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In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice
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Widespread mitochondrial depletion via mitophagy does not compromise necroptosis

Stephen W G Tait1, Andrew Oberst2, Giovanni Quarato3

  • 1CR-UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK.

Cell Reports
|November 26, 2013
PubMed

Insights

Mitochondria are not the cause of programmed necrosis (necroptosis), a cell death pathway regulated by RIPK3. While mitochondrial reactive oxygen species (ROS) are involved, they do not drive this cell death process.

Area of Science:

  • Cellular biology
  • Biochemistry
  • Immunology

Background:

  • Programmed necrosis (necroptosis) is a regulated form of cell death.
  • Receptor interacting protein kinase-3 (RIPK3) activation triggers necroptosis.
  • Mitochondria and mitochondrial reactive oxygen species (ROS) have been suggested to mediate RIPK3-dependent cell death.

Purpose of the Study:

  • To investigate the role of mitochondria and mitochondrial ROS in RIPK3-dependent necroptosis.
  • To determine if mitochondria are essential effectors of programmed necrosis.

Main Methods:

  • Utilized mitophagy to create mitochondria-deficient cells.
  • Induced necroptosis via tumor necrosis factor (TNF) or RIPK3 oligomerization.
  • Assessed cell death in the presence and absence of mitochondria and ROS scavengers like butylated hydroxyanisole (BHA).

Main Results:

  • Mitochondria-deficient cells remained sensitive to RIPK3-dependent necroptosis.
  • Butylated hydroxyanisole (BHA) delayed TNF-induced necroptosis but not RIPK3 oligomerization-induced necroptosis.
  • TNF-induced ROS production was mitochondrial-dependent, but BHA inhibited necroptosis even in mitochondria-depleted cells.

Conclusions:

  • Mitochondrial ROS production accompanies, but is not the causative factor in, RIPK3-dependent necroptosis.
  • Mitochondria are not essential for executing programmed necrosis.
  • The role of ROS in necroptosis is complex and stimulus-dependent.

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