Journal
BIOMEDICINES
Volume 9, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines9020225
Keywords
mitochondria; electron transport chain; oxidative phosphorylation; ATP; brain energy metabolism; neurodegenerative diseases; oxidative stress; nitrative stress
Categories
Funding
- international Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
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The adult human brain consumes a disproportionate amount of energy substrates, with ATP being the universal energy currency. Neurodegenerative diseases may result from factors such as stress damage, genetic mutations, epigenetic modifications, and mitochondrial dysfunction. Mitochondrial therapeutics aims to correct deficiencies in energy production processes.
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 O-2 -mediated oxidation of NADH. Traditional ETC mechanisms require separation between O-2 and electrons flowing from NADH/FADH(2) 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.
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