Abstract

Adult human brains consume a disproportionate amount of energy substrates (2–3% of body weight; 20–25% of total glucose and oxygen). Adenosine triphosphate (ATP) is a universal energy currency in brains and is produced by oxidative phosphorylation (OXPHOS) using ATP synthase, a nano-rotor powered by the proton gradient generated from proton-coupled electron transfer (PCET) in the multi-complex electron transport chain (ETC). ETC catalysis rates are reduced in brains from humans with neurodegenerative diseases (NDDs). Declines of ETC function in NDDs may result from combinations of nitrative stress (NS)–oxidative stress (OS) damage; mitochondrial and/or nuclear genomic mutations of ETC/OXPHOS genes; epigenetic modifications of ETC/OXPHOS genes; or defects in importation or assembly of ETC/OXPHOS proteins or complexes, respectively; or alterations in mitochondrial dynamics (fusion, fission, mitophagy). Substantial free energy is gained by direct O2-mediated oxidation of NADH. Traditional ETC mechanisms require separation between O2 and electrons flowing from NADH/FADH2 through the ETC. Quantum tunneling of electrons and much larger protons may facilitate this separation. Neuronal death may be viewed as a local increase in entropy requiring constant energy input to avoid. The ATP requirement of the brain may partially be used for avoidance of local entropy increase. Mitochondrial therapeutics seeks to correct deficiencies in ETC and OXPHOS.

Highlights

  • Perhaps there exists an as of yet unknown proton acceptor molecule in the intermembrane space with different thermodynamics of proton binding? An alternative mechanism proposed by Leone, et al [7] is that the rotor arms of Adenosine triphosphate (ATP) synthase operate using a gradient using a gradient of un-hydrated protons bound to carboxylate anions, with water molecules separately bound to the rotor arms

  • Mitochondria may properly be considered macroscopic ranged in tandem appears to provide a pathway for electron tunneling through these entities; whether Complex I iron–sulfur centers with low energy molecular orbitals that wires, which reduces activation rates) but has no are separated by 14energies angstroms( or less,increasing and form fortheoretically conducting electrons, effect on the energetics ofsame electron movement and references therein)

  • Protons pumped into the intermembrane space theoretically require protection from thermodynamically favorable hydration, since non-hydrated protons appear to be favored for driving the ATP synthase rotor [7]

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Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Under conditions of normal oxygen availability, most of this ATP is made in mitochondria by oxidative phosphorylation (OXPHOS) of energy substrates directly or indirectly created by solar photons through photosynthesis This amount of ATP (8.31 × 1025 molecules/24 h) requires ~20.8 × 1025 electrons/24 h to be passed through the mitochondrial electron transport chain (ETC), when ~2.5 electrons are required for each ATP generated by ATP synthase under normal coupling. 1000 mitochondria (likely an overestimate), each neuronal mitochondrion in the brain must pass on average 1.40 × 107 electrons/s to maintain ATP production. This estimation is based on glucose utilization/oxygen consumption being split 1–1 between neurons and nonneuronal cells in the brain and is not corrected for glial generation of lactate (from glucose) and neuronal metabolism of glial lactate. Such damage is meaningful for brain energy metabolism and may account for the increased incidence of degenerative brain diseases associated with aging

Quantum Tunneling of Protons and Electrons in Mitochondria
Decoherence
Cartoon of proton
Summary of ETC-OXPHOS
Brain Mitochondrial Therapeutics
Correction of mtDNA Mutations
Conclusions
Full Text
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