Mitochondria can act as energy-sensing regulators of hydrogen peroxide availability

Abstract

Mitochondria are widely recognized as sources of reactive oxygen species in animal cells, with H2O2 being of particular note because it can act not only in oxidative stress but also is important to several signalling pathways. Lesser recognized is that mitochondria can have far greater capacity to consume H2O2 than to produce it; however, the consumption of H2O2 may be kinetically constrained by H2O2 availability especially at the low nanomolar (or lower) concentrations that occur in vivo. The production of H2O2 is a function of many factors, not the least of which are respiratory substrate availability and the protonmotive force (Δp). The Δp, which is predominantly membrane potential (ΔΨ), can be a strong indicator of mitochondrial energy status, particularly if respiratory substrate supply is either not meeting or exceeding demand. The notion that mitochondria may functionally act in regulating H2O2 concentrations may be somewhat implicit but little evidence demonstrating this is available. Here we demonstrate key assumptions that are required for mitochondria to act as regulators of H2O2 by an integrated system of production and concomitant consumption. In particular we show the steady-state level of H2O2 mitochondria approach is a function of both mitochondrial H2O2 consumption and production capacity, the latter of which is strongly influenced by ΔΨ. Our results are consistent with mitochondria being able to manipulate extramitochondrial H2O2 as a means of signalling mitochondrial energetic status, in particular the Δp or ΔΨ. Such a redox-based signal could operate with some independence from other energy sensing mechanisms such as those that transmit information using the cytosolic adenylate pool.