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

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.

Keywords: brain; evolution; free radicals; oxygen; quantum signalling.

Figure 1. Coupled evolution of life and atmospheric oxygen

Major evolutionary and developmental events that have been linked to ‘pulses’ in the atmospheric oxygen (O₂) concentration based on the GEOCARBSULPH model (Berner, 2007; Berner, 2009). A, note that since the origin of life within 500 million years of Earth's formation (LUCA, last universal common ancestor), oxygenic photosynthesis has been responsible for the rapid increase in atmospheric O₂ levels during the Proterozoic aeon of the Precambrian period (∼0–10% in < 1 billion years), preceded by endosymbiosis, emergence of cellular respiration, with adenosine triphosphate the universal energy source, and cephalisation, a characteristic feature of the ancestral bilateria, leading to the first appearance of a central nervous system (Holland et al. 2013). Earth's oxidation was probably paralleled by selective pressure favouring survival of organisms that could tolerate O₂ toxicity and control oxidative processes to harness energy, including cellular protection through evolution of antioxidant defence, though sequence analyses suggest that even LUCA was capable of detoxifying reactive oxygen species (ROS) long before O₂ became abundant in the atmosphere or ocean, probably as a result of localised O₂ formation via abiotic sources (e.g. photolysis of water by ultraviolet light) or cohabitation with an oxidative photosynthesising organism (Case, 2017). Three primary antioxidant enzymes arose prior to the Great Oxidation Event (GOE): superoxide dismutase, catalase and peroxiredoxins (Case, 2017). Pre‐Є, Pre‐Cambrian; Є, Cambrian; O, Ordovician; S, Silurian; D, Devonian; C, Carboniferous; P, Permian; Tr, Triassic; J, Jurassic; K, Cretaceous; T, Tertiary (Berner et al. 2007). B, stochastic changes in atmospheric O₂ levels during the Phanerozoic aeon peaked during the Carboniferous/Permian periods, resulting in gigantism subsequent to augmented O₂ diffusive capacity, and heralded major evolutionary advances that included a 3.5‐fold increase in hominin brain volume over ∼2.75 million years (Seymour et al. 2016). Also note the three major extinction events (red bands) associated with dramatic falls in atmospheric O₂ levels. C, parabolic projection of the decline in future atmospheric O₂ levels using a stochastic model (Livina et al. 2015) applied to original data obtained from recording stations in the Scripps Programme (Keeling, 1988). Note that the model predicts that in ∼3600 years, atmospheric O₂ levels will be so low that hypoxia will be encountered even at sea‐level, equivalent to being exposed to a terrestrial altitude of ∼5340 m, which represents the highest elevation know to sustain lifelong human habitation, with complete (O₂) depletion predicted within ∼4.4 millennia (Martin et al. 2017).

Figure 2. Evolution of the hominin brain and vulnerability to failure

A, exponential increase in cranial capacity observed in fossil hominids over time, beginning with Homo Habilis, and marked encephalisation linked to the physically active ‘hunter gatherer’, Homo Erectus (annotated). Data based on the (calculated) mean of published individual data points (Schoenemann, 2006). Note also the increase in total number of neurones estimated from separate derivations of cranial capacity and corresponding increases in cerebral blood flow calculated from the size of the internal carotid foramina, in relation to endocranial volume (Seymour et al. 2016). B, the human brain's oxygen dependence comes at a cost, with a corresponding high vulnerability to failure, given that it is an entirely aerobic organ characterised by limited energy reserves, which becomes evident when the brain is confronted by complete oxygen lack (anoxia). CMRO₂, cerebral metabolic rate of oxygen; $P_{\mathrm{c}{\mathrm{O}}_2}$ (average) cerebral tissue partial pressure of O₂; cO₂, cerebral oxygen content.

Figure 3. Molecular orbital diagram of the most stable form (electronic ground state) of the diatomic oxygen molecule (³∑g⁻O₂) (A) and biological reactions underpinning oxygen toxicity in the central nervous system (B)

A, each line represents a molecular orbital and the arrows represent electrons, the direction of which indicates their spin quantum number. Note that oxygen (O₂) with an electronic structure of 1s²2s²2p⁴ qualifies as a diradical, since it contains two unpaired electrons each occupying different π^* _2p anti‐bonding orbitals (highlighted in red) with the same spin quantum number (parallel spin) in accordance with Hund's rule. It is for this reason that O₂ is paramagnetic, allowing liquid O₂ to hang magically suspended between the poles of a magnet (upper right insert). During the process of oxidation when O₂ looks to accept a (spin‐opposed) pair of electrons (↑↓), only one of the pair (↓) can ‘fit’ into each of the vacant π^* _2p anti‐bonding orbitals to create a spin‐opposed pair (as indicated). Hence, O₂ thermodynamically prefers to accept only one electron at a time to conform with the Pauli Exclusion Principle (named after the Nobel Prize winning work of the Austrian physicist Wolfgang Pauli (1900–1958), photograph upper left insert). Fortuitously, this ‘spin restriction’ means that O₂ reacts ‘sluggishly’, with the brain's organic compounds with the organic donor having to undergo a ‘slow spin inversion’ to donate its electrons. B, three types of reactions lead to the superoxide anion (O₂ ^•−)‐mediated formation of the damaging hydroxyl radical (HO^•) capable of causing indiscriminate damage to biological cell membranes that characterises O₂ toxicity: (1) one‐electron reduction of molecular O₂ to O₂ ^•− catalysed by transition metals including iron (Fe), (2) Fenton reactions that involve metal‐catalysed formation of HO^• and (3) a Haber‐Weiss reaction involving the combination of O₂ ^•− and hydrogen peroxide (H₂O₂) to yield additional HO^•.

Figure 4. Evolution of genes encoding the hypoxia‐inducible factor (HIF) pathway (A) and importance of mitochondrial‐generated reactive oxygen species (ROS) stabilisation of HIF‐1α during hypoxia including emergent quantum signalling aspects (B)

A, appearance of genes based on published approximations (Taylor & McElwain, 2010). B, during normoxia, hypoxia‐inducible factor‐1 alpha (HIF‐1α) is hydroxylated on prolines by the prolyl hydroxylases (PHD), tagging it for recognition by the von Hippel Lindau tumour suppressor protein (VHL), resulting in the continual ubiquitination and degradation of HIF‐1α. During hypoxia, superoxide anions formed in the mitochondrial at the Q₀ site of the bc1 complex of Complex III are released into the intermembrane space and enter the cytosol to decrease PHD activity, preventing hydroxylation and resulting in HIF‐1α stabilisation and transcription of genes that collectively preserve cerebral oxygen (O₂) homeostasis. Note that ‘quantum’ aspects of cerebral O₂ sensing are also outlined. FIH, factor inhibiting HIF; CBP, cyclic AMP‐response element binding protein; HRE, hypoxia response element.