How is Mitochondrial Function Implicated in Neurodegenerative Disease?

by Nelson Montelauro
Each cell has roughly between 100,000 and 600,000 mitochondria, interactively networking together, and continuously changing, dividing and merging. Mitochondria provide energy for neuronal function, store calcium for cell signaling, and create energy for axon firing and neurotransmitter transmission, vesicle movement, neuroplasticity, and for the metabolism of structural proteins and lipids in the brain.
What was the Origin of Mitochondria?
The integration of the mitochrondria into the cell is hypothesized to have been a symbiotic event in which an organism became engulfed by the cell of another organism. Clues for this lie in the mitochondria’s circular DNA, double-membrane, and specific transcriptional functioning. Thanks to genome sequencing advances, the closest genome to the original mitochrondria appears to be an ancestor of the R. Powazekii protozoan.
What are the Main Functions of the Mitochondria?
The mitochondrial genome is inherited maternally, as the mother’s egg donates the cytoplasm to the embryo. Fusion and division between mitochondria is occurring rapidly at all times and facilitated by special proteins. Large mitochondria can spontaneously form from smaller ones, in a process called hyperfusion. This only happens temporarily during a crisis to buffer stressors like nutrient depletion and UV radiation. During the process of hyperfusion, the energy production increases even if one part of the electron transport chain is broken, and returns when it is fixed.
The specific proteins needed for division and fusion are manufactured in the endoplasmic reticulum, and which use actin fibers to construct complex structures that manipulate nucleotides, which are DNA fragments from the mitochondria, and are used to create scaffolding for division and fusion. Signalling molecules called chapersones are also used to construct pathways for using less respiration.
The outer membrane is far more permeable than the inner membrane, which only allows small molecules into the matrix, and which contains citric acid cycle enzymes to metabolize nutrients. It is within the inner membrane that proteins and other molecules are involved in a series of redox reactions that transport electrons to produce free energy to fuel the phosphorylation of ADP to ATP.
How Mitochondria Respond to Mental Stress
Neuronal mitochondria are highly active, ready to produce energy in an instant when the brain needs them. They move along the tracks of microtubules, and can speed-up, slow-down or change direction based on input from psychological states. Roughly two thirds of mitochondria are anchored on tiny tubules and provide local energy. Because neurons are so long, and have many points of ionic exchange, mitochondria are spread throughout the neuron to facilitate synapse firing and remodeling. Thousands of mitochondria are fusing and dividing along the narrow places in the axon. Neurodegenerative disease results from mitochondrial dysfunction, such as lack of ability to fuse or divide or produce energy. If a neuron is highly active, more mitochondria move towards the synapse.
Because mitochrondria do not have the DNA repairing mechanism that are found in the cell nuclear DNA, they are highly susceptible to mutations. The most mutagenic substances to DNA are reactive oxygen species, which are produced in defective mitochondria.
For example, Alzheimer’s disease is caused by the increase of beta amyloid plaque, which increases production of nitric oxide, which in turn, further damages neurons. Abnormal protein tangles, called Tau protein tangles, combine with beta-amyloid plaques, and form large accumulations of fragmented proteins that clog
brain regions responsible for memory. A study out of UC San Francisco found that tau protein tangles were able to predict the location of neuronal cell death a year in advance, become concentrated in astrocytes (helper cells in the brain that maintain synapses). This process may be linked to early dementia, and stress to the endoplasmic reticulum, and cell damage. Certain amino acids have disulfide bonds, which may act to cause tau protein to become toxic and accumulate, a process that can worsen through oxidative stress. Potential treatment options include enzymes and fasting, which increase macroautophagy and degradation of protein tangles. 
Macroautophagy is involved in the degradation of protein tangles, such as those in amyloid-beta plaques, tau protein tangles, and clearance of dysfunctional mitochondria (Magalhaes, 2021). In neurons, autophagy is responsible for removing toxins, and clearance of autophagosomes which can accumulate in neurons. Autophagosomes engulf organelles and other molecules as they head from neuron ends to the cell soma, where they are retained in the soma if they were produced in distal areas, while soma-produced autophagosomes are able to move freely between dendrites and soma. Autophagic proteins are necessary for macroautophagy and neuroplasticity, and defective production in this protein is linked to neurodegenerative diseases.
Top 8 Supplements that Help Mitchondria Health and Brain Function
Selenium in the form of selenomethionine has been found to reduce cognitive decline by targeting tau protein hyperphosphorlyation, and the clearance of tau by autophagy (Zhang, 2017). Selenium-yeast was found in another study to inhibit beta-amyloid plaque formation, and improve autophagy for various cancer cells, and enhanced the clearance of tau and amyloid-beta proteins (Song, 2018).
Enzymes: Enzymes that degrade β-amyloid (Aβ) like nattokinase and serrapeptase have been shown to breakdown the 20 or so different unrelated proteins that form into amyloid tangles.  
Ginko biloba has had similar effects as selenium in providing antioxidant activity in the brain and improving blood flow and brain function (Qin, et al.). 
Melatonin has also been shown to reduce the cognitive declines associated with Alzheimer's (Luengo, 2019). 
Fermented Foods: Parkinson’s disease is caused by the mutation of an important protein, called parkin, a process that which may be caused by pesticides which fragment mitochondria. Read about how to reduce pesticides by fermenting here.
Lithium: Studies have also found Lithium to be effective in preventing protein tangles, although it has not been shown to be effective in reversing it (Leroy, 2010). Interestingly autophagy disfunction is prevalent in Alzheimer’s patients, and accumulation of autophagosomes has been seen in dendrites and soma of mouse neurons even before the appearance of Aβ plaques (Yu, 2005). This indicates that defects in autophagy are responsible for the accumulation of Aβ and tau oligomers, possibly resulting from impaired lysosome digestion (Wolfe, 2013).
Coconut Oil: MCT have been found to help Alzheimer's patients who need alternative energy sources for brain function. 
Methylene Blue: Studies are finding that the antioxidant power of methylene blue directly improves mitochondrial function and repair of mitochondrial DNA, offering neuroprotective effects (Samoylova, 2023; Yang, 2023). 
 
