In the first review, Wong, Dighe, Mezera, Monternier, and Brand (
- Wong H.-S.
- Dighe P.A.
- Mezera V.
- Monternier P.-A.
- Brand M.D.
Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions.
) describe the mitochondrial sites of O2̇̄
generation under different bioenergetics conditions. Experiments with isolated mitochondria have led to estimates of the magnitude and relative contributions of seven sites in the electron transfer chain to O2̇̄
production. These vary with the substrate being oxidized and with conditions simulating rest versus
mild or intense exercise. Under the conditions tested, succinate was the most prolific inducer of H2
production and ∼5-fold higher than palmitoylcarnitine/carnitine or glutamate/malate. Determining the relevance of these observations to intact cells and tissues is an important gap that remains to be filled, as is elucidating the modulation of mitochondrial ROS
The abbreviations used are:
reactive oxygen species
production in the context of caloric restriction and pathological states. To this end, the development of tools such as small molecule inhibitors that suppress site-specific electron leakage promises to move studies away from isolated mitochondria to intact cells.
In the second review, Chouchani, Kazak, and Spiegelman (
- Chouchani E.T.
- Kazak L.
- Spiegelman B.M.
Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms.
) discuss the role of ROS signaling in regulating thermogenesis with a focus on uncoupling protein 1 (UCP1), which dissipates the mitochondrial proton motive force, generating heat. The authors elegantly describe the challenges associated with faithful modeling of ROS signaling in experimental systems, as well as ascribing the precise ROS involved in driving a physiological response via modification of specific cellular targets. In the case of thermogenesis, elevated O2̇̄
or a general oxidative shift in thiol redox metabolism, be it via Nrf2 (nuclear factor-erythroid 2-related factor), isocitrate dehydrogenase 2, or superoxide dismutase 2 ablation, activates UCP1. This redox effect is transduced in part via sulfenylation of a specific cysteine that sensitizes UCP1 to activation by fatty acids during adrenergic stimulation of thermogenic respiration. The molecular details of how redox signaling, metabolism, and gene expression converge to activate the thermogenic program await further elucidation.
Focused on the Keap1 (Kelch-like ECH-associated protein 1)–Nrf2 system, the third article, by Suzuki and Yamamoto (
Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress.
), describes this major axis of cellular oxidant and stress response. In this protein pair, Nrf2 is a transcriptional factor that induces cytoprotective gene expression and represses inflammatory cytokine gene transcription. Keap1 is a Nrf2 regulator and sensor of oxidative and electrophilic stress. Keap1 marks Nrf2 for proteasomal degradation, albeit only in the absence of stress, and loses this control when it is itself marked by oxidants or electrophiles. Modification of a critical cysteine residue in Keap1 in response to various electrophiles is implicated in modulating ubiquitination of Nrf2. However, the picture is not quite so simple as other cysteines on Keap1 can also be targeted, revealing a possible “cysteine code” that allows for a nuanced response to various chemical and oxidative insults. Mouse models of Nrf2 hyperactivation (by Keap1 gene disruption) reveal a wider role for this stress-response system in organismal homeostasis and in cell fate determination.
In the final article in the series, Xie and Simon (
Oxygen availability and metabolic reprogramming in cancer.
) discuss the broad impacts that O2
insufficiency has on metabolic reprogramming in cancer cells, which is mediated in large part by hypoxia-inducible factor (HIF). Under hypoxic conditions, diminished O2
-dependent hydroxylation of HIF stabilizes it against proteasomal degradation and induces transcription of a massive gene set. Rewiring of central carbon metabolism and other major metabolic arteries ensues through up-regulation of transporters and enzymes. The effect of HIF on glucose metabolism appears to be a two-way street. Although HIF induces an adaptive transcriptional response, it is in turn regulated by direct protein–protein interactions with some gene products whose synthesis it induces, e.g.
pyruvate kinase M2. HIF regulates O2
metabolism by both direct and indirect means. Thus, HIF down-regulates several components of the electron transfer chain, directly impacting O2
consumption. HIF also inhibits pyruvate dehydrogenase via up-regulation of an inhibitory kinase. This disconnects glycolysis from oxidative mitochondrial metabolism and suppresses ROS production. The review concludes by discussing HIF-independent metabolic adaptations to low O2
tension. For instance, hypoxia-induced acidification, as well as subsequent promiscuous activation of lactate dehydrogenase, leads to enhanced synthesis of l
-2-hydroxyglutarate. Like the oncometabolite d
-2-hydroxyglutarate, the l
-isomer is an inhibitor of histone demethylases and leads to epigenetic dysregulation.
Published online: August 24, 2017
Edited by Chris Whitfield
This work was supported by National Institutes of Health Grants DK45776, HL58984, and GM112455 (to R. B.). The author declares that she has no conflicts of interest with the contents of this article. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.
Copyright © 2017 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.