Neurodegenerative diseases arise from oxidative damage to electron tunneling proteins in mitochondria

(A first draft 2024-07-02)
BvS-working hypothesis>
Can sclerosis (hardening, densification thickening of tissue in organs), be a consequence of (slowly developed?) not observe, gradually due to a not enough effective enzymatic quantum tunneling where slow changes in co- to decoherence play an significant, general important role in the early development of many diseases? Especially, when there is (also) an imbalance in main neurotransmitters? Below some (for me) new links (more coming).

Energy, Entropy and Quantum Tunneling of Protons …
BvS see below about specifically Neurodegeneration, e.g. ALS ”..

4. Entropy and Neurodegeneration
Whatever origin of the observable universe hypothesis one subscribes to, all can agree that the cosmological evidence supports the ongoing expansion of the observable universe with a resulting steady increase in entropy. Earlier thermodynamic theorists (such as Clausius) describing the varying forms of this “Second Law of Thermodynamics” developed the concept that the entropy in the Universe may remain constant but is more likely constantly increased, regardless of what happens locally.

The human brain and its ~86 billion neurons display a marked (increase in order)/(decrease in disorder) that represents thermodynamically a decrease in entropy of cellular molecules. In fact, all cells, and life forms themselves, represent a reduction in molecular entropy; from this perspective, cell and organismal death can be viewed as an (inevitable) increase in molecular entropy.

Might neurodegeneration and neuronal death also be viewed as a local increase in entropy, driven ultimately by a reduction in energy input, whatever the “genesis” cause(s) of the bioenergetic deficit? By this paradigm, neuronal death and its attendant increase in molecular entropy would be thermodynamically favored, independent of whether it occurred during “life” or after organismal “death”. If occurring during life, then a clinical phenotype is generated that can be discerned (i.e., loss of cognitive capacity in Alzheimer’s disease (AD); loss of smooth voluntary movement in Parkinson’s disease (PD); loss of muscle mass and appearance of weakness in amyotrophic lateral sclerosis (ALS), etc.).

If this paradigm is true, then prevention of neuronal death (in NDDs) can be viewed as a thermodynamic problem with potential thermodynamic solutions. For example, energy input, which is already disproportionately elevated in adult human brain, could be increased by processes that stimulate mitochondrial energy transformation and ATP synthesis. One could also attempt to increase synaptogenesis and size/interactions of neuronal networks (which should also reduce neuronal molecular entropy). However, we wish to note that no reported therapeutic strategies derived from the above thermodynamic hypothesis of neuronal death have yet been published.

5. Oxidative Phosphorylation (OXPHOS) Alterations in NDDs
OXPHOS is an evolved process in which electron flow through the ETC is coupled to proton translocation from the mitochondrial matrix to the intermembrane space, creating a proton and pH gradient between the mitochondrial matrix and intermembrane space. The resulting proton gradient is used to rotate the arm of ATP synthase, an evolutionarily old enzyme [] that appears to require non-hydrated protons to operate [] (see above). As discussed previously, this PCET may utilize proton tunneling and/or structural alterations in proton-pumping subunits of the ETC (at least for Complex I).

Because electron flow (at least in Complex I) is believed to use a tunneling mechanism (for discussion see [] and references therein), structural alterations to proteins critical to electron tunneling may result in reduced rates of electron flow, leading to reduced rates of proton pumping and ATP synthesis. This could result in a bioenergetic deficiency state, based on maintaining a minimum rate of ATP synthesis necessary for neuronal functions (see above). By this mechanism, proton pumping (PCET) would not be mechanistically impaired per se, just reduced in rate.

In NDDs variable reductions in ETC rates at one or more specific complexes have been described. Epigenetic modifications potentially responsible for these reductions include pre-transcriptional changes to genes such as gene methylation and histone modifications that affect gene promoter or repressor activities. Epigenetic alterations have been described in amyotrophic lateral sclerosis (ALS, []), Parkinson’s disease (PD, [,,,,,,,,]), and Alzheimer’s disease (AD, [,,,,,,,,,,,,]). In many studies, cell or animal models of NDDs are utilized, with the understanding that similar phenomena may occur in the more common sporadic forms of each NDD.

Reductions in bioenergetics may also derive from nitrative damage to proteins, particularly to nitration of tyrosine residues by peroxynitrite anion (ONOO). So-called “nitrative stress”, which is frequently found in models that demonstrate “oxidative stress”, have been described in ALS [,,,,,,,], AD [,,,,,,,,,,,,,,], and PD [,,,,,,,,,,,,,,,,,,,,,,,,] tissues.

