O 2 sensing, mitochondria and ROS signaling: The fog is lifting

Abstract

Mitochondria are responsible for the majority of oxygen consumption in cells, and thus represent a conceptually appealing site for cellular oxygen sensing. Over the past 40 years a number of mechanisms to explain how mitochondria participate in oxygen sensing have been proposed. However, no consensus has been reached regarding how mitochondria could regulate transcriptional and post-translational responses to hypoxia. Nevertheless, a growing body of data continues to implicate a role for increased reactive oxygen species (ROS) signals from the electron transport chain (ETC) in triggering responses to hypoxia in diverse cell types. The present article reviews our progress understanding this field and considers recent advances that provide new insight, helping to lift the fog from this complex topic.

Mitochondrial Energy Signaling and Its Role in the Low-Oxygen Stress Response of Plants

“…The authors used the fluorescent dye 29,79-dichlorofluorescin (DCF), which indicated pronounced ROS production when cells were shifted from normoxic (21% O 2 ) to hypoxic (2% O 2 ) conditions, which they attributed to superoxide production at complex III using mETC inhibitors. While controversies persist, mtROS are now widely considered a potential early trigger in the mammalian transcriptional response to low oxygen (Bailey-Serres and Chang, 2005;Waypa et al, 2016). Whether, however, superoxide itself has a role as trigger remains challenging to answer.…”

A Brief Overview of Nitric Oxide and Reactive Oxygen Species Signaling in Hypoxia-Induced Pulmonary Hypertension

“…In this case, cellular respiration is an important source of ROS (Waypa et al, 2016). Accordingly, ROS role in the development of PH is strongly suggested by studies showing profound alteration in mitochondrial structure and function in that context.…”

“…− ) from complex III to the intermembrane space, where it is converted to hydrogen peroxide (H 2 O 2 ) by superoxide dismutase (Thompson, 2016, Waypa et al, 2016). The H 2 O 2 then enters the cytosol, where it activates multiple responses contributing to smooth muscle contraction and remodeling.…”

Metabolism of Preimplantation Embryo Development

“…It is anticipated that compaction will further differentiate the two environments such that the inner cells find themselves in a more hypoxic environment. It is becoming clear that mammalian cells sense hypoxia through mitochondria's ETCs' generation of ROS, which acts as a signaling molecule to initiate the hypoxic response (Waypa, Smith, & Schumacker, 2016). Could one key to TE differentiation be ROS signaling by more hypoxic inner cells, which serves as a trigger to activate a TE differentiation pathway in the outer cells, leading to changes in mitochondrial morphology in the outer cells?…”