Venkatachalam, M. A.

In: Oncogene, Vol. 17, No. 26, 31.12.1998, p. 3401-3415.

Research output: Contribution to journalArticle

Saikumar, P, Dong, Z, Patel, Y, Hall, K, Hopfer, U, Weinberg, JM & Venkatachalam, MA 1998, 'Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury', Oncogene, vol. 17, no. 26, pp. 3401-3415. https://doi.org/10.1038/sj.onc.1202590
Saikumar, Pothana ; Dong, Zheng ; Patel, Yogi ; Hall, Kristi ; Hopfer, Ulrich ; Weinberg, Joel M. ; Venkatachalam, M. A. / Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury. In: Oncogene. 1998 ; Vol. 17, No. 26. pp. 3401-3415.
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