Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes

Abstract

Reactive oxygen species (ROS) have historically been viewed as toxic metabolic byproducts and causal agents in a myriad of human pathologies. More recent work, however, indicates that ROS are critical intermediates of cellular signaling pathways. Although it is clear that dedicated cellular ROS producers such as NADPH oxidases participate in signaling, evidence suggests that mitochondrial production of ROS is also a tightly controlled process, and plays a role in the maintenance of cellular oxidative homeostasis and propagation of cellular signaling pathways. Production of ROS at mitochondria thus integrates cellular energy state, metabolite concentrations, and other upstream signaling events and has important implications in cellular stress signaling, maintenance of stem cell populations, cellular survival, and oncogenic transformation.

Figure I

Mitochondrial complex III produces superoxide through the Q-cycle.

Figure I

Cysteine oxidation regulates phosphatase activity.

Figure 1. The mitochondrial electron transport chain produces ROS

Mitochondrial complexes I and II use electrons donated from NADH and FADH₂ to reduce coenzyme Q. Coenzyme Q shuttles these electrons to complex III, where they are transferred to cytochrome c. Complex IV uses electrons from cytochrome c to reduce molecular oxygen to water. The action of complexes I, III, and IV produce a proton electrochemical potential gradient, the free energy of which is used to phosphorylate ADP at ATP synthase. Complexes I, II, and III produce superoxide through the incomplete reduction of oxygen to superoxide. Whereas complexes I and II produce superoxide only into the mitochondrial matrix, complex III produces superoxide into both the matrix and the intermembrane space.

Figure 2. Signaling inputs and outputs of mitochondrial ROS signaling

There are multiple inputs that regulate the generation of mitochondrial ROS (e.g., hypoxia, PI3K, TNFα, and oncogenes). These ROS activate multiple outputs including phosphatases, transcription factors, and kinases.

Figure 3. Mitochondrial ROS regulate the cellular response to hypoxia

Hypoxia leads to an induction in the production of mitochondrial ROS. These ROS inhibit the activity of PHD2, leading to stabilization of HIFα subunits (blue) and transcriptional activation. Mitochondrial ROS generated during hypoxia regulate increases in cellular calcium uptake and contraction of pulmonary arteries. Mitochondrial ROS also lead to activation of AMPK, allowing increased cellular energy conservation. AMPK phosphorylates the α-subunit (peach) of the Na/K ATPase leading to endocytosis.

Figure 4. Mitochondrial ROS levels are crucial for biological outcomes

Low levels of mitochondrial ROS production are required for cellular processes such as proliferation and differentiation. An induction in ROS production will lead to adaptive programs including the transcriptional upregulation of antioxidant genes. Even higher levels of ROS will signal the initiation of senescence and apoptosis. Non-signaling, irreversible damage to cellular components is only observed under the highest levels of cellular ROS.