Response of mitochondrial reactive oxygen species generation to steady-state oxygen tension: implications for hypoxic cell signaling

We show that, under all respiratory conditions studied, mitochondrial reactive oxygen species generation decreased as decreased

David L. Hoffman; Jason D. Salter; Paul S. Brookes


Scholarcy highlights

  • Mitochondria are proposed to play an important role in hypoxic cell signaling
  • With the use of the open-flow respirometry system, measurements of respiration and reactive oxygen species generation by isolated rat liver mitochondria were obtained at various steady-state levels
  • The p50 values for states 3 and 4 were 2.7 ± 1.0 and 3.6 ± 0.7 μM O2, respectively. These p50 values are in agreement with those we previously reported in an open-flow respirometry system using isolated rat liver mitochondria, they are slightly higher than those reported by other authors using either open-flow or closed-chamber respirometry systems
  • The notion of increased mitochondrial ROS under hypoxic conditions is based on the hypothesis that O2 limitation at complex IV triggers ROS generation at upstream respiratory complexes. It follows that the signaling machinery for increased mitochondrial ROS in response to hypoxia is intrinsic to the mitochondrial respiratory chain
  • Our main finding was that in this isolated mitochondrial system, free from extramitochondrial signaling pathways, ROS generation decreased in hypoxia
  • It is important to emphasize that this conclusion does not preclude the possibility that mitochondrial ROS generation can increase in response to hypoxia in intact cells; it merely posits that the mechanism by which mitochondria may generate ROS in hypoxia is more complicated than purely O2 limitation at complex IV and backup of electrons in the respiratory chain
  • The current investigation exposed isolated mitochondria to a steady-state controlled environment to test the hypothesis that O2 limitation at complex IV causes an increase in reactive oxygen species generation

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