 
 
References
Leroy K, Ando K, Héraud C, Yilmaz Z, Authelet M, Boeynaems JM, Buée L, De Decker R, Brion JP. Lithium treatment arrests the development of neurofibrillary tangles in mutant tau transgenic mice with advanced neurofibrillary pathology. J Alzheimers Dis. 2010;19(2):705-19. doi: 10.3233/JAD-2010-1276. PMID: 20110614.
Luengo, E., Buendia, I., Fernández‐Mendívil, C., Trigo‐Alonso, P., Negredo, P., Michalska, P., ... & López, M. G. (2019). Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux. Journal of Pineal Research, 67(1), e12578.
Magalhães JD, Fão L, Vilaça R, Cardoso SM, Rego AC. Macroautophagy and Mitophagy in Neurodegenerative Disorders: Focus on Therapeutic Interventions. Biomedicines. 2021 Nov 5;9(11):1625. doi: 10.3390/biomedicines9111625. PMID: 34829854; PMCID: PMC8615936.
Qin, Y., Zhang, Y., Tomic, I., Hao, W., Menger, M. D., Liu, C., ... & Liu, Y. (2018). Ginkgo biloba extract EGb 761 and its specific components elicit protective protein clearance through the autophagy-lysosomal pathway in tau-transgenic mice and cultured neurons. Journal of Alzheimer's Disease, 65(1), 243-263.
Samoylova NA, Gureev AP, Popov VN. Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity. Int J Mol Sci. 2023 Mar 24;24(7):6118.
Song, G. L., Chen, C., Wu, Q. Y., Zhang, Z. H., Zheng, R., Chen, Y., ... & Ni, J. Z. (2018). Selenium-enriched yeast inhibited β-amyloid production and modulated autophagy in a triple transgenic mouse model of Alzheimer's disease. Metallomics, 10(8), 1107-1115.
Wolfe, D.M.; Lee, J.H.; Kumar, A.; Lee, S.; Orenstein, S.J.; Nixon, R.A. Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur. J. Neurosci. 2013, 37, 1949–1961.
Yang L, Youngblood H, Wu C, Zhang Q. Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation. Transl Neurodegener. 2020 Jun 1;9(1):19.
Zhang, Z. H., Wu, Q. Y., Zheng, R., Chen, C., Chen, Y., Liu, Q., ... & Song, G. L. (2017). Selenomethionine mitigates cognitive decline by targeting both tau hyperphosphorylation and autophagic clearance in an Alzheimer's disease mouse model. Journal of Neuroscience, 37(9), 2449-2462.

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