Oxidative stress (OS) is the condition where production rates of oxidizing species exceed rates of inactivation. Oxidizing species may damage lipids, nucleic acids, and proteins and thus are potentially toxic to cells and energy production at several levels. Because most molecular oxygen is utilized by mitochondria for ETC activity (and is reduced to water), mitochondria are particularly susceptible to OS. OS damage has been described in ALS [,], AD [,,,,,,,,,,,,,,,,,,,,,], and PD [,,,,,,,,,,,,,,,,,,,,,,] tissues and models …..

8. Conclusions
Mitochondria have evolved, likely from protobacterial precursors through endosymbiosis [], and now inhabit cells of almost all terrestrial and marine plants and animals, including humans. In addition to their critical roles in modulating cellular calcium signaling and cell death initiation, mitochondria through ETC/OXPHOS appear to supply most of the substantial daily ATP requirement for humans. Adult human brain has a ~10-fold disproportionate (relative to mass) ATP production rate and depends on the stereotyped movement of reducing electrons down an energy gradient in the ETC and conservation of this ETC energy decrease by proton displacement across the mitochondrial inner membrane. This electron movement and proton displacement, however they occur, must respect quantum mechanical constraints.

Both electrons moving through the ETC and proton displacement from the matrix to the intermembrane space (IMS) may utilize quantum tunneling in addition to other mechanisms. It is not yet clear whether tunneling occurs at all, but it is a theoretically appealing mechanism for quantum entities to pass through energy barriers and reduce activation energies (thus increasing rates of proton transfer).

Mitochondria must likely segregate electrons from electrophilic molecular oxygen and protons from solvation by water. How these feats are accomplished remains unclear, but our daily ATP requirements likely require these biochemical gymnastics. Mitochondria may represent a necessary transitional organelle between the quantum world of elementary particles and energy-releasing catabolism of molecules created from absorbed solar-derived photons. Decoherence (loss of quantum-ness) may assist ATP production in mitochondria, and theoretically its presence may vary with energy needs.

Many neurodegenerative diseases (NDDs) afflicting humans may be viewed thermodynamically as increases in molecular entropy during life of the organism as neurons die. Such local entropy increases may arise from decreased neuronal energy production traceable to decline of OXPHOS rates. OXPHOS rates in turn depend on availability of intact ATP synthase complexes and (likely) non-hydrated protons in the intermembrane space or at the proton-binding sites of the ATP synthase rotor.

Mitochondrial therapeutics can address bioenergetic deficiencies at multiple levels, from epigenetic changes in mitochondrial and/or nuclear genomes, through measures to reduce post-translational damage to ETC/OXPHOS proteins. Many such approaches have been/are being developed, and optimism exists for varied solutions to the human problems of mitochondrial ETC/OP dysfunction in NDDs.

Medical hypothesis: Neurodegenerative diseases arise from oxidative damage to electron tunneling proteins in mitochondria – ScienceDirect
”Mitochondria likely arose from serial endosymbiosis by early eukaryotic cells and control electron flow to molecular oxygen to facilitate energy transformation. Mitochondria translate between the quantum and macroscopic worlds and utilize quantum tunneling of electrons to reduce activation energy barriers to electron flow. Electron tunneling has been extensively characterized in Complex I* of the electron transport chain. Age-related increases in oxidative damage to these electron tunneling systems may account for decreased energy storage found in aged and neurodegenerative disease tissues, such as those from sufferers of amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Parkinson’s disease (PD). This hypothesis is testable. If correct, this hypothesis supports pre-symptomatic, mitochondrially-directed oxygen free radical scavenging therapies. ..

What is new in this hypothesis?
“Oxidative stress”, as a pathological phenomenon, has been invoked as an abnormality that may be pathogenic in aging and NDD [1][5][32]. Oxidative stress refers to a situation when the production of oxidizing oxygen (and relevant nitrogen) species exceeds the capacities of cells to remove them, typically using enzymes (superoxide dismutases, catalase, peroxidases) or small molecules (glutathione, tocopherols, vitamin C). It should be noted that the involvement of oxidative stress in aging has been and remains controversial. What is new in the present hypothesis is the designation of decline in electron tunneling in Complex I as a specific pathogenic event that is responsible for the increase in overall oxidative stress, mitochondrial oxidative-phosphorylation decline and subsequent energy deficiencies of aging and NDD.”


More is to come …