Signal transduction by mitochondrial oxidants

Abstract

The production of mitochondrial reactive oxygen species occurs as a consequence of aerobic metabolism. Mitochondrial oxidants are increasingly viewed less as byproducts of metabolism and more as important signaling molecules. Here, I review several notable examples, including the cellular response to hypoxia, aspects of innate immunity, the regulation of autophagy, and stem cell self-renewal capacity, where evidence suggests an important regulatory role for mitochondrial oxidants.

FIGURE 1.

HIF-1α and mitochondrial oxidants. Shown is the potential role of HIF-1α in regulating ROS levels under low oxygen conditions. Evidence suggests that low oxygen levels actually increase the levels of mitochondrial ROS. Once released, these oxidants appear to stabilize HIF-1α protein and thereby increase HIF-1α activity. In turn, through a variety of mechanisms, HIF-1α alters mitochondrial carbon metabolism by regulating such enzymes as lactate dehydrogenase A and PDK1 and potentially alters mitochondrial activity by augmenting cytochrome content. The end result of these HIF-1α-regulated activities is a potential reduction of the increased ROS levels induced by hypoxic stress.

FIGURE 2.

Mitochondrial oxidants as signaling molecules. Shown is a potential model in which the intensity of mitochondrial oxidant production generates a gradient of biological responses. See text for details.