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.Mitochondria are believed to be the major source of intracellular reactive oxygen species (ROS) 2 generation. Working with isolated mitochondria, some estimates have suggested that as much as 3-5% of the oxygen consumed is ultimately diverted toward ROS production (1). Although these estimates are potential benchmarks, the experimental conditions, including substrate concentration and ATP levels, in which many of these measurements were made, as well as the functional alterations that occur with mitochondrial isolation, argue for caution with regard to such in vitro determinations. As such, the precise in vivo amount of mitochondrial superoxide or hydrogen peroxide production remains elusive. Although the magnitude of ROS production remains in doubt, the location of the one-electron reduction of molecular oxygen is less uncertain. Both Complexes I and III of the electron transport chain are thought to be the major sites of ROS production (2, 3), although clearly other electron complexes, as well as other mitochondrial enzymes, can generate ROS. Once generated, superoxide rapidly and spontaneously dismutates to hydrogen peroxide. This conversion is accelerated in the presence of the enzyme superoxide dismutase. To avoid the potential damaging effects of ROS, mitochondria express a number of protein antioxidants, including SOD2, as well as other scavenging enzymes such as peroxiredoxins 3 and 5. Although the activities of intracellular antioxidants and peroxidases determine the magnitude of ROS, the level of ROS generated is also believed to be dependent on certain intrinsic properties of mitochondrial energetics. For instance, a high proton motive force (e.g. high m ) is believed to favor the production of ROS, whereas mitochondrial uncoupling agents result in a lower m and decreased ROS formation. Similarly, mutations in either mitochondrial DNA or nuclear DNA that lead to disruption in any of the components of the electron transport chain also predispose to ROS formation presumably by impeding the flow of electrons down the cytochrome chain.Although the regulation of mitochondrial ROS release was experimentally appreciated, for many years, the prevailing view was that mitochondrial oxidants were autonomously produced solely as a byproduct of metabolism. That notion has slowly given way to a more nuanced view of mitochondrial oxidants as potential regulators of a number of intracellular pathways. Initial reports suggested that increased supply of metabolic substrates augmented mitochondrial oxidant production and that the release of o...

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

“…To understand the mechanism of this induction, we explored a role for ROS, which have been shown to stabilize HIF1a. 10,18 Treatment of cells with NAC confirmed a critical role for ROS, as this antioxidant completely blocked 0.1 Gy-induced increase of HIF1a (Figure 4d). A requirement of HIF1a in 0.1 Gy-induced expression of glycolytic genes (Figure 4e), and GLUT-1 and 3 (Figure 4f) was demonstrated by HIF1a knockdown.…”

“…9 When mildly increased, ROS, however, can function as signal molecules modulating cellular physiology. 10,11 ROS act through oxidation of reactive cysteine residues in specific target proteins controlling various signaling cascades. A prototype of the ROS-susceptible proteins is phosphatases.…”

“…For instance, the NFkB pathway stimulates transcription of HIF-1a, 16,17 the PI3K/AKT/mTOR pathway promotes HIF-1a mRNA translation 18 and ROS inhibits HIF-1a degradation. 10 Upon induction, HIF-1a stimulates transcription of genes encoding glucose transporters and enzymes of glycolysis and the pentose phosphate pathway (PPP). 19,20 HIF-1a also negatively regulates TCA cycle enzymes, indirectly through inducing miR120.…”

A comparison of radiation-induced mitochondrial damage between neural progenitor stem cells and differentiated cells

“…[2][3][4][5] Mitochondria play a key role in maintaining the homeostasis of cells in response to IR, and function as a central platform for cellular signaling. 6 Mitochondria-mediated cellular signaling, including Mn-superoxide dismutase (MnSOD) and nuclear factor kB (NF-kB), is associated with the nontargeted effects of IR, such as the adaptive response, bystander effect, and genomic instability. 7,8 Upon high dose of IR, mitochondria release cytochrome c to induce apoptosis in irradiated cells.…”

A Low-dose Arsenic-induced p53 Protein-mediated Metabolic Mechanism of Radiotherapy Protection

“…However, under certain normoxia conditions, HIF-1␣ expression can also be increased. For instance, the NFB pathway stimulates transcription of HIF-1␣ (6,7), the PI3K/AKT/mammalian target of rapamycin pathway promotes HIF-1␣ mRNA translation (5), and reactive oxygen species inhibit HIF-1␣ degradation (8,9). Upon induction, HIF-1␣ stimulates the transcription of genes encoding glucose transporters and enzymes of glycolysis and the pentose phosphate pathway (2,3).…”