Oxygen, evolution and redox signalling in the human brain; quantum in the quotidian

Summary of the intrinsic links between oxygen (O₂), evolution and human defence of cerebral homeostasis. Rising paleoatmospheric O₂ levels, especially during the past ∼550–600 million years (Phanerozoic aeon) has been linked to major evolutionary and developmental events, including emergence of the mitochondrion and central nervous system. The human brain has since evolved to be entirely dependent on O₂ and as a consequence is especially vulnerable to failure. However, the 'elixir of life' is Janus‐faced, capable of sustaining life in physiologically controlled amounts yet paradoxically deadly when in excess, its toxicity and mutagenicity due to the fact that it exists in air as a free radical with two unpaired electrons located in separate antibonding orbitals. The mitochondrion is able to 'sense' O₂ deprivation (hypoxia), orchestrating release of free radicals and associated reactive oxygen species (ROS) that serve as signal transductants capable of effecting neuroprotective adaptation through stabilisation of hypoxia‐inducible factor alpha (HIF‐1α), with gene transcription ultimately helping defend cerebral O₂ homeostasis. Emerging evidence suggests that mitochondria may harness quantum mechanics to sense O₂ more efficiently than even the best classical equivalent for selective advantage, revealing more complex cellular and molecular mechanisms than previously thought.

Abstract

Rising atmospheric oxygen (O₂) levels provided a selective pressure for the evolution of O₂‐dependent micro‐organisms that began with the autotrophic eukaryotes. Since these primordial times, the respiring mammalian cell has become entirely dependent on the constancy of electron flow, with molecular O₂ serving as the terminal electron acceptor in mitochondrial oxidative phosphorylation. Indeed, the ability to 'sense' O₂ and maintain homeostasis is considered one of the most important roles of the central nervous system (CNS) and probably represented a major driving force in the evolution of the human brain. Today, modern humans have evolved with an oversized brain committed to a continually active state and, as a consequence, paradoxically vulnerable to failure if the O₂ supply is interrupted. However, our pre‐occupation with O₂, the elixir of life, obscures the fact that it is a gas with a Janus face, capable of sustaining life in physiologically controlled amounts yet paradoxically deadly to the CNS when in excess. A closer look at its quantum structure reveals precisely why; the triplet ground state diatomic O₂ molecule is paramagnetic and exists in air as a free radical, constrained from reacting aggressively with the brain's organic molecules due to its 'spin restriction', a thermodynamic quirk of evolutionary fate. By further exploring O₂'s free radical 'quantum quirkiness', including emergent (quantum) physiological phenomena, our understanding of precisely how the human brain senses O₂ deprivation (hypoxia) and the elaborate redox‐signalling defence mechanisms that defend O₂ homeostasis has the potential to offer unique insights into the pathophysiology and treatment of human brain disease.

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