Mitochondria and oxygen homeostasis

Abstract

Molecular oxygen possesses a dual nature due to its highly reactive free radical property: it is capable of oxidizing metabolic substrates to generate cellular energy, but can also serve as a substrate for genotoxic reactive oxygen species generation. As a labile substance upon which aerobic life depends, the mechanisms for handling cellular oxygen have been fine-tuned and orchestrated in evolution. Protection from atmospheric oxygen toxicity as originally posited by the Endosymbiotic Theory of the Mitochondrion is likely to be one basic principle underlying oxygen homeostasis. We briefly review the literature on oxygen homeostasis both in vitro and in vivo with a focus on the role of the mitochondrion where the majority of cellular oxygen is consumed. The insights gleaned from these basic mechanisms are likely to be important for understanding disease pathogenesis and developing strategies for maintaining health.

Keywords: altitude; cancer; cardiovascular; hypoxia; lifespan; metabolism; mitochondria; oxidative stress; oxygen; oxygen toxicity; tissue oxygen.

Figure 1.

The variable partial pressure of O₂ (PO₂) in human tissues. Note that the tissue PO₂ under normal physiological conditions is highly variable between different tissue types or organs. There are also regional differences in PO2 within the same organ such as in brain and kidney. PO₂ can also change depending on functional states such as in exercising skeletal muscle or with cognition in brain. Figure created on BioRender.com website.

Figure 2.

Oxygen homeostasis associated with mitochondrial respiration may affect aging and lifespan. (Based on the following references: Ferrari et al, 2017; Jain et al, 2019.) (A) Schematic representation of the proposed homeostatic relationship between tissue oxygen under normal ambient room air (21%) and its consumption in the mitochondria of wild-type mice resulting in a normal lifespan. (B) Ndufs4^−/− mice with impaired mitochondrial respiration have decreased oxygen consumption and thereby elevated tissue PO₂ which can promote oxygen toxicity and decrease lifespan. (C) Lowering ambient oxygen exposure of Ndufs4^−/− mice by placing in a hypoxia chamber (11% O₂) partially prevents the increase in tissue PO₂ and improves survival time.