Oxygen Is the High-Energy Molecule Powering Complex Multicellular Life: Fundamental Corrections to Traditional Bioenergetics

[Image: see text] A fundamental re-assessment of the overall energetics of biochemical electron transfer chains and cycles is presented, highlighting the crucial role of the highest-energy molecule involved, O(2). The chemical energy utilized by most complex multicellular organisms is not predominantly stored in glucose or fat, but rather in O(2) with its relatively weak (i.e., high-energy) double bond. Accordingly, reactions of O(2) with organic molecules are highly exergonic, while other reactions of glucose, fat, NAD(P)H, or ubiquinol (QH(2)) are not, as demonstrated in anaerobic respiration with its meager energy output. The notion that “reduced molecules” such as alkanes or fatty acids are energy-rich is shown to be incorrect; they only unlock the energy of more O(2), compared to O-containing molecules of similar mass. Glucose contains a moderate amount of chemical energy per bond (<20% compared to O(2)), as confirmed by the relatively small energy output in glycolysis and the Krebs cycle converting glucose to CO(2) and NADH. Only in the “terminal” aerobic respiration reaction with O(2) does a large free energy change occur due to the release of oxygen’s stored chemical energy. The actual reaction of O(2) in complex IV of the inner mitochondrial membrane does not even involve any organic fuel molecule and yet releases >1 MJ when 6 mol of O(2) reacts. The traditional presentation that relegated O(2) to the role of a low-energy terminal acceptor for depleted electrons has not explained these salient observations and must be abandoned. Its central notion that electrons release energy because they move from a high-energy donor to a low-energy acceptor is demonstrably false. The energies of (at least) two donor and two acceptor species come into play, and the low “terminal” negative reduction potential in aerobic respiration can be attributed to the unusually high energy of O(2), the crucial reactant. This is confirmed by comparison with the corresponding half-reaction without O(2), which is endergonic. In addition, the electrons are mostly not accepted by oxygen but by hydrogen. Redox energy transfer and release diagrams are introduced to provide a superior representation of the energetics of the various species in coupled half-reactions. Electron transport by movement of reduced molecules in the electron transfer chain is shown to run counter to the energy flow, which is carried by oxidized species. O(2), rather than glucose, NAD(P)H, or ATP, is the molecule that provides the most energy to animals and plants and is crucial for sustaining large complex life forms. The analysis also highlights a significant discrepancy in the proposed energetics of reactions of aerobic respiration, which should be re-evaluated.